Can We Save the Implant: Rib-based Implant Removal Rates and Risk Factors Following Irrigation and Debridement (I&D) Surgery?

BACKGROUND: In the event of a surgical site infection, management includes surgical debridement in an attempt to treat the infection and retain the implant; however they are often unsuccessful in this regard. Although studies have described the incidence of complications, current literature does not have sufficient evidence to provide clear recommendations regarding retention versus removal of implants. This study aims to identify predictive factors associated with the need for implant removal to decrease unnecessary attempts at implant retention. METHODS: A retrospective review of early-onset scoliosis patients at a single institution treated with rib-based vertical expandable prosthetic titanium rib implants who developed infection requiring irrigation and debridement (I&D) due to wound problems including surgical site infection, skin slough, and wound dehiscence. All patients had a minimum of a 2-year follow-up. Univariate and multivariate logistic regression analyses were conducted to determine the odds of implant removal. RESULTS: Fifty-nine of 181 patients (32%) required an I&D due to a wound problem. These patients underwent the initial implant procedure at a mean age of 4.6±3.8 years. In total, 29 patients ultimately underwent implant removal. Significant predictive factors for removal included total number of wound problems, total number of I&Ds, days from identification of wound problem to I&D procedure, days on antibiotics, total number of surgeries, presence of gastrostomy tube, and nonambulatory status (P<0.0001, 0.001, 0.095, 0.093, 0.082, 0.054, and 0.026, respectively). Multiple logistic regression results indicated a total number of wound problems [odds ratio (OR): 6.00, P=0.001], average days from identification of wound problem to I&D (OR: 1.03, P=0.039), and presence of a gastrostomy tube (OR: 5.7, P=0.07) as independent predictors for implant removal. CONCLUSIONS: Data suggests that time from the onset of signs of infection until debridement surgery inversely correlates with the ability to retain the implants. In addition, gastrostomy tube and history of previous wound infections may be predictive clinical factors for implant removal in patients with a rib-based vertical expandable prosthetic titanium rib instrumentation. Such information can be useful for clinicians in deciding on whom to attempt implant retention versus removal when a wound problem presents itself. LEVEL OF EVIDENCE: Level III.

Understanding Respiratory Restrictions as a Function of the Scoliotic Spinal Curve in Thoracic Insufficiency Syndrome: A 4D Dynamic MR Imaging Study.

BACKGROUND: Over the past 100 years, many procedures have been developed for correcting restrictive thoracic deformities which cause thoracic insufficiency syndrome. However, none of them have been assessed by a robust metric incorporating thoracic dynamics. In this paper, we investigate the relationship between radiographic spinal curve and lung volumes derived from thoracic dynamic magnetic resonance imaging (dMRI). Our central hypothesis is that different anteroposterior major spinal curve types induce different restrictions on the left and right lungs and their dynamics. METHODS: Retrospectively, we included 25 consecutive patients with thoracic insufficiency syndrome (14 neuromuscular, 7 congenital, 4 other) who underwent vertical expandable prosthetic titanium rib surgery and received preimplantation and postimplantation thoracic dMRI for clinical care. We measured thoracic and lumbar major curves by the Cobb measurement method from anteroposterior radiographs and classified the curves as per Scoliosis Research Society (SRS)-defined curve types. From 4D dMRI images, we derived static volumes and tidal volumes of left and right lung, along with left and right chest wall and left and right diaphragm tidal volumes (excursions), and analyzed their association with curve type and major curve angles. RESULTS: Thoracic and lumbar major curve angles ranged from 0 to 136 and 0 to 116 degrees, respectively. A dramatic postoperative increase in chest wall and diaphragmatic excursion was seen qualitatively. All components of volume increased postoperatively by up to 533%, with a mean of 70%. As the major curve, main thoracic curve (MTC) was associated with higher tidal volumes (effect size range: 0.7 to 1.0) than thoracolumbar curve (TLC) in preoperative and postoperative situation. Neither MTC nor TLC showed any meaningful correlation between volumes and major curve angles preoperatively or postoperatively. Moderate correlations (0.65) were observed for specific conditions like volumes at end-inspiration or end-expiration. CONCLUSIONS: The relationships between component tidal volumes and the spinal curve type are complex and are beyond intuitive reasoning and guessing. TLC has a much greater influence on restricting chest wall and diaphragm tidal volumes than MTC. Major curve angles are not indicative of passive resting volumes or tidal volumes. LEVEL OF EVIDENCE: Level II-diagnostic.

Quantitative Dynamic Thoracic MRI: Application to Thoracic Insufficiency Syndrome in Pediatric Patients.

Background Available methods to quantify regional dynamic thoracic function in thoracic insufficiency syndrome (TIS) are limited. Purpose To evaluate the use of quantitative dynamic MRI to depict changes in regional dynamic thoracic function before and after surgical correction of TIS. Materials and Methods Images from free-breathing dynamic MRI in pediatric patients with TIS (July 2009-August 2015) were retrospectively evaluated before and after surgical correction by using vertical expandable prosthetic titanium rib (VEPTR). Eleven volumetric parameters were derived from lung, chest wall, and diaphragm segmentations, and parameter changes before versus after operation were correlated with changes in clinical parameters. Paired analysis from Student t test on MRI parameters and clinical parameters was performed to detect if changes (from preoperative to postoperative condition) were statistically significant. Results Left and right lung volumes at end inspiration and end expiration increased substantially after operation in pediatric patients with thoracic insufficiency syndrome, especially right lung volume with 22.9% and 26.3% volume increase at end expiration (P = .001) and end inspiration (P = .002), respectively. The average lung tidal volumes increased after operation for TIS; there was a 43.8% and 55.3% increase for left lung tidal volume and right lung tidal volume (P < .001 for both), respectively. However, clinical parameters did not show significant changes from pre- to posttreatment states. Thoracic and lumbar Cobb angle were poor predictors of MRI tidal volumes (chest wall, diaphragm, and left and right separately), but assisted ventilation rating and forced vital capacity showed moderate correlations with tidal volumes (chest wall, diaphragm, and left and right separately). Conclusion Vertical expandable prosthetic titanium rib operation was associated with postoperative increases in all components of tidal volume (left and right chest wall and diaphragm, and left and right lung tidal volumes) measured at MRI. Clinical parameters did not demonstrate improvements in postoperative tidal volumes. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Paltiel in this issue.

Management of Asymptomatic Wolff-Parkinson-White Pattern by Pediatric Electrophysiologists.

OBJECTIVE: To determine the present-day approach of pediatric cardiac electrophysiologists to asymptomatic Wolff-Parkinson-White (WPW) pattern and to contrast to both published consensus statements and a similar survey. STUDY DESIGN: A questionnaire was sent to 266 Pediatric and Congenital Electrophysiology Society physician members in 25 countries; 21 questions from the 2003 survey were repeated, with new questions added regarding risk stratification and decision making. RESULTS: We received 113 responses from 13 countries, with responders having extensive electrophysiology experience (median 15 years [IQR 8.5-25 years]). Only 12 (11%) believed that intermittent pre-excitation and 37 (33%) that sudden loss of pre-excitation on exercise test were sufficient evidence of accessory pathway safety to avoid an invasive electrophysiology study. Optimal weight for electrophysiology study was 20 kg (IQR 18-22.5 kg), and 61% and 58% would then ablate all right-sided or left-sided accessory pathways, respectively, regardless of electrophysiological properties, whereas only 23% would ablate all septal accessory pathways (P < .001). Compared with 2003, respondents were more likely to consider inducible arrhythmia (77% vs 26%, P < .001) as sufficient indication alone for ablation. CONCLUSIONS: In the context of recent literature regarding the reliability of risk-stratification tools, most operators are now performing electrophysiology study for asymptomatic Wolff-Parkinson-White regardless of noninvasive findings. Many will then proceed to default ablation of all accessory pathways distant from critical conduction structures.

Increased complications without neurological benefit are associated with prophylactic spinal cord untethering prior to scoliosis surgery in children with myelomeningocele.

PURPOSE: Children with myelomeningocele (MMC) are at increased risk of developing neuromuscular scoliosis and spinal cord re-tethering (Childs Nerv Syst 12:748-754, 1996; Neurosurg Focus 16:2, 2004; Neurosurg Focus 29:1, 2010). Some centers perform prophylactic untethering on asymptomatic MMC patients prior to scoliosis surgery because of concern that additional traction on the cord may place the patient at greater risk of neurologic deterioration peri-operatively. However, prophylactic untethering may not be justified if it carries increased surgical risks. The purpose of this study was to determine if prophylactic untethering is necessary in asymptomatic children with MMC undergoing scoliosis surgery. METHODS: A multidisciplinary, retrospective cohort study from seven children's hospitals was performed including asymptomatic children with MMC < 21 years old, managed with or without prophylactic untethering prior to scoliosis surgery. Patients were divided into three groups for analysis: (1) untethering at the time of scoliosis surgery (concomitant untethering), (2) untethering within 3 months of scoliosis surgery (prior untethering), and (3) no prophylactic untethering. Baseline data, intra-operative reports, and 90-day post-operative outcomes were analyzed to assess for differences in neurologic outcomes, surgical complications, and overall length of stay. RESULTS: A total of 208 patients were included for analysis (mean age 9.4 years, 52% girls). No patient in any of the groups exhibited worsened motor or sensory function at 90 days post-operatively. However, comparing the prophylactic untethering groups with the group that was not untethered, there was an increased risk of surgical site infection (SSI) (31.3% concomitant, 28.6% prior untethering vs. 12.3% no untethering; p = 0.0104), return to the OR (43.8% concomitant, 23.8% prior untethering vs. 17.4% no untethering; p = 0.0047), need for blood transfusion (51.6% concomitant, 57.1% prior untethering vs. 33.8% no untethering; p = 0.04), and increased mean length of stay (LOS) (13.4 days concomitant, 10.6 days prior untethering vs. 6.8 days no untethering; p < 0.0001). In multivariable logistic regression analysis, prophylactic untethering was independently associated with increased adjusted relative risks of surgical site infection (aRR = 2.65, 95% CI 1.17-5.02), unplanned re-operation (aRR = 2.17, 95% CI 1.02-4.65), and any complication (aRR = 2.25, 95% CI 1.07-4.74). CONCLUSION: In this study, asymptomatic children with myelomeningocele who underwent scoliosis surgery developed no neurologic injuries regardless of prophylactic untethering. However, those who underwent prophylactic untethering were more likely to experience SSIs, return to the OR, need a blood transfusion, and have increased LOS than children not undergoing untethering. Based on these data, prophylactic untethering in asymptomatic MMC patients prior to scoliosis surgery does not provide any neurological benefit and is associated with increased surgical risks.

Site-specific Surgical Site Infection Rates for Rib-based Distraction.

BACKGROUND: Implantable rib-based distraction devices have revolutionized the treatment of children with early onset scoliosis and thoracic insufficiency syndrome. Unfortunately, the need for multiple skin incisions and repeated surgeries in a fragile patient population creates considerable infection risk. In order to assess rates of infection for different incision locations and potential risk factors, we generated a prospectively collected database of patients treated with rib-based distraction devices. METHODS: We analyzed a cohort of patients with thoracic insufficiency syndrome from various etiologies that our institution treated with rib-based distraction devices from 2013 to 2016. Surgery type (implantation, expansion, revision/removal), and surgeon adjudicated surgical site infection (SSI) were collected. For this study, we developed a novel, rib-based distraction device surgical site labeling system in which incisions could be labeled as either proximal or distal surgical exposure areas. Treating surgeons documented the operative site, procedure, and SSI site in real-time. RESULTS: A total of 166 unique patients underwent 670 procedures during the study period, producing 1537 evaluable surgical sites; 1299 proximal and 238 distal. Patients were 6.81±4.0 years of age on average. Forty-seven procedures documented SSIs (7.0%), while 40 (24.1%) patients experienced an infection. Analysis showed significant variation in the rate of infection between implantation, and expansion, and revision procedures, with implantation procedures having the highest infection rate at 13.1% (P<0.01). Infections occurred more frequently at distal sites than proximal ones (P=0.02). CONCLUSIONS: Our novel, surgeon-entered, prospective quality improvement database has identified distal surgical sites as being at higher risk for SSI than proximal ones. Further, rib-based distraction device implantation procedures were identified as being at a greater risk for SSI than expansion or revision procedures. We believe this data can lead to improved prevention measures, anticipatory guidance, and patient care. LEVEL OF EVIDENCE: Level II-prognostic study.

VEPTR: Are We Reducing Respiratory Assistance Requirements?

BACKGROUND: The assisted ventilation rating (AVR) indicates the degree of external respiratory support required in children with thoracic insufficiency syndrome (TIS) and early onset scoliosis. For skeletally immature patients with TIS, the vertical expandable prosthetic titanium rib (VEPTR) device can be used to improve lung volume and growth. We hypothesized that patients who underwent early thoracic reconstruction by VEPTR treatment had an improved respiratory status. METHODS: Preoperative and postoperative AVR ratings were prospectively collected in a multicenter study group and compared to determine change after VEPTR treatment. Patients under 10 years of age at initial implant with minimum of 2-year follow-up data were included. Patients were excluded if there were incomplete data or if initial AVR was normal (breathing on room air). Statistical analysis was performed on groups which had stable, declined, and improved AVR at final follow-up. RESULTS: Database search yielded 77 patients with initial abnormal AVR. Average follow-up was 5.6 years. The most frequent primary diagnoses were congenital scoliosis (n=14) and spinal muscular atrophy (n=14). In total, 19 (24%) demonstrated improvement, 9 (12%) patients deteriorated, and 49 (64%) remained at the same level. The average preoperative major curve in those with improvement (58.4 degrees) and those with no change (63.5 degrees) was less than in those with deterioration (85.5 degrees) (P=0.014). The average age in years at implant of those with improvement (4) was less than those declined (6.7) and those with no change (5.5). In total, 16 (84.2%) of those that improved had a normal AVR and did not require respiratory support at last follow-up. CONCLUSIONS: There is evidence that a subset of patients with early onset scoliosis and TIS who received early thoracic reconstruction with VEPTR treatment show complete resolution of pulmonary support at final follow-up. In total, 89% of 79 patients did not experience respiratory deterioration. A total of 24% (n=19) had a positive change with over 84% (n=16) of this group no longer requiring support. LEVEL OF EVIDENCE: Level III-prognostic.

Comprehensive comparative economic evaluation of woody biomass energy from silvicultural fuel treatments.

Fuel treatments are used in overstocked, fire-prone forests to alter wildfire behavior and reduce fire risk. Some of the benefits they provide are not captured in markets, and therefore represent unaccounted environmental externalities that can lead to inefficient decision making. This study uses a replicable method to integrate market and nonmarket economic values into a comprehensive economic evaluation of fuel treatment and bioenergy production using a case study of ponderosa pine and mixed-conifer forests in Colorado's wildland-urban interface. Treatment costs and people's willingness to pay for better forest health, lower likelihood of wildfire, improved air quality, and expanded renewable energy production are incorporated into techno-economic analysis of biopower production. Results show that fuel treatments are likely to be undervalued when evaluated strictly on a financial basis. Under the standard practice of disposing of treatment residues through pile-burning, net present value (NPV) of fuel treatment on 138,034 ha over 20 years is -$275 million, without consideration of nonmarket benefits. If nonmarket benefits associated with forest health, wildfire likelihood and air quality are included, NPV improves to -$116 million. Without the consideration of nonmarket benefits, when treatment resides are used for biopower production, NPV is -$178 million, with net cost savings compared to pile burning attributable to reduced biomass disposal costs and electricity revenue. Accounting for additional air quality benefits and nonmarket value associated with renewable energy, the bioenergy scenario improves NPV to -$25 million, with 27.7% of outcomes having positive NPV. The impact of additional nonmarket values and potential revenues from timber harvest are discussed, and are likely to make mean NPV positive for this scenario.

Quantitative Profiling of the Activity of Protein Lysine Methyltransferase SMYD2 Using SILAC-Based Proteomics.

The significance of non-histone lysine methylation in cell biology and human disease is an emerging area of research exploration. The development of small molecule inhibitors that selectively and potently target enzymes that catalyze the addition of methyl-groups to lysine residues, such as the protein lysine mono-methyltransferase SMYD2, is an active area of drug discovery. Critical to the accurate assessment of biological function is the ability to identify target enzyme substrates and to define enzyme substrate specificity within the context of the cell. Here, using stable isotopic labeling with amino acids in cell culture (SILAC) coupled with immunoaffinity enrichment of mono-methyl-lysine (Kme1) peptides and mass spectrometry, we report a comprehensive, large-scale proteomic study of lysine mono-methylation, comprising a total of 1032 Kme1 sites in esophageal squamous cell carcinoma (ESCC) cells and 1861 Kme1 sites in ESCC cells overexpressing SMYD2. Among these Kme1 sites is a subset of 35 found to be potently down-regulated by both shRNA-mediated knockdown of SMYD2 and LLY-507, a selective small molecule inhibitor of SMYD2. In addition, we report specific protein sequence motifs enriched in Kme1 sites that are directly regulated by endogenous SMYD2 activity, revealing that SMYD2 substrate specificity is more diverse than expected. We further show direct activity of SMYD2 toward BTF3-K2, PDAP1-K126 as well as numerous sites within the repetitive units of two unique and exceptionally large proteins, AHNAK and AHNAK2. Collectively, our findings provide quantitative insights into the cellular activity and substrate recognition of SMYD2 as well as the global landscape and regulation of protein mono-methylation.

Cost and performance tradeoffs between mail and internet survey modes in a nonmarket valuation study.

Using the results of a choice modeling survey, internet, mail-only and mixed internet and mail survey modes were examined with regards to their cost-effectiveness, representativeness, and willingness to pay (WTP). The topical focus of the study was biomass energy generation preferences of the residents of Montana, Colorado and Arizona, USA. Compared to the mail and mixed mode samples, the internet-only mode produced a sample of respondents that was younger, more likely to have a college degree, and more likely to have a household income of at least $100,000 per year. However, observed differences in the characteristics of the collected sample did not result in significant differences in estimates of WTP. The internet survey mode was the most cost-effective method of collecting the target sample size of 400 responses. Sensitivity analysis showed that as the target number of responses increased the cost advantage of internet over the mail-only and mixed mode surveys increased because of the low marginal cost associated with extending additional invitations.

Appropriateness of Outpatient Echocardiograms Ordered by Pediatric Cardiologists or Other Clinicians.

OBJECTIVE: To assess the appropriateness and diagnostic yield of TTEs ordered by various pediatric providers according to the pediatric appropriate use criteria (AUC) for outpatient transthoracic echocardiography (TTE) before its release. STUDY DESIGN: Clinic notes of patients aged ≤18 years who underwent initial outpatient TTE between April and September 2014 were reviewed to determine the AUC indication, and appropriateness was assigned based on the AUC document. Ordering physicians were categorized into cardiologists, primary care physicians (PCPs; including pediatricians and family practitioners [FPs]), and noncardiology subspecialists. RESULTS: Of the 1921 TTEs ordered during the study period, 84.6% were by cardiologists, 9.2% by pediatricians, 3.4% by FPs, and 2.8% by noncardiology subspecialists. The appropriateness rate for cardiologists was higher than that for PCPs (86% vs 64%; P < .001) but not noncardiology subspecialist (86% vs 87%; P = .80). PCPs had a significantly higher proportion of studies that could not be classified compared with cardiologists (35% vs 5%; P < .001) and noncardiology subspecialists (35% vs 11%; P < .001), owing primarily to a lack of adequate clinical information. The likelihood of an abnormal finding was higher in TTEs ordered by a cardiologist vs those ordered by a noncardiologist (OR, 4.8; 95% CI, 2.1-10.9; P < .001). CONCLUSIONS: Compared with PCPs, cardiologists ordered more TTEs, had the highest yield of abnormal findings, and had greater appropriateness of TTE orders. A large proportion of TTEs ordered by PCPs were unclassifiable owing to insufficient information. This study lays a framework for provider education and improvement in the TTE order intake process.

Application of the Pediatric Appropriate Use Criteria for Chest Pain.

OBJECTIVES: To characterize the subgroup of outpatient pediatric patients presenting with chest pain and to determine the effectiveness of published pediatric appropriate use criteria (PAUC) to detect pathology. STUDY DESIGN: The Pediatric Appropriate Use of Echocardiography study evaluated the use and yield of transthoracic echocardiography (TTE) before and after PAUC release. Data were reviewed on patients ?18 years of age who underwent TTE for chest pain. Indications were classified as appropriate (A), may be appropriate (M), and rarely appropriate (R) based on PAUC ratings, and findings were normal, incidental, or abnormal. RESULTS: Chest pain was the primary indication in 772 of 4562 outpatient TTE studies (17%) (median age 14 years, IQR 10-16) ordered during the study period: 458 of 772 before (59%) and 314 of 772 after (41 %) the release of PAUC with no change in appropriateness. In A indications (n?=?654), 642 (98%) were normal, 5 (1%) had incidental findings, and 7 (1%) were abnormal. A and M detected 100% of all abnormal findings (A: n?=?7; M: n?=?6; R: n?=?0), with an association between ratings and findings (P?<.001). There was no association between R rating and any pathology. CONCLUSIONS: There was no change in ordering patterns with publication of the PAUC. Despite the high rate of TTEs ordered for indications rated A, most studies were normal. Studies that detected pathology were performed for indications rated A or M, but not R. This study supports PAUC as a useful tool in pediatric chest pain evaluation that may subsequently improve the use of TTE.

Application of pediatric appropriate use criteria for initial outpatient evaluation of syncope.

BACKGROUND: Syncope is a common reason for outpatient transthoracic echocardiography (TTE). We studied the applicability of pediatric appropriate use criteria (AUC) on initial outpatient evaluation of children (≤18 years) with syncope. METHODS: Data were obtained before (Phase I, April-September 2014) and after (Phase II, January-April 2015) the release of the AUC document from six participating pediatric cardiology centers. Site investigators determined the indication for TTE and assigned appropriateness rating based on the AUC document: Appropriate (A), May Be Appropriate (M), Rarely Appropriate (R), or "unclassifiable" (U) if it did not fit any scenario in the AUC document. RESULTS: Of the total 4562 TTEs, 310 (6.8%) were performed for syncope: 174/2655 (6.6%) Phase I and 136/1907 (7.1%) Phase II, P=.44. Overall, 168 (50.5%) were for indications rated A, 63 (18.9%) for M, 79 (23.7%) for R, and 23 (6.9%) for U. Release of AUC did not change the appropriateness of TTEs [A=51.6% vs 49.0%, P=.63, R=20.2% vs 28.3%, P=.09]. Overall syncope-related R indications formed 15.7% of R indications for all the echocardiograms performed in the entire Pediatric Appropriate Use (PAUSE) study (11.9% Phase I and 22.4% Phase II, P=.002). TTEs were normal in majority of the patients except 7 that had incidental findings. CONCLUSIONS: In conclusion, syncope is a common reason for indications rated R and release of the AUC document did not improve appropriate utilization of TTE in syncope. Targeted educational interventions are needed to reduce unnecessary TTEs in children with syncope.

LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2.

SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary carcinomas, and that overexpression correlates with poor patient survival. However, the mechanism(s) by which SMYD2 promotes oncogenesis is not understood. A small molecule probe for SMYD2 would allow for the pharmacological dissection of this biology. In this report, we disclose LLY-507, a cell-active, potent small molecule inhibitor of SMYD2. LLY-507 is >100-fold selective for SMYD2 over a broad range of methyltransferase and non-methyltransferase targets. A 1.63-Å resolution crystal structure of SMYD2 in complex with LLY-507 shows the inhibitor binding in the substrate peptide binding pocket. LLY-507 is active in cells as measured by reduction of SMYD2-induced monomethylation of p53 Lys(370) at submicromolar concentrations. We used LLY-507 to further test other potential roles of SMYD2. Mass spectrometry-based proteomics showed that cellular global histone methylation levels were not significantly affected by SMYD2 inhibition with LLY-507, and subcellular fractionation studies indicate that SMYD2 is primarily cytoplasmic, suggesting that SMYD2 targets a very small subset of histones at specific chromatin loci and/or non-histone substrates. Breast and liver cancers were identified through in silico data mining as tumor types that display amplification and/or overexpression of SMYD2. LLY-507 inhibited the proliferation of several esophageal, liver, and breast cancer cell lines in a dose-dependent manner. These findings suggest that LLY-507 serves as a valuable chemical probe to aid in the dissection of SMYD2 function in cancer and other biological processes.

Training residents/fellows in paediatric cardiology: the Emory experience.

Pediatric cardiology fellowship is a very busy time, with new responsibilities, new knowledge, new technology and fast pace. Above and beyond the science and art of pediatric cardiology, we emphasize that our cardiology fellows are in the middle of the "people business", with additional roles and responsibilities as they serve their patients and communities. This manuscript provides insight into these opportunities for our pediatric cardiac professionals.

Crystal structure of the human PRMT5:MEP50 complex.

Protein arginine methyltransferases (PRMTs) play important roles in several cellular processes, including signaling, gene regulation, and transport of proteins and nucleic acids, to impact growth, differentiation, proliferation, and development. PRMT5 symmetrically di-methylates the two-terminal ω-guanidino nitrogens of arginine residues on substrate proteins. PRMT5 acts as part of a multimeric complex in concert with a variety of partner proteins that regulate its function and specificity. A core component of these complexes is the WD40 protein MEP50/WDR77/p44, which mediates interactions with binding partners and substrates. We have determined the crystal structure of human PRMT5 in complex with MEP50 (methylosome protein 50), bound to an S-adenosylmethionine analog and a peptide substrate derived from histone H4. The structure of the surprising hetero-octameric complex reveals the close interaction between the seven-bladed ß-propeller MEP50 and the N-terminal domain of PRMT5, and delineates the structural elements of substrate recognition.

Management of Thoracic Insufficiency Syndrome in Patients With Jeune Syndrome Using the 70 mm Radius Vertical Expandable Prosthetic Titanium Rib.

BACKGROUND: Jeune syndrome (JS) often results in lethal thoracic insufficiency syndrome. Since 1991, vertical expandable prosthetic titanium rib Dynamic PosteroLateral Expansion Thoracoplasty was used at our institution for treatment of JS. This study assesses the safety and efficacy of this procedure. METHODS: Twenty-four JS patients were treated, 2 lost to follow-up, 17 with a minimum of 2-year follow-up retrospectively reviewed for clinical course: Assisted Ventilation Rate, respiratory rate, capillary blood gases, pulmonary function testings, and complications. Upright anteroposterior/lateral radiographs were measured for Cobb angle, kyphosis, lordosis, thoracic width, and thoracic/lumbar spinal height. Computed tomography scan lung volumes were obtained in 12 patients. RESULTS: Mean age at initial implant was 23 months (7 to 62 mo) with an average 8.4 years (2.3 to 15.6 y) of follow-up. Average chest width increased from 121 to 168 mm at follow-up (P<0.001). Preoperatively, 7/17 (41%) patients had scoliosis. The remainder developed scoliosis during treatment, 8 requiring additional implants. Thoracic and lumbar spinal height was normal preoperatively and stayed normal during treatment. Thoracic kyphosis/lumbar lordosis was stable. Average computed tomography scan total lung volumes increased 484 to 740 mm3 (P<0.001), and Assisted Ventilation Rate status tended to improve (P=0.07). Average forced vital capacity was 34% predicted at first test and 27% predicted at last follow-up. Early demise after surgery was common with multisystem disease. Mean respiratory rate decreased from 35 to 24 bpm at last follow-up (P<0.05). Survival rate of the 22 patients was 68%. Migration of the rib cradles/titanium slings occurred in 12 patients, superficial infections in 5 patients, deep infections in 4 patients, and wound dehiscence in 5 patients. Infection rate was 4.6% per procedure. CONCLUSIONS: The survival rate in JS with surgery was nearly 70% (compared with 70% to 80% mortality without treatment) with less ventilator dependence. Both C1 stenosis and scoliosis are common in JS. Spinal height in JS is normal. Complications are frequent, but tolerable in view of the clinical gains and increase in survival.

A comprehensive review of thoracic deformity parameters in scoliosis.

PURPOSE: The combined spine and rib cage deformity in scoliosis is best described as a thoracic deformity, and recent advances in imaging have enabled better definition of three-dimensional (3D) deformity of the thorax in scoliosis. However, a comprehensive report that summarizes the published thorax deformity quantification parameter studies is lacking in the orthopaedic literature. METHODS: An extensive literature review on the quantification of thorax deformity was performed, and a total of 25 thorax deformity parameters were compiled into eight independent categories based on their similarities of deformity assessment. RESULTS: This review serves as the first comprehensive summary of radiographic and CT-based thorax deformity quantification measures. CONCLUSIONS: Future work on the complex relationships between spine and ribcage deformity and the relationship with pulmonary function could help improve clinical interventions for scoliosis treatment.

Targeting the synthetic lethal relationship between FOCAD and TUT7 represents a potential therapeutic opportunity for TUT4/7 small molecule inhibitors in cancer.

Targeting synthetic lethal interactions between genes has emerged as a promising strategy for cancer therapy. This study explores the intricate interplay between terminal uridyltransferase 4 (TUT4) and terminal uridyltransferase 7 (TUT7), the 3'-5' exoribonuclease DIS3L2, and the SKI complex-interacting factor Focadhesin (FOCAD) in the context of cancer vulnerability. Using CRISPR and public functional genomics data, we show impairment of cell proliferation upon knockout of TUT7 or DIS3L2, but not TUT4, on cancer cells with FOCAD loss. Moreover, we report the characterization of the first potent and selective TUT4/7 inhibitors that substantially reduce uridylation and demonstrate in vitro and in vivo antiproliferative activity specifically in FOCAD-deleted cancer. FOCAD deficiency post-transcriptionally disrupts the stability of the SKI complex, whose role is to safeguard cells against aberrant RNA. Re-introduction of FOCAD restores the SKI complex and makes these cells less sensitive to TUT4/7 inhibitors, indicating that TUT7 dependency is FOCAD loss-driven. We propose a model where, in absence of FOCAD, TUT7 and DIS3L2 function as a salvage mechanism that degrades aberrant RNA, and genetic or pharmacological inhibition of this pathway leads to cell death. Our findings underscore the significance of FOCAD loss as a genetic driver of TUT7 vulnerability and provide insights into the potential utility of TUT4/7 inhibitors for cancer treatment.

Internalizing symptoms and functional disability in children with noncardiac chest pain and innocent heart murmurs.

OBJECTIVE: To examine the occurrence of internalizing symptoms and functional disability in children with noncardiac chest pain (NCCP) compared with children with innocent heart murmurs (IHMs). METHOD: 67 children with NCCP (M [SD] age = 12.61 [2.63]; 68.7% Caucasian) and 62 children with IHM (M [SD] age = 12.67 [2.62]; 50% Caucasian) were recruited from pediatric cardiology offices. Children and parents completed measures of psychological functioning and functional disability during a first visit to the cardiologist before diagnosis. RESULTS: Children with NCCP reported greater levels of anxiety, depression, and anxiety sensitivity than children with IHM. Children with NCCP and their parents reported greater levels of functional disability and somatization than children with IHM and their parents. CONCLUSION: Children with NCCP experience greater levels of psychosocial distress and impairment than similarly physically healthy children with IHM. Consideration of psychosocial influences on NCCP would likely be beneficial in aiding assessment and treatment.