Development of a defibrinated human blood hemolysis assay for rapid testing of hemolytic activity compared to computational prediction.

Cytotoxicity studies determining hemolytic properties of antimicrobial peptides or other drugs are an important step in the development of novel therapeutics for clinical use. Hemolysis is an affordable, accessible, and rapid method for initial assessment of cellular toxicity for all drugs under development. However, variability in species of red blood cells and protocols used may result in significant differences in results. AMPs generally possess higher selectivity for bacterial cells but can have toxicity against host cells at high concentrations. Knowing the hemolytic activity of the peptides we are developing contributes to our understanding of their potential toxicity. Computational approaches for predicting hemolytic activity of AMPs exist and were tested head-to-head with our experimental results. RESULTS: Starting with an observation of high hemolytic activity of LL-37 peptide against human red blood cells that were collected in EDTA, we explored alternative approaches to develop a more robust, accurate and simple hemolysis assay using defibrinated human blood. We found significant differences between the sensitivity of defibrinated red blood cells and EDTA treated red blood cells. SIGNIFICANCE: Accurately determining the hemolytic activity using human red blood cells will allow for a more robust calculation of the therapeutic index of our potential antimicrobial compounds, a critical measure in their pre-clinical development. CONCLUSION: We introduce a standardized, more accurate protocol for assessing hemolytic activity using defibrinated human red blood cells. This approach, facilitated by the increased commercial availability of de-identified human blood and defibrination methods, offers a robust tool for evaluating toxicity of emerging drug compounds, especially AMPs.

Is peak hamstrings muscle-tendon length criterion a sufficient indicator to recommend against surgical lengthening of hamstrings?

BACKGROUND: Excessive knee flexion during stance in children with cerebral palsy is often treated by surgical hamstrings lengthening. Pre-operative hamstrings muscle-tendon length can be estimated from kinematics and often used for decision making to rule out surgical lengthening if peak hamstrings muscle-tendon length is 'Not Short'. RESEARCH QUESTION: If peak hamstrings muscle-tendon length is within two standard deviations of typical, is that a sufficient indicator to rule out surgical hamstrings lengthening? METHODS: Three motion analysis centers retrospectively identified children with cerebral palsy, age 6-17 years, who had consecutive gait analyses with knee flexion at initial contact > 20° and popliteal angle > 35° at initial study. Three groups were considered: Medial Hamstrings Lengthening (MHL), Medial and Lateral Hamstrings Lengthening (MLHL), no surgical intervention (Control). Peak hamstrings muscle-tendon length at initial gait study was computed and categorized as 'Short' or 'Not Short'. Two outcomes variables were considered: change in peak knee extension (PKE) and change in pelvic tilt. Univariate comparisons of all variables were assessed along with a multivariate stepwise regression analysis to identify pre-operative characteristics that may predict post-operative improvement. RESULTS: 440 individuals met inclusion criteria. Percentage of individuals with improved PKE by grouping were- MHL-'Short': 60%, MHL-'Not Short': 65%, MLHL-'Short': 74%, MLHL-'Not Short': 74%, Control 'Short': 20%, Control 'Not Short': 19%. Percentage of individuals with worsened pelvic tilt were- MHL-'Short': 25%, MHL-'Not Short': 11%, MLHL-'Short': 42%, MLHL-'Not Short': 21% with significantly more individuals in MHL-'Short' subgroup compared to MHL-'Not Short'. Multivariate analysis suggested that pre-operative pelvic tilt and weak hip extensor strength have the largest effect on predicting post-operative increase in APT. Peak muscle-tendon length was not a significant predictor of post-operative knee kinematics or increase in APT. SIGNIFICANCE: This study suggests that hamstrings muscle-tendon length criteria by itself is not a sufficient indicator to recommend against hamstrings lengthening.

GATR-3, a Peptide That Eradicates Preformed Biofilms of Multidrug-Resistant Acinetobacter baumannii.

Acinetobacter baumannii is a gram-negative bacterium that causes hospital-acquired and opportunistic infections, resulting in pneumonia, sepsis, and severe wound infections that can be difficult to treat due to antimicrobial resistance and the formation of biofilms. There is an urgent need to develop novel antimicrobials to tackle the rapid increase in antimicrobial resistance, and antimicrobial peptides (AMPs) represent an additional class of potential agents with direct antimicrobial and/or host-defense activating activities. In this study, we present GATR-3, a synthetic, designed AMP that was modified from a cryptic peptide discovered in American alligator, as our lead peptide to target multidrug-resistant (MDR) A. baumannii. Antimicrobial susceptibility testing and antibiofilm assays were performed to assess GATR-3 against a panel of 8 MDR A. baumannii strains, including AB5075 and some clinical strains. The GATR-3 mechanism of action was determined to be via loss of membrane integrity as measured by DiSC3(5) and ethidium bromide assays. GATR-3 exhibited potent antimicrobial activity against all tested multidrug-resistant A. baumannii strains with rapid killing. Biofilms are difficult to treat and eradicate. Excitingly, GATR-3 inhibited biofilm formation and, more importantly, eradicated preformed biofilms of MDR A. baumannii AB5075, as evidenced by MBEC assays and scanning electron micrographs. GATR3 did not induce resistance in MDR A. baumannii, unlike colistin. Additionally, the toxicity of GATR-3 was evaluated using human red blood cells, HepG2 cells, and waxworms using hemolysis and MTT assays. GATR-3 demonstrated little to no cytotoxicity against HepG2 and red blood cells, even at 100 µg/mL. GATR-3 injection showed little toxicity in the waxworm model, resulting in a 90% survival rate. The therapeutic index of GATR-3 was estimated (based on the HC50/MIC against human RBCs) to be 1250. Overall, GATR-3 is a promising candidate to advance to preclinical testing to potentially treat MDR A. baumannii infections.

Accelerating Multi-site Health Informatics with Streamlined Data Infrastructure using OMOP-on-FHIR.

Shriners Children's (SHC) is a hospital system whose mission is to advance the treatment and research of pediatric diseases. SHC success has generated a wealth of clinical data. Unfortunately, barriers to healthcare data access often limit data-driven clinical research. We decreased this burden by allowing access to clinical data via the standardized data access standard called FHIR (Fast Healthcare Interoperability Resources). Specifically, we converted existing data in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) standard into FHIR data elements using a technology called OMOP-on-FHIR. In addition, we developed two applications leveraging the FHIR data elements to facilitate patient cohort curation to advance research into pediatric musculoskeletal diseases. Our work enables clinicians and clinical researchers to use hundreds of currently available open-sourced FHIR applications. Our successful implementation of OMOP-on-FHIR within a large hospital system will accelerate advancements in pediatric disease treatment and research.

The impact of weight loss on physical function and symptoms in overweight or obese breast cancer survivors: results from POWER-remote.

PURPOSE: In pre-planned observational analysis of the POWER-remote trial, we examined the impact of weight loss on patient-reported outcomes (PROs). We hypothesized a priori that survivors with ≥ 5% weight loss would have improved physical function (PF) at 6 months vs. those who did not. METHODS: Patients with stage 0-III breast cancer who completed local therapy and chemotherapy with BMI ≥ 25 kg/m2 were randomized to POWER-remote (telephone coaching; diet/activity tracking) or self-directed weight loss (booklet). Participants completed PROs at baseline, 6, and 12 months: PROMIS PF, pain, fatigue, anxiety, depression, sleep; FACT-endocrine symptoms; MOS-sexual function. Changes in PROs among those with ≥ 5% weight loss vs. those with < 5% were tested with multivariable mixed effect models, across randomized groups. RESULTS: Of 94 women who completed PROs, 84 and 69 participants were evaluable at 6 and 12 months, respectively. Regardless of intervention, PF improved in those with ≥ 5% weight loss vs. those with < 5% at 6 months (4.4 vs. 0.3 points; p = 0.02) and 12 months (3.6 vs. 0 points; p = 0.04). While endocrine symptoms, fatigue, and anxiety improved at 6 months in those who lost ≥ 5%, differences were not significant vs. those who lost < 5%. There was no significant change within or between groups in sexual function, depression, or sleep. Findings at 12 months were similar, except pain improved in those losing ≥ 5%. CONCLUSIONS: These results support the benefits of weight loss in overweight/obese breast cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Weight management in breast cancer survivors may improve PF.

Terminal Syme Amputation of the Great Toe in the Pediatric Population.

BACKGROUND: In the pediatric population, chronic ingrown toenails (onychocryptosis) can cause infection (paronychia), debilitating pain, and may be unresponsive to conservative treatments. Following multiple failed interventions, a terminal Syme amputation is one option for definitive treatment of chronic onychocryptosis. This procedure involves amputation of the distal aspect of the distal phalanx of the great toe with complete removal of the nail bed and germinal center, preventing further nail growth and recurrence. METHODS: A retrospective review was performed to determine outcomes of a terminal Syme amputation in the pediatric population. Inclusion criteria included treatment of onychocryptosis involving terminal Syme amputation with a minimum follow-up of 1 year. The medical record was reviewed to assess previous failed treatment efforts, perioperative complications, radiographic outcomes, and the need for additional procedures. RESULTS: From 1984 to 2017, 11 patients (13 halluces) with onychocryptosis were treated with a terminal Syme amputation. There were no intraoperative complications. One hallux had a postoperative infection requiring antibiotics as well as partial nail regrowth following the terminal Syme procedure that required subsequent removal of the residual nail. Following partial nail ablation, the patient had no further nail growth. An additional patient also developed a postoperative infection requiring oral antibiotic treatment. All patients returned to full weight-bearing physical activities within 6 weeks of surgery. CONCLUSIONS: Terminal Syme amputation was successful in treating pediatric patients who have recalcitrant onychocryptosis and paronychia. There was little functional consequence following terminal Syme amputation of the great toe in this patient population, making it an effective salvage procedure. LEVEL OF EVIDENCE: Level IV-retrospective comparative study.

Patient-Reported Outcome Measurement Information System (PROMIS) Scores in Pediatric Patients With Arthrogryposis.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is a clinical term that is used to describe congenital contractures that lead to childhood deformities. Treatment aims are to maximize function while minimizing pain and disability. Few studies have explored patient-reported outcomes in the pediatric arthrogrypotic population, particularly concerning mobility. The aim of this study was to report scores for the Patient-Reported Outcome Measurement Information System (PROMIS) questionnaire for pediatric patients with arthrogryposis with regards to mobility, upper extremity (UE) function, pain interference, and peer relationships. METHODS: A retrospective chart review of 76 patients with AMC aged 5 to 17 who completed the PROMIS questionnaire between January 1, 2017 to March 24, 2020 was performed. Results were collected for four domains: mobility, UE function, pain interference, and peer relationships. Outcomes were stratified by type of arthrogryposis: Amyoplasia (Am), Distal Arthrogryposis (DA), and Other Diagnoses (OD). Results of subjects with isolated upper or lower extremity involvement were compared with subjects with involvement of upper and/or lower extremities. Outcomes were correlated with history of surgical intervention. RESULTS: Children with Am and OD demonstrated moderate impairment of mobility (average: 35.2 and 35.9, respectively), while those with DA reported only mild impairment (average: 44.9). UE function was severely impaired for children with Am (average: 23.0), moderately impaired for OD (average: 33.0), and mildly impaired for DA (average: 43.4). All patient groups reported normal ranges of pain interference, as well as good peer relationships. A moderate negative correlation between number of surgical interventions and mobility scores, and a weak negative correlation between number of surgeries and pain interference scores were found. CONCLUSIONS: Children with AMC experience limited mobility and UE function, but normal levels of pain interference and good peer relationships. The average values provided in this study will serve as a baseline from which to evaluate the efficacy of both nonoperative and surgical interventions. LEVEL OF EVIDENCE: Level II-prognostic study; retrospective study.

Updated Results of TBCRC026: Phase II Trial Correlating Standardized Uptake Value With Pathological Complete Response to Pertuzumab and Trastuzumab in Breast Cancer.

PURPOSE: Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake value corrected for lean body mass (SULmax) on 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) would predict pathologic complete response (pCR) to pertuzumab and trastuzumab (PT). PATIENTS AND METHODS: Patients with stage II or III, estrogen receptor-negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percent change in SULmax by C1D15 predicting pCR is ≤ 0.65, with a one-sided type I error rate of 10%. RESULTS: Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 22%. Receiver operator characteristic analysis of percent change in SULmax by C1D15 yielded an area under the curve of 0.72 (80% CI, 0.64 to 0.80; one-sided P = .12), which did not reject the null hypothesis. However, between patients who obtained pCR and who did not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 41.8%; P = .004) and SULmax reduction ≥ 40% was more prevalent (83% v 52%; P = .03; positive predictive value, 31%). Participants not obtaining a 40% reduction in SULmax by C1D15 were unlikely to obtain pCR (negative predictive value, 91%). CONCLUSION: Although the primary objective was not met, early changes in SULmax predict response to PT in estrogen receptor-negative and HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate tailoring of therapy in this setting.

Outcomes of Patellar Tendon Imbrication With Distal Femoral Extension Osteotomy for Treatment of Crouch Gait.

BACKGROUND: Crouch gait is a frequent gait abnormality observed in children with cerebral palsy. Distal femoral extension osteotomy (DFEO) with the tightening of the extensor mechanism is a common treatment strategy to address the pathologic knee flexion contracture and patella alta. The goal of this study was to review the results of a patellar tendon imbrication (PTI) strategy to address quadriceps insufficiency in the setting of children undergoing DFEO. METHODS: After institutional review board approval, all patients with crouch gait treated at a single institution with DFEO and PTI were identified. Clinical, radiographic, and instrumented gait analysis data were analyzed preoperatively and at 1 year following surgery. RESULTS: Twenty-eight patients (54 extremities) with a diagnosis of cerebral palsy and crouch gait were included. Significant improvements were appreciated in the degree of knee flexion contracture, quadriceps strength, knee extensor lag, and popliteal angle (P<0.01). Knee flexion at initial contact and during mid-stance improved significantly (P<0.0001), and knee moments in late stance were significantly reduced (P<0.01). The anterior pelvic tilt, however, significantly increased postoperatively (P<0.0001). Radiographic improvements were seen in the knee flexion angle and patellar station as assessed by the Koshino Sugimoto Index (P<0.0001). Four patients (14.2%) developed a recurrence of knee flexion contracture requiring further intervention. CONCLUSIONS: PTI is a simplified and safe technique to address quadriceps insufficiency when performing DFEO. The short-term results of patients who underwent DFEO with PTI demonstrated improvements in clinical, radiographic, and gait analysis variables of the knee. Investigating long-term outcomes, comparing techniques, and assessing quality of life measures are important next steps in research. LEVEL OF EVIDENCE: Level IV-case series.

Surgical Outcomes for Severe Idiopathic Toe Walkers.

BACKGROUND: Idiopathic toe walking (ITW) is a diagnosis of exclusion and represents a spectrum of severity. Treatment for ITW includes observation and a variety of conservative treatment methods, with surgical intervention often reserved for severe cases. Previous studies reviewing treatment outcomes are often difficult to interpret secondary to a mixture of case severity. The goal of this study was to review surgical outcomes in patients with severe ITW who had failed prior conservative treatment, as well as determine differences in outcomes based on the type of surgery performed. METHODS: After IRB approval, all patients with surgical management of severe ITW at a single institution were identified. Zone II or zone III plantar flexor lengthenings were performed in all subjects. Clinical, radiographic, and motion analysis data were collected preoperatively and at 1 year following surgery. RESULTS: Twenty-six patients (46 extremities) with a diagnosis of severe ITW from 2002 to 2017 were included. Zone II lengthenings were performed in 25 extremities (mean age=9.9 y) and zone III lengthenings were performed in 21 extremities (mean age=8.6 y). At the most recent follow-up, 100% of zone III lengthening extremities and 88% of zone II lengthening demonstrated decreased severity of ITW. Six extremities required additional treatment, all of which were initially managed with zone II lengthenings. CONCLUSIONS: Severe ITW or ITW that has not responded to conservative treatment may benefit from surgical intervention. More successful outcomes, including continued resolution of toe walking, were observed in subjects treated with zone III lengthenings. LEVEL OF EVIDENCE: Level III-case series.

Outcomes of knee arthrodesis in proximal femoral focal deficiency.

Treatment options for patients with severe forms of proximal femoral focal deficiency include limb salvage procedures or foot ablation and use of a prosthesis. In patients with amputation, an ipsilateral knee arthrodesis can provide an efficient lever arm that is easy to contain in a prosthetic socket. We performed a retrospective review of proximal femoral focal deficiency patients treated at a single institution with knee arthrodesis. From 1986 to 2018, 26 patients (18 males, eight females) met study inclusion criteria (mean follow-up 13.2 years). Aitken C or D deformities were present in 65% of extremities. Ten patients had concomitant knee fusion with foot ablation (mean age 4.3 years). Fifteen patients had staged procedures with initial foot ablation (mean age 1.3 years) followed by a knee arthrodesis (mean age 4.7 years). One patient was managed with knee arthrodesis and retention of a three-ray foot. Subsequent realignment osteotomies were required in six patients to correct progressive malalignment with growth, often due to retained physis or incomplete physeal resection during the arthrodesis. In severe forms of proximal femoral focal deficiency, a straight residual limb can be achieved with foot ablation and knee arthrodesis to improve weight-bearing alignment in an above knee prosthesis. Progressive deformity, which may interfere with prosthetic fitting and require repeat osteotomy, may occur if complete excision of the physis is not achieved.

Calcaneocuboid distraction arthrodesis for children with symptomatic pes planovalgus: does fixation improve outcomes?

Lateral column lengthening is a common surgical procedure for addressing symptomatic pes planovalgus foot deformity. For more severe cases, the use of a calcaneocuboid distraction arthrodesis (CCDA) can allow for more powerful correction. Previous reports have cited an increased risk of graft collapse with loss of correction when this procedure is performed without supplemental hardware fixation. The purpose of this study was to assess the outcomes of CCDA in children with and without supplemental locking fixation. A retrospective review from 2008 to 2016 of CCDA procedures with and without supplemental fixation was performed. The primary endpoint was graft collapse. Secondary objectives included evaluation of radiographic loss of correction, hardware failure, pain at 1-year follow-up, reoperations, and changes in the foot loading pattern foot per pedobarography. Twenty-nine feet in 24 patients were eligible for review. Supplemental locked fixation was used in 18 feet [hardware (HW)], with the remaining 11 feet managed without fixation [no hardware (NoHW)]. The overall failure rate on the basis of graft collapse and loss of correction was 55% (56% for the HW group, 55% for the NoHW group). Eleven patients (61%) in the HW group experienced hardware failure, with six (33%) of these requiring hardware removal. Fifty-six percent of the HW group and 45% of the NoHW group reported continued pain at 1-year follow-up. One patient from each group underwent revision arthrodesis. Supplemental locked fixation did not provide additional benefit in preventing graft collapse and loss of correction in this cohort. Alternative strategies should be considered to improve the outcomes for this procedure.

Outcomes of Naviculectomy for Severe Recurrent Clubfoot Deformity.

BACKGROUND: Naviculectomy was originally described for resistant congenital vertical talus deformity but was later expanded to use in rigid cavus deformity. This study reviews the operative outcomes of complete excision of the navicular for recurrent deformity in the talipes equinovarus (TEV) population. METHODS: After institutional review board approval, all patients undergoing naviculectomy at a single institution were identified. Clinical, radiographic, and pedobarographic data (minimum 2 years' follow-up) were reviewed. RESULTS: Twelve patients (14 feet) with TEV from 1984 to 2019 were included. All feet had minimum 1 prior operative intervention on the affected foot (mean age = 4.0 years, range 0.2-14.5), with 8/14 having at least 3 prior operative procedures. Complete navicular excision with concomitant procedures was performed in all patients (mean age = 11.7 years, range 5.5-16.1). Mean clinical follow-up from naviculectomy was 5.1 years (range, 2.2-11.2). During follow-up, 6 patients required subsequent surgery, most often secondary to pain and progressive deformity. One patient underwent elective below-knee amputation of the affected extremity. Of the remaining 11 patients, 7 of 11 reported continued pain and 8 of 11 maintained adequate range of motion at the ankle at the most recent follow-up. CONCLUSION: Clinical follow-up demonstrated deteriorating results in a large percentage of patients. The high rate of additional procedures and continued pain in the current series suggests that even as a salvage procedure, naviculectomy may not provide adequate results for patients. LEVEL OF EVIDENCE: Level IV, case series.

Patella Alta in Ambulatory Children With Cerebral Palsy: Prevalence and Functional Significance.

BACKGROUND: Gait dysfunction associated with patella alta (PA) in subjects with cerebral palsy (CP) has been presumed but not objectively established clinically or through biomechanical modeling. It is hypothesized that PA is associated with increasing level of motor impairment, increasing age, obesity, and worse stance phase knee kinematics and kinetics in children with CP. METHODS: Retrospective case series of 297 subjects with CP studied in our Motion Analysis Center. Data analyzed included patient demographics (age, body mass index, CP classification), patella height (Koshino-Sugimoto Index), and knee kinematics and kinetics. RESULTS: PA was present in 180 of 297 subjects (61%), in 68 of the 146 (47%) with unilateral CP, and 112 of 151 subjects (74%) with bilateral CP. For unilateral CP, the prevalence of PA was not significantly different between Gross Motor Function Classification System (GMFCS) I and II (P=0.357). For bilateral CP, the prevalence of PA in GMFCS III was significantly greater than in GMFCS I and II (P=0.02). Regression analysis showed a significant trend between increasing age and PA in unilateral and bilateral groups (P<0.001 and 0.001, respectively). The prevalence of PA was not significantly different across body mass index categories for either unilateral or bilateral groups. There were only 2 of 10 significant correlations between PA and gait parameters for subjects with unilateral CP functioning at the GMFCS I and II levels. There were 8 of 12 significant correlations between PA and gait parameters for subjects with bilateral CP functioning at the GMFCS I, II, and III levels. CONCLUSIONS: PA is common in ambulatory children with CP across topographic types and motor functional levels. PA is well tolerated with respect to gait dysfunction in unilateral CP, but may contribute to crouch gait in bilateral CP. Gait dysfunction cannot be inferred from the radiographic assessment of patellar height, and radiographic evidence of PA by itself does not justify surgical correction with patellar tendon advancement or shortening. LEVEL OF EVIDENCE: Level III-prognostic, retrospective series.

Guided Growth for Ankle Valgus Deformity: The Challenges of Hardware Removal.

BACKGROUND: Ankle valgus deformity is associated with conditions such as clubfoot, cerebral palsy, and myelodysplasia. Guided growth strategies using a transphyseal screw provide effective correction of ankle valgus deformity. When correction occurs before skeletal maturity, screw removal is required to prevent overcorrection in the coronal plane. In this study, we reviewed the outcomes of guided growth procedures for correction of ankle valgus and related difficulty with hardware extraction. METHODS: A retrospective review of patients with ankle valgus managed with transphyseal screw placement was performed. Clinical and radiographic data, including the lateral distal tibial angle (LDTA), type of screw placed, and time to correction was recorded. At hardware removal, we reviewed elements associated with difficult extraction defined as requiring the use of specialized screw removal/extraction sets or inability to remove the entirety of the screw. RESULTS: One hundred nineteen patients (189 extremities) with a mean age of 11.7 years at time of screw placement met study inclusion criteria. Following correction of the valgus deformity, hardware removal occurred at an average of 18.4 months after placement of the screw. Preoperatively, the mean LDTA for the entire cohort was 81.3 degrees, and was corrected to a mean LDTA of 91.1 degrees. Complicated hardware removal occurred in 69 (37%) extremities. These 69 extremities had hardware in place an average of 1.8 years compared with an average of 1.4 years in extremities without difficult extraction (P<0.01). Six (9%) screws were unable to be removed in their entirety. Rebound valgus deformity occurred in 5 extremities (3%). CONCLUSIONS: Extraction of transphyseal screws in the correction of ankle valgus can be problematic. Specialized instrumentation was required in approximately one third of cases. Longevity of screw placement may be a factor that affects the ease of extraction. Additional exposure, access to specialized instrumentation, and additional operative time may be required for extraction. LEVEL OF EVIDENCE: Level IV-case series.

The Detection of 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine in Circulating Cell-Free DNA: A Step Towards Longitudinal Monitoring of Health.

Chronic stress appears to accelerate biological aging, and oxidative damage is an important potential mediator of this process. Many chronic diseases are accompanied by an increase in overall oxidation of genomic DNA. In course of exposure to daily environmental insults, DNA accumulates oxidative damage, which is, in part, repaired, while the cells with the most damaged DNA die either by necrosis or by apoptosis. The oxidized DNA released from the dying cells contributes to the pool of cell-free/extracellular DNA present in plasma and other biological fluids. This cell-free DNA contains a great deal of 8-oxodG bases. The ratio of 8-oxo-dG and unmodified guanine may serve as a cumulative biomarker of stress encountered by a human body within a previous 24 h-period. This true end-point biomarker may outperform other short-lived molecules that reflect only the most current state of oxidant stress. Patient-specific baselines for oxidative damage may be established by measuring of 8-oxo-dG in circulating DNA. Longitudinal profiling of oxiDNA may aid in reliable quantification of the effects of various self-administered nutraceutical and lifestyle based health interventions. Development of wearable electrochemical sensor patches that will quantify oxiDNA in near real-time is warranted to produce life- and health-modifying event awareness feedback.

Management of Tibial Bow in Fibular Deficiency.

BACKGROUND: Deformity of the tibia, including shortening and angulation, may accompany severe forms of postaxial hypoplasia (fibular deficiency). The current literature reflects varying opinions on the appropriate management for tibial deformity in the setting of fibular deficiency. METHODS: We performed a retrospective review to determine outcomes of tibial deformity correction in patients with a primary diagnosis of fibular deficiency. Clinical and radiographic outcomes of patients treated with foot ablation were reviewed to establish indications for tibial deformity correction, identify occurrence of additional surgical procedures related to limb alignment or deformity, and characterize difficulties with prosthetic wear potentially related to residual or recurrent tibial deformity. RESULTS: From 1989 to 2016, 51 patients (57 extremities) with fibular deficiency were managed with a foot ablation procedure. Twenty-five (44%) had simultaneous correction of the tibial deformity. The initial tibial deformity measured 42.5 degrees, was corrected to 5.6 degrees intraoperatively, and measured 18.6 degrees at follow-up, suggesting recurrent deformity. In follow-up, approximately half of the patients complained of redness and one third complained of a continued prominence along the anterior tibia. Thirty-two extremities had an isolated foot ablation procedure without tibial osteotomy. Radiographic review demonstrated mild tibial bowing at the time of amputation with a mean angular deformity of 15.4 degrees and remained unchanged during the follow-up period (mean, 12.7 degrees). Similar to the osteotomy group, approximately half of the patients complained of redness and erythema over the anterior bow, with one fourth noting prominence, and only 2 reporting significant pain. CONCLUSIONS: Tibial osteotomies in patients with more significant degrees of angular deformity can be safely performed at the same setting as foot ablative procedures for fibular deficiency. Recurrent deformity with growth may occur. Patients and their caregivers should be aware that rebound deformity may occur, but typically can be managed with prosthetic adjustment and without significant disruption to the child's daily activities. LEVEL OF EVIDENCE: Level IV (case series).

Correction of Genu Valgum in Patients With Congenital Fibular Deficiency.

BACKGROUND: Patients with congenital fibular deficiency often develop genu valgum secondary to lateral femoral condylar hypoplasia. Guided growth strategies are often performed to correct limb alignment when adequate skeletal growth remains. METHODS: A retrospective review of patients with postaxial hypoplasia of the lower extremity managed with an amputation strategy and who had a guided growth procedure for coronal plane limb malalignment during their course of treatment was performed. Clinical and radiographic data, including measures of coronal plane deformity and alignment, type of amputation, subsequent operative procedures, and complications were recorded. RESULTS: Seventeen patients (20 extremities) met study inclusion criteria (mean follow-up 8.8 y). Foot ablation and hemiepiphysiodesis for valgus deformity of the knee was performed in all extremities. The average age at the time of initial hemiepiphysiodesis was 11.2 years at an average of 8.8 years from the initial amputation procedure. The mean preoperative mechanical axis deviation was 26.5 mm, which was corrected to a mean mechanical axis deviation of 7.0 mm. Fifteen (75%) of the extremities had correction of the deformity to neutral alignment after the initial procedure. Lack of correction occurred in 3 extremities, and overcorrection occurred in 2 extremities. Additional procedures were required in 5 extremities for rebound valgus deformity after hardware removal. CONCLUSIONS: In patients with postaxial hypoplasia, regular monitoring of the residual limb for growth-related changes must occur to ensure optimal function and prosthetic fit. Timing of the guided growth procedure is critical, as younger patients may be more likely to experience rebound deformity. Families and patients should be made aware that growth might be unpredictable in this population with risks of both overcorrection and undercorrection. LEVEL OF EVIDENCE: Level IV-case series.

The Effects of a Remote-based Weight Loss Program on Adipocytokines, Metabolic Markers, and Telomere Length in Breast Cancer Survivors: the POWER-Remote Trial.

PURPOSE: We initiated a clinical trial to determine the proportion of breast cancer survivors achieving ≥5% weight loss using a remotely delivered weight loss intervention (POWER-remote) or a self-directed approach, and to determine the effects of the intervention on biomarkers of cancer risk including metabolism, inflammation, and telomere length. EXPERIMENTAL DESIGN: Women with stage 0-III breast cancer, who completed local therapy and chemotherapy, with a body mass index ≥25 kg/m2 were randomized to a 12-month intervention (POWER-remote) versus a self-directed approach. The primary objective was to determine the number of women who achieved at least 5% weight loss at 6 months. We assessed baseline and 6-month change in a panel of adipocytokines (adiponectin, leptin, resistin, HGF, NGF, PAI1, TNFα, MCP1, IL1ß, IL6, and IL8), metabolic factors (insulin, glucose, lipids, hs-CRP), and telomere length in peripheral blood mononuclear cells. RESULTS: From 2013 to 2015, 96 women were enrolled, and 87 were evaluable for the primary analysis; 45 to POWER-remote and 42 to self-directed. At 6 months, 51% of women randomized to POWER-remote lost ≥5% of their baseline body weight, compared with 12% in the self-directed arm [OR, 7.9; 95% confidence interval (CI), 2.6-23.9; P = 0.0003]; proportion were similar at 12 months (51% vs 17%, respectively, P = 0.003). Weight loss correlated with significant decreases in leptin, and favorable modulation of inflammatory cytokines and lipid profiles. There was no significant change in telomere length at 6 months. CONCLUSIONS: A remotely delivered weight loss intervention resulted in significant weight loss in breast cancer survivors, and favorable effects on several biomarkers.

The Role of MRI in Children With Congenital Limb Deficiencies With Associated Scoliosis.

BACKGROUND: The association of scoliosis and congenital limb deficiency has been well described. However, the incidence of neural axis abnormalities in this population is not known. The ability to assess the neural axis by physical examination may be limited in patients with a limb deficiency. Although mobility of the spine is important for all children, it can be especially so in children with a limb deficiency. As spinal fusion in children with limb deficiency potentially has more functional impact, detecting reversible forms of scoliosis seems particularly important. METHODS: Retrospective review of children treated at 1 institution between 1990 and 2017 with both a diagnosis of a congenital limb deficiency, upper or lower, and scoliosis. Children were excluded if they had any neurological difference on history or physical examination, if they had sacral agenesis or spina bifida, or if their limb deficiency was related to trauma or early amniotic rupture sequence. RESULTS: Twenty-four children were identified, 11 with lower extremity deficiency, 14 with upper extremity deficiency with 1 having both. Fifteen children demonstrated neural axis abnormalities, 6 (40%) required neurosurgery. Five (45%) of 11 lower extremity deficiency children had MRI findings, 3 of these needing neurosurgery. Of the 14 upper extremity deficiency children, 10 had MRI changes, and 3 required neurosurgery. Eight children with congenital scoliosis, 5 had MRI findings, with 4 children requiring neurosurgery. The other 16 children had scoliosis without vertebral abnormalities, 10 had MRI findings, and 2 required neurosurgery. CONCLUSIONS: There is a high incidence of neural axis abnormalities (63%) in children with congenital limb deficiencies and scoliosis. A large portion of these require neurosurgical intervention. MRI should be considered soon after presentation in this population of children. LEVEL OF EVIDENCE: Level IV. DESIGN: Retrospective cohort.