Correction: Genetic and metabolomic architecture of variation in diet restriction-mediated lifespan extension in Drosophila.

[This corrects the article DOI: 10.1371/journal.pgen.1008835.].

Dyssynchronous diaphragm contractions impair diaphragm function in mechanically ventilated patients.

BACKGROUND: Pre-clinical studies suggest that dyssynchronous diaphragm contractions during mechanical ventilation may cause acute diaphragm dysfunction. We aimed to describe the variability in diaphragm contractile loading conditions during mechanical ventilation and to establish whether dyssynchronous diaphragm contractions are associated with the development of impaired diaphragm dysfunction. METHODS: In patients receiving invasive mechanical ventilation for pneumonia, septic shock, acute respiratory distress syndrome, or acute brain injury, airway flow and pressure and diaphragm electrical activity (Edi) were recorded hourly around the clock for up to 7 days. Dyssynchronous post-inspiratory diaphragm loading was defined based on the duration of neural inspiration after expiratory cycling of the ventilator. Diaphragm function was assessed on a daily basis by neuromuscular coupling (NMC, the ratio of transdiaphragmatic pressure to diaphragm electrical activity). RESULTS: A total of 4508 hourly recordings were collected in 45 patients. Edi was low or absent (≤ 5 µV) in 51% of study hours (median 71 h per patient, interquartile range 39-101 h). Dyssynchronous post-inspiratory loading was present in 13% of study hours (median 7 h per patient, interquartile range 2-22 h). The probability of dyssynchronous post-inspiratory loading was increased with reverse triggering (odds ratio 15, 95% CI 8-35) and premature cycling (odds ratio 8, 95% CI 6-10). The duration and magnitude of dyssynchronous post-inspiratory loading were associated with a progressive decline in diaphragm NMC (p < 0.01 for interaction with time). CONCLUSIONS: Dyssynchronous diaphragm contractions may impair diaphragm function during mechanical ventilation. TRIAL REGISTRATION: MYOTRAUMA, ClinicalTrials.gov NCT03108118. Registered 04 April 2017 (retrospectively registered).

Synchronized and proportional sub-diaphragmatic unloading in an animal model of respiratory distress.

BACKGROUND: A sealed abdominal interface was positioned below the diaphragm (the "NeoVest") to apply synchronized and proportional negative pressure ventilation (NPV) and was compared to positive pressure ventilation (PPV) using neurally adjusted ventilatory assist (NAVA). Both modes were controlled by the diaphragm electrical activity (Edi). METHODS: Eleven rabbits (mean weight 2.9 kg) were instrumented, tracheotomized, and ventilated with either NPV or PPV (sequentially) with different loads (resistive, dead space, acute lung injury). Assist with either PPV or NPV was titrated to reduce Edi by 50%. RESULTS: In order to achieve a 50% reduction in Edi, NPV required slightly more negative pressure (-8 to -12 cm H2O) than observed in PPV (+6 to +10 cm H2O). The efficiency of pressure transmission from the NeoVest into gastric pressure was 69.6% (range 61.3-77.4%). Swings in esophageal pressure were more negative during NPV than PPV, for all conditions, due to transmission of negative pressure. Transpulmonary pressure was lower during NPV. Transdiaphragmatic pressure swings were reduced similarly for PPV and NPV, suggesting equivalent unloading of the diaphragm. NPV did not affect hemodynamics. CONCLUSIONS: It is feasible to apply NPV sub-diaphragmatically in synchrony and in proportion to Edi in an animal model of respiratory distress. IMPACT: Negative pressure ventilation (NPV), for example, the "Iron Lung," may offer advantages over positive pressure ventilation. In the present work, we describe the "NeoVest," a system consisting of a sealed abdominal interface and a ventilator that applies NPV in synchrony and in proportion to the diaphragm electrical activity (Edi).

Estimation of transpulmonary driving pressure during synchronized mechanical ventilation using a single lower assist maneuver (LAM) in rabbits: a comparison to measurements made with an esophageal balloon.

BACKGROUND: Mechanical ventilation is applied to unload the respiratory muscles, but knowledge about transpulmonary driving pressure (ΔPL) is important to minimize lung injury. We propose a method to estimate ΔPL during neurally synchronized assisted ventilation, with a simple intervention of lowering the assist for one breath ("lower assist maneuver", LAM). METHODS: In 24 rabbits breathing spontaneously with imposed loads, titrations of increasing assist were performed, with two neurally synchronized modes: neurally adjusted ventilatory assist (NAVA) and neurally triggered pressure support (NPS). Two single LAM breaths (not sequentially, but independently) were performed at each level of assist by acutely setting the assist to zero cm H2O (NPS) or NAVA level 0 cm H2O/uV (NAVA) for one breath. NPS and NAVA titrations were followed by titrations in controlled-modes (volume control, VC and pressure control, PC), under neuro-muscular blockade. Breaths from the NAVA/NPS titrations were matched (for flow and volume) to VC or PC. Throughout all runs, we measured diaphragm electrical activity (Edi) and esophageal pressure (PES). We measured ΔPL during the spontaneous modes (PL_PES) and controlled mechanical ventilation (CMV) modes (PL_CMV) with the esophageal balloon. From the LAMs, we derived an estimation of ΔPL ("PL_LAM") using a correction factor (ratio of volume during the LAM and volume during assist) and compared it to measured ΔPL during passive (VC or PC) and spontaneous breathing (NAVA or NPS). A requirement for the LAM was similar Edi to the assisted breath. RESULTS: All animals successfully underwent titrations and LAMs for NPS/NAVA. One thousand seven-hundred ninety-two (1792) breaths were matched to passive ventilation titrations (matched Vt, r = 0.99). PL_LAM demonstrated strong correlation with PL_CMV (r = 0.83), and PL_PES (r = 0.77). Bland-Altman analysis revealed little difference between the predicted PL_LAM and measured PL_CMV (Bias = 0.49 cm H2O and 1.96SD = 3.09 cm H2O). For PL_PES, the bias was 2.2 cm H2O and 1.96SD was 3.4 cm H2O. Analysis of Edi and PES at peak Edi showed progressively increasing uncoupling with increasing assist. CONCLUSION: During synchronized mechanical ventilation, a LAM breath allows for estimations of transpulmonary driving pressure, without measuring PES, and follows a mathematical transfer function to describe respiratory muscle unloading during synchronized assist.

Genetic and metabolomic architecture of variation in diet restriction-mediated lifespan extension in Drosophila.

In most organisms, dietary restriction (DR) increases lifespan. However, several studies have found that genotypes within the same species vary widely in how they respond to DR. To explore the mechanisms underlying this variation, we exposed 178 inbred Drosophila melanogaster lines to a DR or ad libitum (AL) diet, and measured a panel of 105 metabolites under both diets. Twenty four out of 105 metabolites were associated with the magnitude of the lifespan response. These included proteinogenic amino acids and metabolites involved in α-ketoglutarate (α-KG)/glutamine metabolism. We confirm the role of α-KG/glutamine synthesis pathways in the DR response through genetic manipulations. We used covariance network analysis to investigate diet-dependent interactions between metabolites, identifying the essential amino acids threonine and arginine as "hub" metabolites in the DR response. Finally, we employ a novel metabolic and genetic bipartite network analysis to reveal multiple genes that influence DR lifespan response, some of which have not previously been implicated in DR regulation. One of these is CCHa2R, a gene that encodes a neuropeptide receptor that influences satiety response and insulin signaling. Across the lines, variation in an intronic single nucleotide variant of CCHa2R correlated with variation in levels of five metabolites, all of which in turn were correlated with DR lifespan response. Inhibition of adult CCHa2R expression extended DR lifespan of flies, confirming the role of CCHa2R in lifespan response. These results provide support for the power of combined genomic and metabolomic analysis to identify key pathways underlying variation in this complex quantitative trait.

Controlled Ankle Movement (CAM) Boot Provides Improved Outcomes With Lower Complications Than Short Leg Walking Cast in Low-energy Pediatric Lateral Ankle Injuries: A Prospective, Randomized Study.

BACKGROUND: Low-energy lateral ankle injuries (Salter-Harris 1 distal fibula, distal fibula avulsion fractures, and radiograph-negative lateral ankle injuries) are common in pediatric patients. Patient-based outcomes for the 2 treatment options, short leg walking cast (CAST) and controlled ankle motion (CAM) boot, are unknown. This study aims to determine differences between 2 treatments of low-energy lateral ankle injuries in pediatric patients. METHODS: A prospective, randomized controlled trial comparing the acute outcomes of CAST and CAM treatment for low-energy lateral ankle injuries in pediatric patients was completed. Patients were evaluated in-person at presentation and 4 weeks for ankle range of motion and Oxford foot and ankle score. A novel survey defining patient and parent satisfaction and time away from school/work was also completed. Treatment complications were documented. Patients were called at 8 weeks postinjury to determine other complications and the final time of return to sport. Mixed effects linear regression models evaluated change over time between the 2 treatment groups. RESULTS: After 60 patients were enrolled, 28 patients in the CAST group and 27 patients in the CAM group completed the study. Males comprised 51% (28), with 38 (69%) patients identifying as Hispanic. The patient's average age was 11.3±2.9 years and the average body mass index was 23.At the 4-week evaluation, the CAM group had improved range of motion, higher satisfaction scores (5.26 CAM vs. 4.25 CAST, P <0.05), similar pain scores (0.32 CAST vs. 0.41 CAM, P =0.75), and lower complications (0.54/patient CAST vs. 0.04/patient CAM, P <0.0001) than the CAST group. Female patients had improved inversion with CAM treatment than males ( P <0.05). Patients over age 12 in the CAST group had significantly decreased plantarflexion at week 4 ( P =0.002). Improvement in Oxford scores was similar between the CAST and CAM groups between the initial presentation and 4 weeks, except for increased improvement in CAM group Oxford scores for difficulty running and symptoms with walking/walking. At the 8-week evaluation, patients in the CAST group had a higher rate of continued symptoms than the CAM group (15.4% vs. 0%). CONCLUSIONS: CAM boot treatment of low-energy lateral ankle injuries in pediatric patients results in improved results and lower complications than CAST treatment. LEVEL OF EVIDENCE: Level I -randomized, controlled trial with a statistically significant difference.

Variability in Pain Management Practices for Pediatric Anterior Cruciate Ligament Reconstruction.

BACKGROUND: The opioid epidemic in the United States is a public health crisis. Pediatric orthopaedic surgeons must balance adequate pain management with minimizing the risk of opioid misuse or dependence. There is limited data available to guide pain management for anterior cruciate ligament reconstruction (ACLR) in the pediatric population. The purpose of this study was to survey current pain management practices for ACLR among pediatric orthopaedic surgeons. METHODS: A cross-sectional survey study was conducted, in which orthopaedic surgeons were asked about their pain management practices for pediatric ACLR. The voluntary survey was sent to members of the Pediatric Orthopaedic Society of North America. Inclusion criteria required that the surgeon perform anterior cruciate ligament repair or reconstruction on patients under age 18. Responses were anonymous and consisted of surgeon demographics, training, practice, and pain management strategies. Survey data were assessed using descriptive statistics. RESULTS: Of 64 included responses, the average age of the survey respondent was 48.9 years, 84.4% were males, and 31.3% practiced in the southern region of the United States. Preoperative analgesia was utilized by 39.1%, 90.6% utilized perioperative blocks, and 89.1% prescribed opioid medication postoperatively. For scheduled non-narcotic medications postoperatively 82.8% routinely advocated and 93.8% recommended cryotherapy postoperatively.Acetaminophen was the most used preoperative medication (31.3%), the most common perioperative block was an adductor canal block (81.0%), and the most common postoperative analgesic medication was ibuprofen (60.9%). Prior training or experience was more frequently reported than published research as a primary factor influencing pain management protocols. CONCLUSIONS: Substantial variability exists in pain management practices in pediatric ACLR. There is a need for more evidence-based practice guidelines regarding pain management. LEVEL OF EVIDENCE: Level V.

A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster.

Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these disorders, the genetic pathways influencing UA metabolism and the association with disease remain poorly understood. In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene around 15 million years ago. Therefore, we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan when reared on diets containing high levels of yeast extract. Furthermore, high levels of dietary purines, but not protein or sugar, were sufficient to produce the same effects of shortened lifespan and concretion formation in the Drosophila model. The insulin-like signaling (ILS) pathway has been shown to respond to changes in nutrient status in several species. We observed that genetic suppression of ILS genes reduced both UA levels and concretion load in flies fed high levels of yeast extract. Further support for the role of the ILS pathway in modulating UA metabolism stems from a human candidate gene study identifying SNPs in the ILS genes AKT2 and FOXO3 being associated with serum UA levels or gout. Additionally, inhibition of the NADPH oxidase (NOX) gene rescued the reduced lifespan and concretion phenotypes in Uro knockdown flies. Thus, components of the ILS pathway and the downstream protein NOX represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones, as well as extending human healthspan.

Should Adolescents Run Marathons?: Youth Marathon Training Injury Epidemiology and Risk Factors.

OBJECTIVE: Youth participation in distance running has increased, yet little data exist about the injury patterns and safety of such activity. This study seeks to determine the types and rates of injuries seen in an adolescent marathon training program. DESIGN: Observational prospective cohort study. SETTING: Community-based adolescent marathon training program. PARTICIPANTS: The study enrolled 1927 students from 50 high schools (HS) and 34 middle schools (MS) participating in the 2017 to 2018 Students Run Los Angeles marathon training program. ASSESSMENT OF RISK FACTORS: Weekly injury reports completed by running coaches. Data elements included participant demographics, weekly training distance, injury type, injury acuity, and missed training time. MAIN OUTCOME MEASURES: Epidemiology of self-reported injury in adolescent runners. RESULTS: A total of 583 injuries occurred in 18% of runners during the training program. High schools runners were more likely to be injured than MS runners (20.8% vs 14.2%, P < 0.001). Seventy-two percent of injuries were acute with a mean missed training time of 4.8 days (SD 4.8). The most frequent site of injury was the knee (33%). Overall, runners with injuries ran a significantly greater distance per week than uninjured runners (14.6 mi vs 12.0 mi, P < 0.001). Ninety-nine percent of marathon participants completed the race. CONCLUSIONS: During a 28-week marathon training program, 18% of adolescent participants reported an injury. More injuries occurred in HS students, were acute, and involved the knee. This study represents one of the largest descriptions of injury prevalence in adolescent distance running and highlights a lower injury rate than adults during marathon training.

Neurally adjusted ventilatory assist as a weaning mode for adults with invasive mechanical ventilation: a systematic review and meta-analysis.

BACKGROUND: Prolonged ventilatory support is associated with poor clinical outcomes. Partial support modes, especially pressure support ventilation, are frequently used in clinical practice but are associated with patient-ventilation asynchrony and deliver fixed levels of assist. Neurally adjusted ventilatory assist (NAVA), a mode of partial ventilatory assist that reduces patient-ventilator asynchrony, may be an alternative for weaning. However, the effects of NAVA on weaning outcomes in clinical practice are unclear. METHODS: We searched PubMed, Embase, Medline, and Cochrane Library from 2007 to December 2020. Randomized controlled trials and crossover trials that compared NAVA and other modes were identified in this study. The primary outcome was weaning success which was defined as the absence of ventilatory support for more than 48 h. Summary estimates of effect using odds ratio (OR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with accompanying 95% confidence interval (CI) were expressed. RESULTS: Seven studies (n = 693 patients) were included. Regarding the primary outcome, patients weaned with NAVA had a higher success rate compared with other partial support modes (OR = 1.93; 95% CI 1.12 to 3.32; P = 0.02). For the secondary outcomes, NAVA may reduce duration of mechanical ventilation (MD = - 2.63; 95% CI - 4.22 to - 1.03; P = 0.001) and hospital mortality (OR = 0.58; 95% CI 0.40 to 0.84; P = 0.004) and prolongs ventilator-free days (MD = 3.48; 95% CI 0.97 to 6.00; P = 0.007) when compared with other modes. CONCLUSIONS: Our study suggests that the NAVA mode may improve the rate of weaning success compared with other partial support modes for difficult to wean patients.

Trochlear Morphology Development: Study of Normal Pediatric Knee MRIs.

INTRODUCTION: Trochlear dysplasia is a known risk factor for patellar dislocations yet normal trochlea development is not well described. This study will define the articular cartilage (AC) and subchondral trochlear morphology development in pediatric patients using magnetic resonance imaging (MRI) evaluation. METHODS: A retrospective knee MRI review included patients aged 3 to 16 years with nonpatellofemoral-related diagnoses. International classification of diseases-9/International classification of diseases-10 codes were used to identify eligible study patients. Measurements of the trochlea were made on the basis of previously established methods using the axial MRI just distal to the physis at the deepest portion of the trochlear groove. Three linear [lateral trochlear height (LTH), medial trochlear height (MTH), and central trochlear height (CTH)] and 3 angular [sulcus angle (SA), lateral trochlear slope (LTS), and medial trochlear slope (MTS)] were made at AC and subchondral bone (SCB). The 12 measurements were made independently by 2 study authors. Inter-rater reliability was assessed using an interclass correlation coefficient for absolute agreement to the average of the scores. Trochlea measurements were summarized across age quartiles defined as first quartile (age, 5.1 to 8.3 y), second quartile (8.3 to 11.5 y), third quartile (11.5 to 14.3 y), fourth quartile (14.3to 16.9 y). Associations between age and trochlea measures were assessed using linear regression with Huber-White-adjusted SEs to account for clustering from a small number of patients (N=16) with >1 MRI. RESULTS: In total, 246 knee MRIs from 230 patients were included in this study; 113 patients (51%) were female, whereas 117 (49%) were male. A total of 116 MRIs (47%) were of the left knee and 130 (53%) were right knee. The average patient age was 11.4±3.4 years. Inter-rater agreement was high across all measures with interclass correlation coefficient values >0.7. Mean values for measurements are presented by age quartiles. LTH, MTH, and CTH showed a linear increase with age (range, 2 to 2.6 cm/y; P<0.001). SA, LTS, MTS measured at AC showed no change with age (P>0.05); however, LTS and MTS measured at SCB showed significant increases with age (0.6 and 0.9 degrees/y; P<0.001), whereas SA showed a decrease with age (-1.4 degrees/y; P<0.001). There were no significant differences found in the age associations by laterality, left versus right. There were no sex differences in the age associations for SA, LTS (P>0.05); however, for MTH, LTH, and CTH, males were found to have a significantly greater growth rate (P<0.001). CONCLUSIONS: This study found an increase in AC and SCB MTH, LTH, and CTH over time, as well as an increase in SCB LTS and MTS, with a decrease in SA. However, AC of the LTS and SA remained constant, with no significant change throughout growth. This normative data indicate that the LTS and SA of AC are predictors of final trochlea shape in normal development. Final trochlear morphologic development is nearly complete around age 12 years, with no significant changes occurring thereafter.

What Is New in Pediatric Bone Health.

BACKGROUND: This review paper aims to report on the last 5 years of relevant research on pediatric bone health in regard to nutrition and obesity, ethnic disparities, common orthopaedic conditions, trauma, spine, and sports medicine. METHODS: A search of the PubMed database was completed using the following terms: bone health, Vitamin D, pediatric, adolescent, sports medicine, fractures, spine, scoliosis, race, ethnicity, obesity, Slipped Capital Femoral Epiphysis, Osteogenesis Imperfecta, Duchenne's Muscular Dystrophy, neuromuscular, and cancer. Resultant papers were reviewed by study authors and determined to be of quality and relevance for description in this review. Papers from January 1, 2015 to August 31, 2020 were included. RESULTS: A total of 85 papers were selected for review. General results include 7 key findings. (1) Obesity inhibits pediatric bone health with leptin playing a major role in the process. (2) Socioeconomic and demographic disparities have shown to have a direct influence on bone health. (3) Vitamin D deficiency has been linked to an increased fracture risk and severity in children. (4) Formal vitamin D monitoring can aid with patient compliance with treatment. (5) Patients with chronic medical conditions are impacted by low vitamin D and need ongoing monitoring of their bone health to decrease their fracture risk. (6) Vitamin D deficiency in pediatrics has been correlated to low back pain, spondylolysis, and adolescent idiopathic scoliosis. Osteopenic patients with AIS have an increased risk of curve progression requiring surgery. Before spine fusion, preoperative screening for vitamin D deficiency may reduce complications of fractures, insufficient tissue repair, loosening hardware, and postoperative back pain. (7) Increasing youth sports participation has resulted in increased bone health related injuries. However, improved understanding of Relative Energy Deficiency in Sport effects on bone health has recently occurred. CONCLUSIONS: Increasing awareness of bone health issues in children will improve their recognition and treatment. Further research is needed on diagnosis, treatment, outcomes, and most importantly prevention of pediatric bone health diseases.

Nationwide Ethnic/Racial Differences in Surgical Treatment of Discoid Meniscus in Children: A PHIS Database Study.

BACKGROUND: Discoid meniscus, a congenital meniscus variant, may have greater incidence in Asian populations. No US population-based studies have examined the discoid meniscus ethnic/racial distribution. In pediatric patients undergoing meniscus surgery, it is hypothesized that ethnic/racial variability exists in patients with discoid meniscus and this variability is different than in patients with medial meniscus tears. METHODS: The Pediatric Health Information System was queried from 48 hospitals to examine patients 18 years of age and younger between 2015 and 2019, using International Classification of Diseases, 10th Revision, Clinical Modification codes. A cohort of patients treated surgically for discoid meniscus was compared with a cohort of patients treated surgically for medial meniscal tear. These 2 populations were compared based on age, sex, ethnicity/race, Current Procedural Terminology code, insurance, urban versus rural, and region of country. Univariate testing and multivariable logistic modeling were used to test for associations. RESULTS: A discoid meniscus cohort of 399 children (median age, 13.0 y) was compared with a medial meniscus tear cohort of 3157 children (median age, 16.0 y) (P<0.001). Hispanic/Latino children accounted for 36.8% of the discoid lateral meniscus and 22.7% of the medial meniscus populations (P<0.001). Among pediatric patients that had surgery for discoid lateral meniscus or medial meniscus, Hispanic/Latino children had 2.36 times the odds of surgery for discoid meniscus compared with White patients after adjusting for age and insurance (P<0.001). Asian children also had 2.41 times the odds of surgery for discoid meniscus compared with White patients (P=0.017). CONCLUSIONS: This study shows a significant association of ethnicity/race with discoid versus medial meniscus surgical treatment in children. Among pediatric patients undergoing surgery for discoid meniscus, Hispanic/Latino and Asian patients were a significantly larger percentage of the population than White patients. Hispanic/Latino children made up a greater percentage of the population having surgery for a torn discoid meniscus versus a torn medial mensicus. When evaluating pediatric patients, younger age and Asian or Hispanic/Latino ethnicity should increase attention to the possibility of a discoid meniscus. LEVEL OF EVIDENCE: Level IV.

Development of High-Specificity Fluorescent Probes to Enable Cannabinoid Type 2 Receptor Studies in Living Cells.

Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment of numerous conditions, including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite the significance of this receptor, researchers lack reliable tools to address questions concerning the expression and complex mechanism of CB2R signaling, especially in cell-type and tissue-dependent contexts. Herein, we report for the first time a versatile ligand platform for the modular design of a collection of highly specific CB2R fluorescent probes, used successfully across applications, species, and cell types. These include flow cytometry of endogenously expressing cells, real-time confocal microscopy of mouse splenocytes and human macrophages, as well as FRET-based kinetic and equilibrium binding assays. High CB2R specificity was demonstrated by competition experiments in living cells expressing CB2R at native levels. The probes were effectively applied to FACS analysis of microglial cells derived from a mouse model relevant to Alzheimer's disease.

A study of Pt(II)-phenanthroline complex interactions with double-stranded and G-quadruplex DNA by ESI-MS, circular dichroism, and computational docking.

The binding interactions of a series of square-planar platinum(II)-phenanthroline complexes of the type [Pt(PL)(AL)]2+ [where PL = variously methyl-substituted 1,10-phenanthroline (phen) and AL = ethane-1,2-diamine (en)] were assessed with a G-quadruplex DNA (5'-TTG GGG GT-3', G4DNA) and a double-stranded DNA (5'-CGC GAA TTC GCG-3', dsDNA) sequence by ESI-MS. The results indicate a strong correlation between G4DNA affinity and increasing phenanthroline methyl substitution. Circular dichroism (CD) spectroscopy and molecular docking studies also support the finding that increased substitution of the phenanthroline ligand increased selectivity for G4DNA. ESI-MS was used to probe the interaction of a range of square-planar Pt(II)-phenanthroline complexes with double-stranded and G-quadruplex DNA.

Low Energy, Lateral Ankle Injuries in Pediatric and Adolescent Patients: A Systematic Review of Ankle Sprains and Nondisplaced Distal Fibula Fractures.

BACKGROUND: Lateral ankle injuries are one of the most common musculoskeletal injuries sustained by pediatric and adolescent athletes. These injuries can result in significant time lost from competition, affect performance when returning to play, and represent a significant burden on the health care system as a whole. The purpose of this study was to systematically review the literature on the diagnosis, treatment, and prevention of acute lateral ankle injuries and their chronic effects in pediatric and adolescent athletes (younger than 19 y). METHODS: This systematic review was conducted according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) guidelines between September and December 2018. PubMed and Google Scholar were systematically searched using the search terms: ("distal fibula fracture" OR "ankle sprain") AND ("youth" OR "pediatric" OR "adolescent"). All authors participated in article review (N=172) for relevance and age restrictions in which 30 met the inclusion criteria. RESULTS: Thirty articles met inclusion criteria [Levels of Evidence I to IV (I: n=4, II: n=16, III: n=9, and IV: n=1)] including distal fibula fracture diagnosis and treatment, and risk factors, prevention, and chronic sequela of lateral ankle injuries in pediatric and adolescent patients. CONCLUSIONS: Low-energy, lateral ankle injuries are common in pediatric and adolescent patients, yet underrepresented in the medical literature. There is a lack of high-quality literature on diagnosis, treatment, and outcomes after Salter-Harris I distal fibula fractures. Available literature, however, suggests that there remains over diagnosis and over treatment of presumed Salter-Harris I distal fibula fractures. Adolescent ankle sprains dominate the available literature likely due to the high recurrence rate. Youth athletes and coaches should address risk factors and engage in injury prevention programs to prevent and minimize the effect of acute lateral ankle injuries. LEVELS OF EVIDENCE: Level III-Systematic review.

Evaluation of General and Musculoskeletal Health Literacy Disparities in Pediatric Sports Injury Patient and Guardian Populations.

BACKGROUND: Increased participation of adolescents in organized sports has led to an increase in pediatric sports injury. Limited health literacy puts patients at risk for worse outcomes through decreased compliance. We aim to evaluate the extent of health literacy disparities in pediatric sports medicine populations. METHODS: Patients aged 10 to 17 years and their consenting guardians visiting clinic for treatment of a sports-related injury completed a unique questionnaire including self-reported health literacy measures and direct assessment of knowledge regarding care for musculoskeletal injuries. Statistical analysis based on socioeconomic factors and demographics was performed using t tests. RESULTS: A total of 268 patient surveys (14.37±1.94 y) and 251 guardian surveys (43.62±9.08 y) were collected. In self-reported general health literacy scores for guardians, all categories except ethnicity played a statistically significant role, with higher health literacy scores associated with higher education, use of English as the primary language at home, private insurance, and female guardians (P<0.001, <0.001, <0.001, 0.011). In contrast, age was the only factor affecting scores in the patient population (P=0.015). Among self-reported musculoskeletal health literacy and directly measured musculoskeletal literacy scores, there were significant differences in groups by age, primary language, and level of education (P=0.020, 0.003). CONCLUSIONS: Significant disparities in general and musculoskeletal health literacy exist within pediatric sports medicine populations, most notably between guardian groups. Improving disparities in health literacy for these populations may best be aimed at guardians, using medical education through verbal/written instruction in multiple languages. LEVEL OF EVIDENCE: Level IV.

Delays in Obtaining Knee MRI in Pediatric Sports Medicine: Impact of Insurance Type.

BACKGROUND: Increased enrollment in government-based insurance plans has been reported. With youth sports injuries on the rise, increased ordering of advanced imaging such as magnetic resonance imaging (MRI) has occurred. This study sought to report on the impact of insurance type on access to and results of knee MRI in pediatric sports medicine patients. METHODS: A retrospective review of 178 consecutive pediatric sports medicine clinics was completed. INCLUSION CRITERIA: patients younger than 18 years, routine knee MRI ordered, sports medicine diagnosis, and insurance. Data included basic demographics, injury date, date and location (urgent care vs. clinic) of the first presentation, details of MRI ordering and approval, date and location of MRI follow-up, MRI results (negative, minor findings, major findings), and eventual treatment required. RESULTS: A total of 168 charts underwent a complete review. The patients' average age was 14±3 years and 54% (N=90) were female. Ninety-eight had government insurance and 70 had commercial insurance. The time between injury and MRI completion was significantly longer with government insurance (34 vs. 67 d, P<0.01). Government insurance had increased wait time between the first visit and MRI completion (11 vs. 40 d, P<0.001) as well as MRI order and completion (9 vs. 16.5 d, P<0.001). There was no significant difference in positive findings on MRI between insurance groups, including both major and minor findings nor in the proportion receiving eventual operative treatment. CONCLUSION: Pediatric sports medicine patients with government insurance have delays in obtaining knee MRI, despite there being no difference in the rate of positive findings and subsequent operative treatments. LEVEL OF EVIDENCE: Level III-case-control study.

Iliotibial band autograft: what size is the graft? A mathematical and cadaveric model : ITB single and double strand size.

BACKGROUND: The iliotibial band (ITB) is used in anterior cruciate ligament (ACL) reconstruction in skeletally immature patients as well as several other orthopedic reconstructions. The purpose of this study is to determine the size of the ITB as an autograft option in ACL reconstruction surgery or other orthopedic soft tissue reconstructions. METHODS: Five adult cadavers resulting in nine ITB were used. Thickness and width of the ITB were determined. Using ITB width of 15-60 mm, single and doubled graft sizes were determined using standard surgical graft size technique. Geometric calculations based on average graft thickness were used to mathematically confirm the graft size of the ITB. RESULTS: The ITB is less than 1 mm in thickness in males and females. Cadaveric measurements were less than 1 mm larger than mathematical measurements, in majority of measurements. ITB autograft can be harvested to a maximum 9 mm single-stranded graft or > 12 mm doubled graft. A minimum of 50 mm of ITB width is required to make a 8 mm graft. CONCLUSIONS: ITB is a versatile graft that can be used for a graft size up to 9 mm single strand and over 12 mm double strand. A minimum of 50 mm width of ITB is required to obtain a 8 mm-diameter autograft. To ensure appropriate graft size, surgeons should consider harvesting the maximum amount of ITB when performing ACL reconstructions in skeletally immature patients. CLINICAL RELEVANCE: Surgeons have a quick reference for the width of ITB they should harvest based on the size of graft they require for a successful surgery.

Physiological Effect of Prone Position in Children with Severe Bronchiolitis: A Randomized Cross-Over Study (BRONCHIO-DV).

OBJECTIVE: To assess the effect of the prone position on physiological measures, including inspiratory effort, metabolic cost of breathing, and neural drive to the diaphragm as compared with the supine position in infants with severe bronchiolitis requiring noninvasive ventilation. STUDY DESIGN: Fourteen infants, median age 33 days (IQR [first and third quartiles], 25-58) were randomized to receive 7 cmH2O continuous positive airway pressure for 1 hour in the prone position or in the supine position, which was followed by cross-over to the supine position and the prone position for 1 hour, respectively. Flow, esophageal, airway, gastric, and transdiaphragmatic pressures, as well as electrical activity of the diaphragm were simultaneously recorded. The modified Wood clinical asthma score was also assessed. RESULTS: Median esophageal pressure-time product per minute was significantly lower in the prone position than in the supine position (227 cmH2O*s/minute [IQR, 156-282] cmH2O*s/minute vs 353 cmH2O*s/minute [IQR, 249-386 cmH2O*s/minute]; P = .048), as were the modified Wood clinical asthma score (P = .033) and electrical activity of the diaphragm (P = .006). The neuromechanical efficiency of the diaphragm, as assessed by transdiaphramagtic pressure to electrical activity of the diaphragm swing ratio, was significantly higher in the prone position than in the supine position (1.1 cmH2O/µV [IQR, 0.9-1.3 cmH2O/µV] vs 0.7 cmH2O/µV [IQR, 0.6-1.2 cmH2O/µV], respectively; P = .022). CONCLUSIONS: This study suggests a benefit of the prone position for infants with severe bronchiolitis requiring noninvasive ventilation by significantly decreasing the inspiratory effort and the metabolic cost of breathing. Further studies are needed to evaluate the potential impact of these physiological findings in a larger population. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02602678.