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).

Utility of Adult-Based Discoid Lateral Meniscus Diagnostic Criteria in a Pediatric Population.

Background: Commonly cited discoid lateral meniscus (DLM) imaging definitions are based on adult magnetic resonance imaging (MRI) measurements. This pathology commonly presents in pediatric populations; however, whether accepted adult measurements reliably apply to children and adolescents is unknown. Purpose/Hypothesis: This purposes of the study were to determine (1) the utility of applying adult-accepted MRI definitions of DLM to pediatric patients, (2) whether sex differences affect the applicability of the criteria, and (3) whether MRI magnet strength and/or tear presence affect MRI measurements for diagnosing DLM in pediatric patients. It was hypothesized that MRI criteria for DLM would be similar in adults and pediatric patients. Study Design: Case series; Level of evidence, 4. Methods: A total of 100 consecutive MRIs from pediatric patients with DLM were evaluated, with 91 scans included. Two study authors independently reviewed the MRIs, evaluating meniscal height and width on sagittal and coronal images, "bow tie signs" on sagittal images, tibial sagittal and coronal width, and tear presence. For analysis, MRI magnet strength was dichotomized into high (>1.5 T) and low (<1.5 T) groups. Results: The mean age of the patients at MRI evaluation was 12.3 ± 3.4 years; 51% of the patients were male, and 56% of the scans were of left knees. Included patients with DLM showed a mean of 3.68 bow tie signs, a sagittal total anterior to posterior meniscal width/tibial width ratio of 73%, a coronal meniscal width/tibial width ratio of 30%, and a coronal, transverse width of the lateral meniscus at the midportion of the meniscal body of 20.6 ± 7.7 mm. The MRI tesla strength of the images included in this study ranged from 0.3 to 3. It was determined that high- versus low-resolution MRI scans did not affect the inter- or intraobserver reliability of the MRI measurments (P > .05). However, several measurements showed improved intraclass correlation coefficients with increased tesla strength. Conclusion: This study confirms that pediatric patients with DLM, diagnosed by board-certified pediatric sports medicine orthopaedic surgeons, have measurements on MRI consistent with adult DLM diagnostic criteria. This finding held true regardless of sex or MRI tesla strength. Pediatric patients with DLM had >3 bow tie signs, >70% sagittal tibial plateau coverage, >14 mm coronal width, and >20% coronal tibial plateau coverage on MRI.

Patient-Reported Outcomes After Surgically Treated Anterior Horn Tears in the Pediatric Discoid Meniscus.

Background: As a subset of symptomatic discoid lateral meniscal (DLM) tears, anterior horn (AH) meniscal tears are not well studied in the pediatric population. There are even fewer studies reporting patient-reported outcomes after surgical treatment of AH tears in DLM. Purpose: To compare reported outcomes after surgical treatment of DLM tears involving the AH versus other locations in pediatric patients. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review of prospectively collected patient data between 2013 and 2020 was conducted. Patients aged <18 years who underwent arthroscopic treatment of a symptomatic DLM were included. Pathology was classified as tears of the AH or tears not involving the anterior horn (NAH). Demographic data along with patient-reported outcome scores (Pediatric International Knee Documentation Committee [Pedi-IKDC] and Patient Assessment Questionnaire [PAQ]) were collected preoperatively through 24 months of follow-up. Results: A total of 41 patients were included (median age, 12.9 years; range, 7-17 years; 32% female, 68% male). The mean follow-up time for was 25 months (range, 8-58 months). There were 17 (41%) patients in the AH group and 24 (59%) patients in the NAH group. Of the AH group, 16 (94%) were treated with meniscal repair (vs menisectomy), while 19 (79%) of the NAH group were treated with meniscal repair. All patients achieved significant pre- to postoperative improvement on both the Pedi-IKDC and the PAQ. At 24-month follow-up, there were no differences between the AH and NAH groups on the Pedi-IKDC (92.51 vs 89.72; P = .18) or the PAQ (2.57 vs 2.61; P = .06). Conclusion: Patients who underwent meniscal repair for AH DLM reported positive postoperative outcomes.

OXR1 maintains the retromer to delay brain aging under dietary restriction.

Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 is associated with aging and neurological diseases. mtd/OXR1 overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in preserving retromer function and is critical for neuronal health and longevity.

Tidal volume delivery during nasal intermittent positive pressure ventilation: infant cannula vs. nasal continuous positive airway pressure prongs.

OBJECTIVE: To measure tidal volume delivery during nasal intermittent positive pressure ventilation with two nasal interfaces: infant cannula and nasal prongs. STUDY DESIGN: A single-center crossover study of neonates with mild respiratory distress. Fifteen preterm neonates were randomized to initial interface of infant cannula or nasal prongs and monitored on a sequence of pressure settings first on the initial interface, then repeated on the alternate interface. We compared relative tidal volumes between the two interfaces with two-way repeated measures ANOVA during three breath types: synchronized (I), patient effort without ventilator breaths (II), and ventilator breaths without patient effort (III). Clinical trial #NCT04326270. RESULTS: Type III breaths delivered no significant tidal volume. No significant difference was measured in relative tidal volume delivery between the interfaces when breath types were matched. CONCLUSIONS: Nasal intermittent positive pressure ventilation delivers neither clinically nor statistically significant tidal volume with either infant cannula or nasal prongs.

Predicting extubation in patients with traumatic cervical spinal cord injury using the diaphragm electrical activity during a single maximal maneuver.

BACKGROUND: The unsuccessful extubation in patients with traumatic cervical spinal cord injuries (CSCI) may result from impairment diaphragm function and monitoring of diaphragm electrical activity (EAdi) can be informative in guiding extubation. We aimed to evaluate whether the change of EAdi during a single maximal maneuver can predict extubation outcomes in CSCI patients. METHODS: This is a retrospective study of CSCI patients requiring mechanical ventilation in the ICU of a tertiary hospital. A single maximal maneuver was performed by asking each patient to inhale with maximum strength during the first spontaneous breathing trial (SBT). The baseline (during SBT before maximal maneuver), maximum (during the single maximal maneuver), and the increase of EAdi (ΔEAdi, equal to the difference between baseline and maximal) were measured. The primary outcome was extubation success, defined as no reintubation after the first extubation and no tracheostomy before any extubation during the ICU stay. RESULTS: Among 107 patients enrolled, 50 (46.7%) were extubated successfully at the first SBT. Baseline EAdi, maximum EAdi, and ΔEAdi were significantly higher, and the rapid shallow breathing index was lower in patients who were extubated successfully than in those who failed. By multivariable logistic analysis, ΔEAdi was independently associated with successful extubation (OR 2.03, 95% CI 1.52-3.17). ΔEAdi demonstrated high diagnostic accuracy in predicting extubation success with an AUROC 0.978 (95% CI 0.941-0.995), and the cut-off value was 7.0 µV. CONCLUSIONS: The increase of EAdi from baseline SBT during a single maximal maneuver is associated with successful extubation and can help guide extubation in CSCI patients.

Neuronal Glycogen Breakdown Mitigates Tauopathy via Pentose Phosphate Pathway-Mediated Oxidative Stress Reduction.

Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Unfortunately, current treatment approaches for tauopathies have yielded limited success, underscoring the pressing need for novel therapeutic strategies. We observed distinct signatures of impaired glycogen metabolism in the Drosophila brain of the tauopathy model and the brain of AD patients, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen by activating glycogen phosphorylase (GlyP) ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC) derived neurons from FTD patients. We observed that glycogen breakdown redirects the glucose flux to the pentose phosphate pathway to alleviate oxidative stress. Our findings uncover a critical role for increased GlyP activity in mediating the neuroprotection benefit of dietary restriction (DR) through the cAMP-mediated protein kinase A (PKA) activation. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy treatment.

Relationship Between Age and Pathology With Treatment of Pediatric and Adolescent Discoid Lateral Meniscus: A Report From the SCORE Multicenter Database.

BACKGROUND: Surgical treatment options of discoid lateral meniscus in pediatric patients consist of saucerization with or without meniscal repair, meniscocapular stabilization, and, less often, subtotal meniscectomy. PURPOSE: To describe a large, prospectively collected multicenter cohort of discoid menisci undergoing surgical intervention, and further investigate corresponding treatment of discoid menisci. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A multicenter quality improvement registry (16 institutions, 26 surgeons), Sports Cohort Outcomes Registry, was queried. Patient characteristics, discoid type, presence and type of intrasubstance meniscal tear, peripheral rim instability, repair technique, and partial meniscectomy/debridement beyond saucerization were reviewed. Discoid meniscus characteristics were compared between age groups (<14 and >14 years old), based on receiver operating characteristic curve, and discoid morphology (complete and incomplete). RESULTS: In total, 274 patients were identified (mean age, 12.4 years; range, 3-18 years), of whom 55.6% had complete discoid. Meniscal repairs were performed in 55.1% of patients. Overall, 48.5% of patients had rim instability and 36.8% had >1 location of peripheral rim instability. Of the patients, 21.5% underwent meniscal debridement beyond saucerization, with 8.4% undergoing a subtotal meniscectomy. Patients <14 years of age were more likely to have a complete discoid meniscus (P < .001), peripheral rim instability (P = .005), and longitudinal tears (P = .015) and require a meniscal repair (P < .001). Patients ≥14 years of age were more likely to have a radial/oblique tear (P = .015) and require additional debridement beyond the physiologic rim (P = .003). Overall, 70% of patients <14 years of age were found to have a complete discoid meniscus necessitating saucerization, and >50% in this young age group required peripheral stabilization/repair. CONCLUSION: To preserve physiological "normal" meniscus, a repair may be indicated in >50% of patients <14 years of age but occurred in <50% of those >14 years. Additional resection beyond the physiological rim may be needed in 15% of younger patients and 30% of those aged >14 years.

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.

Reliability of MRI Interpretation of Discoid Lateral Meniscus: A Multicenter Study.

Background: Discoid lateral meniscus (DLM) has a varied and complex morphology that can be challenging to assess and treat. Preoperative magnetic resonance imaging (MRI) is frequently used for diagnosis and surgical planning; however, it is not known whether surgeons are reliable and accurate in their interpretation of MRI findings when defining the pathomorphology of DLM. Hypothesis: Surgeons experienced in treating DLM are able to reliably interpret DLM pathology using MRI. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: Knee MRI scans from 44 patients (45 knees) were selected from a pool of surgically treated patients with DLM. Five reviewers (fellowship-trained pediatric sports medicine surgeons) performed independent review of each MRI scan using the PRiSM Discoid Meniscus Classification. Inter- and intraobserver reliability of the rating factors-primary (width, height, presence of peripheral instability or tear) and secondary (location of instability or tear, tear type)-was assessed using the Fleiss κ coefficient, designed for multiple readers with nominal variables (fair reliability, 0.21-0.40; moderate, 0.41-0.60; substantial, 0.61-0.80; excellent, 0.81-1.00). Reliability is reported as κ (95% CI). Results: Interobserver reliability in assessing most primary and secondary characteristics ranged from substantial (meniscal width) to moderate (peripheral instability, anterior instability, posterior instability, and posterior tear). Intraobserver reliability for most characteristics ranged from substantial (peripheral instability, presence of tear, anterior instability, posterior instability, and posterior tear) to moderate (meniscal width, anterior tear, and tear type). Notable exceptions were presence of tear, anterior tear, and tear type-all with fair interobserver reliability. Height had poor interobserver reliability and fair intraobserver reliability. Conclusion: Orthopaedic surgeons reliably interpret MRI scans using the PRiSM Discoid Meniscus Classification for the majority of DLM characteristics but vary in their assessment of height and presence and type of tear. MRI evaluation may be helpful to diagnose discoid by width and identify the presence of instability: 2 major factors in the decision to proceed with surgery. Arthroscopic evaluation should be used in conjunction with MRI findings for complete DLM diagnosis.

From CO2 to DME: Enhancement through Heteropoly Acids from a Catalyst Screening and Stability Study.

The direct synthesis of dimethyl ether (DME) via CO2 hydrogenation in a single step was studied using an improved class of bifunctional catalysts in a fixed bed reactor (T R: 210-270 °C; 40 bar; gas hourly space velocity (GHSV) 19,800 NL kgcat -1 h-1; ratio CO2/H2/N2 3:9:2). The competitive bifunctional catalysts tested in here consist of a surface-basic copper/zinc oxide/zirconia (CZZ) methanol-producing part and a variable surface-acidic methanol dehydration part and were tested in overall 45 combinations. As dehydration catalysts, zeolites (ferrierite and ß-zeolite), alumina, or zirconia were tested alone as well as with a coating of Keggin-type heteropoly acids (HPAs), i.e., silicotungstic or phosphotungstic acid. Two different mixing methods to generate bifunctional catalysts were tested: (i) a single-grain method with intensive intra-particular contact between CZZ and the dehydration catalyst generated by mixing in an agate mortar and (ii) a dual-grain approach relying on physical mixing with low contact. The influence of the catalyst mixing method and HPA loading on catalyst activity and stability was investigated. From these results, a selection of best-performing bifunctional catalysts was investigated in extended measurements (time on stream: 160 h/7 days, T R: 250 and 270 °C; 40 bar; GHSV 19,800 NL kgcat -1 h-1; ratio CO2/H2/N2 3:9:2). Silicotungstic acid-coated bifunctional catalysts showed the highest resilience toward deactivation caused by single-grain preparation and during catalysis. Overall, HPA-coated catalysts showed higher activity and resilience toward deactivation than uncoated counterparts. Dual-grain preparation showed superior performance over single grain. Furthermore, silicotungstic acid coatings with 1 KU nm-2 (Keggin unit per surface area of carrier) on Al2O3 and ZrO2 as carrier materials showed competitive high activity and stability in extended 7-day measurements compared to pure CZZ. Therefore, HPA coating is found to be a well-suited addition to the CO2-to-DME catalyst toolbox.

Feasibility and Safety of Personalized, Multi-Target, Adoptive Cell Therapy (IMA101): First-in-Human Clinical Trial in Patients with Advanced Metastatic Cancer.

IMA101 is an actively personalized, multi-targeted adoptive cell therapy (ACT), whereby autologous T cells are directed against multiple novel defined peptide-HLA (pHLA) cancer targets. HLA-A*02:01-positive patients with relapsed/refractory solid tumors expressing ≥1 of 8 predefined targets underwent leukapheresis. Endogenous T cells specific for up to 4 targets were primed and expanded in vitro. Patients received lymphodepletion (fludarabine, cyclophosphamide), followed by T-cell infusion and low-dose IL2 (Cohort 1). Patients in Cohort 2 received atezolizumab for up to 1 year (NCT02876510). Overall, 214 patients were screened, 15 received lymphodepletion (13 women, 2 men; median age, 44 years), and 14 were treated with T-cell products. IMA101 treatment was feasible and well tolerated. The most common adverse events were cytokine release syndrome (Grade 1, n = 6; Grade 2, n = 4) and expected cytopenias. No patient died during the first 100 days after T-cell therapy. No neurotoxicity was observed. No objective responses were noted. Prolonged disease stabilization was noted in three patients lasting for 13.7, 12.9, and 7.3 months. High frequencies of target-specific T cells (up to 78.7% of CD8+ cells) were detected in the blood of treated patients, persisted for >1 year, and were detectable in posttreatment tumor tissue. Individual T-cell receptors (TCR) contained in T-cell products exhibited broad variation in TCR avidity, with the majority being low avidity. High-avidity TCRs were identified in some patients' products. This study demonstrates the feasibility and tolerability of an actively personalized ACT directed to multiple defined pHLA cancer targets. Results warrant further evaluation of multi-target ACT approaches using potent high-avidity TCRs. See related Spotlight by Uslu and June, p. 865.

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.

Continuous Electrospray Ionization Mass Spectrometry Assay for Measuring Phospholipase Activity against Liposomes.

Phospholipases have diverse roles in lipid and cell membrane biology. In animal venoms, they can have roles as neurotoxins or myotoxins that disrupt the integrity of cell membranes. In this work, we describe a temperature-controlled, continuous electrospray ionization mass spectrometry (ESI-MS) assay for measuring phospholipase A2 activity against liposomes. The enzyme used in this assay was paradoxin, which is a neurotoxic trimeric phospholipase A2 from inland taipan snake venom. Previously developed ESI-MS-based phospholipase assays have been discontinuous and analyzed hydrolysis of single lipid molecules by liquid chromatography ESI-MS. In this work, a continuous assay was developed against liposomes, a more complex substrate that more closely reflects the natural substrate for paradoxin. The assay confirmed the requirement for Ca2+ and allowed measurement of Michaelis-Menten-type parameters. The use of ESI-MS for lipid detection enabled nuanced insights into the effect of changing assay conditions not only on the enzyme but also on the liposome substrate. Changing the metal ion concentrations did not significantly change the liposomes but did affect enzymatic activity. Increasing temperature did not substantially affect the secondary structure of paradoxin but affected liposome size, resulting in increased enzymatic activity consistent with the disruption of the phosphatidylcholine membrane, increasing accessibility of sn-2 ester bonds. The continuous ESI-MS method described herein can be applied to other enzyme reactions, particularly those which utilize complex lipid substrates.

First Rib Stress Fracture in an Adolescent Elite Tennis Player: A Case Report.

CASE: A 16-year-old, right-hand-dominant, Asian male, elite tennis player presented to the clinic with a 1-month history of left shoulder pain. Originally, the pathology was believed to be shoulder-based, but lack of improvement after several weeks of therapy warranted further imaging, which ultimately revealed a nondisplaced fracture of the posterior left first rib. CONCLUSION: Stress injuries are not uncommon in the sport of tennis, but atraumatic rib fractures are rare. Given the increase in youth sports specialization and overtraining and other risk factors such as adolescent age and race, it is important to keep rib stress fracture on the differential.

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.

Age, Sex, and BMI Differences Related to Repairable Meniscal Tears in Pediatric and Adolescent Patients.

BACKGROUND: The incidence of meniscus tears and ACL tears in pediatric patients continues to rise, bringing to question the risk factors associated with these injuries. As meniscus tears are commonly repaired in pediatric populations, the epidemiology of repairable meniscus tears is an important for consideration for surgeons evaluating treatment options. PURPOSE: To describe meniscal tear patterns in pediatric and adolescent patients who underwent meniscal repair across multiple institutions and surgeons, as well as to evaluate the relationship between age, sex, and body mass index (BMI) and their effect on the prevalence, type, and displacement of repaired pediatric meniscal tears. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Data within a prospective multicenter cohort registry for quality improvement, Sport Cohort Outcome Registry (SCORE), were reviewed to describe repaired meniscal tear patterns. All consecutive arthroscopic meniscal repairs from participating surgeons in patients aged <19 years were analyzed. Tear pattern, location, and displacement were evaluated by patient age, sex, and BMI. A subanalysis was also performed to investigate whether meniscal tear patterns differed between those occurring in isolation or those occurring with a concomitant anterior cruciate ligament (ACL) injury. Analysis of variance was used to generate a multivariate analysis of specified variables. Sex, age, and BMI results were compared across the cohort. RESULTS: There were 1185 total meniscal repairs evaluated in as many patients, which included 656 (55.4%) male and 529 (44.6%) female patients. Patients underwent surgery at a mean age of 15.3 years (range, 5-19 years), with a mean BMI of 24.9 (range, 12.3-46.42). Of the 1185 patients, 816 (68.9%) had ACL + meniscal repair and 369 (31.1%) had isolated meniscal repair. The male patients underwent more lateral tear repairs than the female patients (54.3% to 40.9%; P < .001) and had a lower incidence of medial tear repair (32.1% vs 41.4%; P < .001). Patients with repaired lateral tears had a mean age of 15.0 years, compared with a mean age of 15.4 years for patients with repaired medial or bilateral tears (P = .001). Higher BMI was associated with "complex" and "radial" tear repairs of the lateral meniscus (P < .001) but was variable with regard to medial tear repairs. CONCLUSION: In pediatric and adolescent populations, the data suggest that the surgical team treating knees with potential meniscal injury should be prepared to encounter more complex meniscal tears, commonly indicated in those with higher BMI, while higher rates of lateral meniscal tears were seen in male and younger patients. Future studies should analyze correlates for meniscal repair survival and outcomes in this pediatric cohort undergoing knee surgery.

First-in-Human Study of OBI-999, a Globo H-Targeting Antibody-Drug Conjugate, in Patients With Advanced Solid Tumors.

PURPOSE: OBI-999 is a novel antibody-drug conjugate comprising the Globo H-targeting antibody (OBI-888) linked to the cytotoxic payload monomethyl auristatin E. OBI-999 demonstrated excellent dose-dependent tumor growth inhibition in breast, gastric, and pancreatic cancer xenograft models as well as a lung cancer patient-derived xenograft model. We conducted a phase I study of OBI-999 monotherapy in patients with advanced cancer (ClinicalTrials.gov identifier: NCT04084366). PATIENTS AND METHODS: OBI-999 was administered intravenously at doses of 0.4, 0.8, 1.2, and 1.6 mg/kg every 21 days as part of a 3 + 3 trial design. Primary end points were the incidence of dose-limiting toxicities and adverse events and determination of the maximum tolerated dose (MTD)/recommended phase II dose. RESULTS: Fifteen adult patients were treated. OBI-999 was well tolerated up to 1.2 mg/kg, the maximum tolerated dose. The most common treatment-emergent adverse events were neutropenia and anemia. OBI-999 exhibited nonlinear pharmacokinetics at all doses, with lower clearance at higher doses. The three patients treated at the 1.6 mg/kg dose level developed grade 4 neutropenia during cycles 1 and 2. Five (33.3%) patients had stable disease (SD) including one patient with adenoid cystic carcinoma of the oropharynx with SD for 13 cycles and one patient with gastroesophageal junction adenocarcinoma with SD for eight cycles. OBI-999 was well tolerated; however, dose-dependent, noncumulative neutropenia was dose-limiting. CONCLUSION: The recommended phase II dose was determined to be 1.2 mg/kg once every 3 weeks. A phase II cohort-expansion study is now enrolling patients with pancreatic, colorectal, and other cancers expressing high levels of Globo H.

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).