Influence of test paradigm on loading dynamics during proximal femur fracture tests simulating sideways falls.

Fall-related hip fractures are a serious public health issue in older adults. As most mechanistic hip fracture risk prediction models incorporate tissue tolerance, test methods that can accurately characterize the fracture force of the femur (and factors that influence it) are imperative. While bone possesses viscoelastic properties, experimental characterization of rate-dependencies has been inconsistent in the whole-femur literature. The goal of this study was to investigate the influence of experimental paradigm on loading rate and fracture force (both means and variability) during mechanical tests simulating lateral fall loadings on the proximal femur. Six pairs of matched femurs were split randomly between two test paradigms: a 'lower rate' materials testing system (MTS) with a constant displacement rate of 60 mm/s, and a hip impact test system (HIT) comprised of a custom-built vertical drop tower utilizing an impact velocity of 4 m/s. The loading rate was 88-fold higher for the HIT (mean (SD) = 2465.49 (807.38) kN/s) compared to the MTS (27.78 (10.03) kN/s) paradigm. However, no difference in fracture force was observed between test paradigms (mean (SD) = 4096.4 (1272.6) N for HIT, and 3641.3 (1285.8) N for MTS). Within-paradigm variability was not significantly different across paradigms for either loading rate or fracture force (coefficients of variation ranging from 0.311 to 0.361). Within each test paradigm, significant positive relationships were observed between loading rate and fracture force (HIT adjusted R2 = 0.833, p = 0.007; MTS adjusted R2 = 0.983, p < 0.0001). Overall, this study provides evidence that energy-based impact simulators can be a valid method to measure femoral bone strength in the context of fall-related hip fractures. This study motivates future research to characterize potential non-linear relationships between loading rate and fracture threshold at both macro and microscales.

A kinematically complex multi-articular motor skill for investigating implicit motor learning.

Here we present a task developed to probe implicit learning of a complex motor skill. This task addresses limitations related to task complexity noted in the literature for methods investigating implicit motor learning, namely the serial reaction time task and continuous tracking task. Specifically, the serial reaction time task is limited by the kinematic simplicity of the required movement and the continuous tracing task faces time-on-task confounds and limitations in the control of task difficulty. The task presented herein addresses these issues by employing a kinematically complex multi-articular movement that controls factors that contribute to task difficulty: stimulus animation velocity and trajectory complexity. Accordingly, our objective was to validate the use of this task in probing implicit motor learning, hypothesizing that participants would learn one of the repeating stimuli implicitly. Participants engaged in six blocks of training whereby they first observed and then reproduced a seemingly random complex trajectory. Repeated trajectories were embedded amongst random trajectories. In line with the hypothesis, error for the repeated trajectories was decreased in comparison to that observed for the random trajectories and 73% of participants were unable to identify one of the repeated trajectories, demonstrating the occurrence of implicit learning. While the task requires minor alteration to optimize learning, ultimately the findings underline the task's potential to investigate implicit learning of a complex motor skill.

Heterogeneity of mature oligodendrocytes in the central nervous system.

ABSTRACT: Mature oligodendrocytes form myelin sheaths that are crucial for the Insulation of axons and efficient signal transmission in the central nervous system. Recent evidence has challenged the classical view of the functionally static mature oligodendrocyte and revealed a gamut of dynamic functions such as the ability to modulate neuronal circuitry and provide metabolic support to axons. Despite the recognition of potential heterogeneity in mature oligodendrocyte function, a comprehensive summary of mature oligodendrocyte diversity is lacking. We delve into early 20th-century studies by Robertson and Río-Hortega that laid the foundation for the modern identification of regional and morphological heterogeneity in mature oligodendrocytes. Indeed, recent morphologic and functional studies call into question the long-assumed homogeneity of mature oligodendrocyte function through the identification of distinct subtypes with varying myelination preferences. Furthermore, modern molecular investigations, employing techniques such as single cell/nucleus RNA sequencing, consistently unveil at least six mature oligodendrocyte subpopulations in the human central nervous system that are highly transcriptomically diverse and vary with central nervous system region. Age and disease related mature oligodendrocyte variation denotes the impact of pathological conditions such as multiple sclerosis, Alzheimer's disease, and psychiatric disorders. Nevertheless, caution is warranted when subclassifying mature oligodendrocytes because of the simplification needed to make conclusions about cell identity from temporally confined investigations. Future studies leveraging advanced techniques like spatial transcriptomics and single-cell proteomics promise a more nuanced understanding of mature oligodendrocyte heterogeneity. Such research avenues that precisely evaluate mature oligodendrocyte heterogeneity with care to understand the mitigating influence of species, sex, central nervous system region, age, and disease, hold promise for the development of therapeutic interventions targeting varied central nervous system pathology.

Circadian regulation of locomotion, respiration, and arousability in adult blacklegged ticks (Ixodes scapularis).

The blacklegged tick, Ixodes scapularis, is an ectoparasitic arachnid and vector for infectious diseases, including Lyme borreliosis. Here, we investigate the diurnal activity and respiration of wild-caught and lab-reared adult ticks with long-term video recording, multi-animal tracking and high-resolution respirometry. We find male and female ticks are in a more active, more arousable state during circadian night. We find respiration is augmented by light, with dark onset triggering more frequent bouts of discontinuous gas exchange and a higher overall volume of CO2 respired. Observed inactivity during the day meets the criteria of sleep: homeostatic in nature, rapidly reversible, a characteristic pose, and reduced arousal threshold. Our findings indicate that blacklegged ticks are in a distinct, heightened state of activity and arousability during night and in dark, suggesting this period may carry higher risk for tick bites and subsequent contraction of tick-borne diseases.

Biological and therapeutic insights from animal modeling of fusion-driven pediatric soft tissue sarcomas.

Survival for children with cancer has primarily improved over the past decades due to refinements in surgery, radiation and chemotherapy. Although these general therapies are sometimes curative, the cancer often recurs, resulting in poor outcomes for patients. Fusion-driven pediatric soft tissue sarcomas are genetically defined by chromosomal translocations that create a chimeric oncogene. This distinctive, almost 'monogenic', genetic feature supports the generation of animal models to study the respective diseases in vivo. This Review focuses on a subset of fusion-driven pediatric soft tissue sarcomas that have transgenic animal tumor models, which includes fusion-positive and infantile rhabdomyosarcoma, synovial sarcoma, undifferentiated small round cell sarcoma, alveolar soft part sarcoma and clear cell sarcoma. Studies using the animal models of these sarcomas have highlighted that pediatric cancers require a specific cellular state or developmental stage to drive tumorigenesis, as the fusion oncogenes cause different outcomes depending on their lineage and timing of expression. Therefore, understanding these context-specific activities could identify targetable activities and mechanisms critical for tumorigenesis. Broadly, these cancers show dependencies on chromatin regulators to support oncogenic gene expression and co-opting of developmental pathways. Comparative analyses across lineages and tumor models will further provide biological and therapeutic insights to improve outcomes for these children.

Evaluation of the biodistribution and preliminary safety profile of a novel brain-targeted manganese dioxide-based nanotheranostic system for Alzheimer's disease.

A novel brain-targeted and reactive oxygen species-activatable manganese dioxide containing nanoparticle system functionalized with anti-amyloid-ß antibody (named aAß-BTRA-NC) developed by our group has shown great promise as a highly selective magnetic resonance imaging (MRI) contrast agent for early detection and multitargeted disease-modifying treatment of Alzheimer's disease (AD). To further evaluate the suitability of the formulation for future clinical application, we investigated the safety, biodistribution, and pharmacokinetic profile of aAß-BTRA-NC in a transgenic TgCRND8 mouse AD model, wild type (WT) littermate, and CD-1 mice. Dose-ascending studies demonstrated that aAß-BTRA-NC was well-tolerated by the animals up to 300 µmol Mn/kg body weight [b.w.], 3 times the efficacious dose for early AD detection without apparent adverse effects; Histopathological, hematological, and biochemical analyses indicated that a single dose of aAß-BTRA-NC did not cause any toxicity in major organs. Immunotoxicity data showed that aAß-BTRA-NC was safer than commercially available gadolinium-based MRI contrast agents at an equivalent dose of 100 µmol/kg b.w. of metal ions. Intravenously administered aAß-BTRA-NC was taken up by main organs with the order of liver, kidneys, intestines, spleen, followed by other organs, and cleared after one day to one week post injection. Pharmacokinetic analysis indicated that the plasma concentration profile of aAß-BTRA-NC followed a 2-compartmental model with faster clearance in the AD mice than in the WT mice. The results suggest that aAß-BTRA-NC exhibits a strong safety profile as a nanotheranostic agent which warrants more robust preclinical development for future clinical applications.

Traditional versus dynamic sitting: Lumbar spine kinematics and pain during computer work and activity guided tasks.

Dynamic sitting may mitigate low back pain during prolonged seated work. The current study compared pelvis and lumbar spine kinematics, pain, and work productivity, in traditional and dynamic sitting. Sixteen participants completed three 20-min blocks of computer work and activity guided tasks in a traditional office chair or backless and multiaxial rotating seat pan while kinematics were measured from accelerometers on the low back. Pain ratings were recorded on a visual analogue scale every 10 min. Similar pelvis and lumbar kinematics emerged when performing computer work in traditional and dynamic sitting. Pelvis and lumbar sagittal and frontal plane shifts and fidgets were largest for dynamic sitting in the activity guided tasks. Buttocks pain was higher in dynamic sitting, but low back pain and work productivity were unaffected. Dynamic sitting increased spine movement during activity guided tasks, without negatively impacting lumbar kinematics, low back pain, or productivity during seated computer work.

The NLRP3 inflammasome is essential for IL-18 production in a model of macrophage activation syndrome.

Hyperinflammatory disease is associated with an aberrant immune response resulting in cytokine storm. One such instance of hyperinflammatory disease is known as macrophage activation syndrome (MAS). The pathology of MAS can be characterised by significantly elevated serum levels of interleukin (IL)-18 and interferon (IFN)-γ. Given the role for IL-18 in MAS, we sought to establish the role of inflammasomes in the disease process. Using a murine model of CpG-DNA induced MAS, we discovered that the expression of the NLRP3 inflammasome was increased and correlated with IL-18 production. Inhibition of the NLRP3 inflammasome, or downstream caspase-1, prevented MAS-mediated upregulation of plasma IL-18 but interestingly did not alleviate key features of hyperinflammatory disease including hyperferritinaemia and splenomegaly. Furthermore IL-1 receptor blockade with IL-1Ra did not prevent the development of CpG-induced MAS, despite being clinically effective in the treatment of MAS. These data demonstrate that in the development of MAS, the NLRP3 inflammasome was essential for the elevation in plasma IL-18, a key cytokine in clinical cases of MAS, but was not a driving factor in the pathogenesis of CpG-induced MAS.

Plasmid targeting and destruction by the DdmDE bacterial defence system.

Although eukaryotic Argonautes have a pivotal role in post-transcriptional gene regulation through nucleic acid cleavage, some short prokaryotic Argonaute variants (pAgos) rely on auxiliary nuclease factors for efficient foreign DNA degradation1. Here we reveal the activation pathway of the DNA defence module DdmDE system, which rapidly eliminates small, multicopy plasmids from the Vibrio cholerae seventh pandemic strain (7PET)2. Through a combination of cryo-electron microscopy, biochemistry and in vivo plasmid clearance assays, we demonstrate that DdmE is a catalytically inactive, DNA-guided, DNA-targeting pAgo with a distinctive insertion domain. We observe that the helicase-nuclease DdmD transitions from an autoinhibited, dimeric complex to a monomeric state upon loading of single-stranded DNA targets. Furthermore, the complete structure of the DdmDE-guide-target handover complex provides a comprehensive view into how DNA recognition triggers processive plasmid destruction. Our work establishes a mechanistic foundation for how pAgos utilize ancillary factors to achieve plasmid clearance, and provides insights into anti-plasmid immunity in bacteria.

Can environmental traffic light warning labels reduce meat meal selection? A randomised experimental study with UK meat consumers.

An important area for tackling climate change and health improvement is reducing population meat consumption. Traffic light labelling has successfully been implemented to reduce the consumption of unhealthy foods and sugary drinks. The present research extends this work to meat selection. We tested 1,300 adult UK meat consumers (with quotas for age and gender to approximate a nationally representative sample). Participants were randomised into one of four experimental groups: (1) a red traffic light label with the text 'High Climate Impact' displayed on meat meal options only; (2) a green traffic light label with the text 'Low Climate Impact' displayed on vegetarian and vegan meal options only; (3) red/orange/green (ROG) traffic light labels displayed on relevant meals; and (4) control (no label present). Participants made meal selections within their randomised group across 20 meal trials. A beta-regression was performed to ascertain the change in primary outcome (proportion of meat meals selected across the 20 trials) across the different groups. The red-only label and ROG labels significantly reduced the proportion of meat meals selected compared to the unlabelled control group, by 9.2% and 9.8% respectively. The green-only label did not differ from control. Negatively framed traffic light labels seem to be effective at discouraging meat selection. The labels appeared to be moderately acceptable to meat eaters, who did not think the labels impacted the appeal of the products. These encouraging findings require replication in real-life settings.

Detection of Alteration in Carotid Artery Volumetry Using Standard-of-care Computed Tomography Surveillance Scans Following Unilateral Radiation Therapy for Early-stage Tonsillar Squamous Cell Carcinoma Survivors: A Cross-Sectional Internally-Matched Carotid Isodose Analysis.

Purpose: Radiation induced carotid artery disease (RICAD) is a major cause of morbidity and mortality among survivors of oropharyngeal cancer. This study leveraged standard-of-care CT scans to detect volumetric changes in the carotid arteries of patients receiving unilateral radiotherapy (RT) for early tonsillar cancer, and to determine dose-response relationship between RT and carotid volume changes, which could serve as an early imaging marker of RICAD. Methods and Materials: Disease-free cancer survivors (>3 months since therapy and age >18 years) treated with intensity modulated RT for early (T1-2, N0-2b) tonsillar cancer with pre- and post-therapy contrast-enhanced CT scans available were included. Patients treated with definitive surgery, bilateral RT, or additional RT before the post-RT CT scan were excluded. Pre- and post-treatment CTs were registered to the planning CT and dose grid. Isodose lines from treatment plans were projected onto both scans, facilitating the delineation of carotid artery subvolumes in 5 Gy increments (i.e. received 50-55 Gy, 55-60 Gy, etc.). The percent-change in sub-volumes across each dose range was statistically examined using the Wilcoxon rank-sum test. Results: Among 46 patients analyzed, 72% received RT alone, 24% induction chemotherapy followed by RT, and 4% concurrent chemoradiation. The median interval from RT completion to the latest, post-RT CT scan was 43 months (IQR 32-57). A decrease in the volume of the irradiated carotid artery was observed in 78% of patients, while there was a statistically significant difference in mean %-change (±SD) between the total irradiated and spared carotid volumes (7.0±9.0 vs. +3.5±7.2, respectively, p<.0001). However, no significant dose-response trend was observed in the carotid artery volume change withing 5 Gy ranges (mean %-changes (±SD) for the 50-55, 55-60, 60-65, and 65-70+ Gy ranges [irradiated minus spared]: -13.1±14.7, -9.8±14.9, -6.9±16.2, -11.7±11.1, respectively). Notably, two patients (4%) had a cerebrovascular accident (CVA), both occurring in patients with a greater decrease in carotid artery volume in the irradiated vs the spared side. Conclusions: Our data show that standard-of-care oncologic surveillance CT scans can effectively detect reductions in carotid volume following RT for oropharyngeal cancer. Changes were equivalent between studied dose ranges, denoting no further dose-response effect beyond 50 Gy. The clinical utility of carotid volume changes for risk stratification and CVA prediction warrants further evaluation.

Clinical Developments and Challenges in Treating FGFR2-Driven Gastric Cancer.

Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement in survival outcomes; however, metastatic GC remains a lethal malignancy and amongst the leading causes of cancer-related mortality worldwide. Importantly, the ongoing molecular characterisation of GCs continues to uncover potentially actionable molecular targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from FGFR2 amplification, occurs in approximately 3-11% of GCs. However, whilst several inhibitors of FGFR have been clinically tested to-date, there are currently no approved FGFR-directed therapies for GC. In this review, we summarise the significance of FGFR2 as an actionable therapeutic target in GC, examine the recent pre-clinical and clinical data supporting the use of small-molecule inhibitors, antibody-based therapies, as well as novel approaches such as proteolysis-targeting chimeras (PROTACs) for targeting FGFR2 in these tumours, and discuss the ongoing challenges and opportunities associated with their clinical development.

Experimentally Dissociating the Acute Mechanisms of Endplate Fracture Lesions and Schmorl's node Injuries Using a Porcine Cervical Spine Model.

STUDY DESIGN: In vitro biomechanical study. OBJECTIVE: This study evaluated the influence of localized trabecular bone strength deficits and loading rate as determinants of Schmorl's node and fracture lesion incidence. The failure load (ultimate compression tolerance (UCT)), loading stiffness, and failure morphology were assessed after acute compression loading and failure. SUMMARY OF BACKGROUND DATA: The cartilaginous endplate is vulnerable to injuries such as Schmorl's nodes and fracture lesions. While both injuries are associated with acute compression traumas, the factors that distinguish their incidence are poorly understood. METHODS: Forty-eight porcine spinal units (domestic hog, 5 - 10 months, ~110 kg) were assigned to one of eight experimental groups that differed by initial condition (control, sham, experimentally produced chemical fragility, structural void) and loading rate (3 kN/s, 9kN/s). A servo-hydraulic materials testing system was used to perform acute compression testing until observed failure in the specimen. Post-loading dissection was performed to classify injury morphologies. Between group differences in UCT and loading stiffness were evaluated using a general linear model and injury distributions were evaluated using chi-squared statistics. RESULTS: Schmorl's nodes occurred exclusively in chemical fragility (63%) and structural void groups (37%) and were more prevalent with a 9 kN/s (75%) loading rate, compared to 3 kN/s (25%). In contrast, fracture lesions occurred in all FSUs assigned to the control groups (100%) and the majority of those assigned to the sham groups (92%). No between-group differences were observed for UCT and loading stiffness. CONCLUSION: Pre-existing strength deficits of the subchondral trabecular bone can alter endplate injury morphology, particularly when coupled with high loading rates, but the localized strength deficits that were associated with Schmorl's nodes did not appreciably influence measured joint properties.

Intraoperative Augmented Reality for Complex Glioma Resection: A Case Report.

Augmented reality (AR) is an emerging technology that can display three-dimensional patient anatomy in the surgeons' field of view. The use of this technology has grown considerably for both presurgical and intraoperative guidance. A patient diagnosed with breast cancer started to experience numbness in the left hand, which progressed to weakness in the left hand and arm. An MRI was performed demonstrating a 2.9 cm X 1.8 cm lesion with extensive surrounding edema in the posterior fronto-parietal lobes. Surgery was recommended for presumed metastatic disease. Preoperatively, an AR system and Brainlab navigation were registered to the patient. AR, traditional navigation, and ultrasound were all used to localize the lesion and determine the craniotomy site and size. The tumor was removed along the direction of the lesion. Intraoperatively, we used AR to reexamine the tumor details and could appreciate that we had to redirect our surgical trajectory anteriorly and laterally in order to follow along the main axis of the tumor. In doing this, we were able to more confidently remain with the tumor, which by this time was poorly defined by 2D navigation and by direct vision. Postoperative MRI confirmed gross total removal of the tumor. The patient had an uneventful postoperative course with resolution of preoperative symptoms and the final surgical pathology was grade 4 glioblastoma. Here, we describe the valuable use of AR for the resection of a glioma. The system has a seamless registration process and provides the surgeon with a unique view of 3D anatomy overlaid onto the patient's head. This exciting technology can add tremendous value to complex cranial surgeries.

Lateral Pelvis and Lumbar Motion in Seated and Standing Office Work and Their Association With Transient Low Back Pain.

OBJECTIVE: To assess frontal plane motion of the pelvis and lumbar spine during 2 h of seated and standing office work and evaluate associations with transient low back pain. BACKGROUND: Although bending and twisting motions are cited as risk factors for low back injuries in occupational tasks, few studies have assessed frontal plane motion during sedentary exposures. METHODS: Twenty-one participants completed 2 h of seated and standing office work while pelvic obliquity, lumbar lateral bending angles, and ratings of perceived low back pain were recorded. Mean absolute angles were compared across 15-min blocks, amplitude probability distribution functions were calculated, and associations between lateral postures and low back pain were evaluated. RESULTS: Mean pelvic obliquity (sit = 4.0 ± 2.8°, stand = 3.5 ± 1.7°) and lumbar lateral bending (sit = 4.5 ± 2.5°, stand = 4.1 ± 1.6°) were consistently asymmetrical. Pelvic obliquity range of motion was 4.7° larger in standing (13.6 ± 7.5°) than sitting (8.9 ± 8.7°). In sitting, 52% (pelvis) and 71% (lumbar) of participants, and in standing, 71% (pelvis and lumbar) of participants, were considered asymmetric for >90% of the protocol. Lateral postures displayed weak to low correlations with peak low back pain (R ≤ 0.388). CONCLUSION: The majority of participants displayed lateral asymmetries for the pelvis and lumbar spine within 5° of their upright standing posture. APPLICATION: In short-term sedentary exposures, associations between lateral postures and pain indicated that as the range in lateral postures increases there may be an increased possibility of pain.

Examining biopsychosocial predictors of risk for cognitive impairment among a racially diverse sample of men who have sex with men living with HIV.

Background: Cognitive decline among people living with HIV (PLWH) is growing concern as world populations become increasing older including higher proportions of PLWH. It is vitally important to understand psychosocial predictors of age-related cognitive decline men who have sex with men (MSM) living with HIV. Objectives: The current study seeks to examine psychosocial risk factors the contribute to the risk of age-related cognitive impairment as measured by Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score in a racially diverse sample of MSM living with HIV. Design: The present analysis utilizes data from the baseline (n = 196) and 6-month follow-up (n = 135) time points of a longitudinal cohort study of PLWH. Methods: Using a self-report survey, we examine the associations between psychosocial predictors (e.g. trauma, mental health, chronic pain, sleep disturbance, etc.) and risk of dementia using the CAIDE risk score. Analyses include linear and logistic regression. Results: In adjusted model stress, chronic pain, Black racial identity, and having a sexual identity that is bisexual or another category are all positively associated with CAIDE scores. Childhood sexual abuse history was negatively associated with CAIDE scores indicating a protective effect. Sleep disorder has a positive association with CAIDE scores after adjusting for the baseline CAIDE scores. Conclusion: These results indicate modifiable correlates of cognitive risk (stress and chronic pain). Interventions should seek to address these comorbid factors including the consideration of minority stress and stigma. Interventions should seek to reach Black and bisexual men living with HIV, including possible cultural tailoring to interventions and messaging. Lastly, future research should examine the impact of variation within childhood sexual abuse histories to better understand their association with cognitive impairment later in life. This may include considering the nature, severity, and potential treatment of trauma symptoms.

What makes middle-aged or older people who have HIV more likely to have memory problems later in life? We asked a racially diverse group of gay and bisexual men who have HIV. Why was the study done? Older people are becoming a larger portion of our communities including older people living with HIV. It's important to understand what makes older people more likely to have memory problems as they age including older people living with HIV. What did the researchers do? We asked 196 middle-aged and older adults who have HIV to answer questions about their health including things that we know might make them more likely to have memory problems later in life. What did the researchers find? We found that having more stress or reoccurring pain was related to being more likely to have memory problems later in life. People who have trouble sleeping were more likely to have memory problems later in life. We also found that Black people were more likely to have memory problems later in life. People who had been abused sexually as children were less likely to have memory problems later in life. What do the findings mean? These findings help us understand things that may make someone more likely to have memory problems later in life. These include things that could be changed like reoccurring pain and troubles sleeping. It also highlighted that Black people may need more support to prevent memory problems later in life.

Exploring the Influence of Facet Orientation and Tropism on Neutral Zone Properties.

Lumbar spine pathologies have been linked independently to both neutral zone (NZ) properties and facet joint anatomical characteristics; however, the effect of facet joint orientation (FO) and tropism (FT) on NZ properties remains unclear. The aim of the present study was to investigate how axial plane FO and FT relate to NZ range and stiffness in the human lumbar spine and porcine cervical spine. Seven human lumbar functional spine units (FSUs) and 94 porcine cervical FSUs were examined. FO and FT were measured, and in vitro mechanical testing was used to determine anterior-posterior (AP) and flexion-extension (FE) NZ range and stiffness. FO and FT were found to have no significant relationship with AP and FE NZ range. Increases in FT were associated with greater FE and AP NZ stiffness in human FSUs, with no FT-NZ stiffness relationship observed in porcine specimens. A significant relationship (p < 0.001) between FO and FE NZ stiffness was observed for both porcine and human FSUs, with a more sagittal orientation of the facet joints being associated with decreased FE NZ stiffness. Given the link between NZ stiffness and pathological states of the lumbar spine, further research is warranted to determine the practical significance of the observed facet joint anatomical characteristic-NZ property relationship.

Implementing Change: Sustaining Enhanced Recovery After Surgery Protocols in Pediatric Surgery Using Iterative Assessments.

INTRODUCTION: While Enhanced Recovery After Surgery (ERAS) protocols are becoming more common in pediatric surgery, there is still little published about protocol compliance and sustainability. METHODS: This is a prospective observational study to evaluate the compliance of an ERAS protocol for pectus repair at a large academic children's hospital. Our primary outcome was overall protocol compliance at 1-y postimplementation of the ERAS protocol. Our comparison group included all pectus repairs for 2 y before protocol implementation. RESULTS: Overall protocol compliance at 12 mo was 89%. Of the 16 pectus repairs included in the ERAS protocol group, 94% (n = 15) and 94% (n = 15) received preoperative acetaminophen and gabapentin, respectively, which was significantly greater than the historical control group (P < 0.001). For the intraoperative components analyzed, only the intrathecal morphine was significantly different than historical controls (100% versus 49%, P < 0.001). Postoperatively, the time from operating room to return to normal diet was shorter for the ERAS group (0.53 d versus 1.16 d, P < 0.001). There was no significant difference in readmission rates between the two groups. CONCLUSIONS: ERAS protocol compliance varies based on phase of care. Solutions to sustain protocols depend on the institution and the patient population. However, the utilization of implementation science fundamentals was invaluable in this study to identify and address areas for improvement in protocol compliance. Other institutions may adapt these strategies to improve protocol compliance at their centers.

Age-dependent effects of metformin on human oligodendrocyte lineage cell ensheathment capacity.

Metformin restores the myelination potential of aged rat A2B5+ oligodendrocyte progenitor cells and may enhance recovery in children with post-radiation brain injury. Human late progenitor cells (O4+A2B5+) have a superior capacity to ensheath nanofibres compared to mature oligodendrocytes, with cells from paediatric sources exceeding adults. In this study, we assessed the effects of metformin on ensheathment capacity of human adult and paediatric progenitors and mature oligodendrocytes and related differences to transcriptional changes. A2B5+ progenitors and mature cells, derived from surgical tissues by immune-magnetic separation, were assessed for ensheathment capacity in nanofibre plates over 2 weeks. Metformin (10 µM every other day) was added to selected cultures. RNA was extracted from treated and control cultures after 2 days. For all ages, ensheathment by progenitors exceeded mature oligodendrocytes. Metformin enhanced ensheathment by adult donor cells but reduced ensheathment by paediatric cells. Metformin marginally increased cell death in paediatric progenitors. Metformin-induced changes in gene expression are distinct for each cell type. Adult progenitors showed up-regulation of pathways involved in the process of outgrowth and promoting lipid biosynthesis. Paediatric progenitors showed a relatively greater proportion of down- versus up-regulated pathways, these involved cell morphology, development and synaptic transmission. Metformin-induced AMP-activated protein kinase activation in all cell types; AMP-activated protein kinase inhibitor BML-275 reduced functional metformin effects only with adult cells. Our results indicate age and differentiation stage-related differences in human oligodendroglia lineage cells in response to metformin. Clinical trials for demyelinating conditions will indicate how these differences translate in vivo.