KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

Risk of Two Sport-Related Concussions in the Same Year: Is the Second Concussion Worse?

OBJECTIVES: 1) Evaluate the frequency of same-year, repeat concussions; (2) assess predictors of sustaining a repeat concussion; and (3) compare outcomes of athletes with repeat concussions with athletes with single concussion. DESIGN: A retrospective, case-control study. SETTING: Regional sports concussion center. PATIENTS: Adolescents sustaining a sport-related concussions (SRC) from November 2017 to October 2020. INDEPENDENT VARIABLES: Participants were dichotomized into 2 groups: (1) athletes with a single concussion; and (2) athletes with repeat concussions. MAIN OUTCOME MEASURES: Between group and within group analyses were completed to look for differences in demographics, personal and family history, concussion history, and recovery metrics between the 2 groups. RESULTS: Of 834 athletes with an SRC, 56 (6.7%) sustained a repeat concussion and 778 (93.3%) had a single concussion. Between group: Personal history of migraines (19.6% vs 9.5%, χ 2 = 5.795, P = 0.02), family history of migraines (37.5% vs 24.5%, χ 2 = 4.621, P = 0.03), and family history of psychiatric disorders (25% vs 13.1%, χ 2 = 6.224, P = 0.01) were significant predictors of sustaining a repeat concussion. Within group: Among those with a repeat concussion, initial symptom severity was greater (Z = -2.422; P = 0.02) during the repeat concussion and amnesia was more common (χ 2 = 4.775, P = 0.03) after the initial concussion. CONCLUSIONS: In a single-center study of 834 athletes, 6.7% suffered a same-year, repeat concussion. Risk factors included personal/family migraine history and family psychiatric history. For athletes with repeat concussions, initial symptom score was higher after the second concussion, yet amnesia was more common after the initial concussion.

Using biomarkers to allocate patients in a response-adaptive clinical trial.

In this paper, we discuss a response adaptive randomization method, and why it should be used in clinical trials for rare diseases compared to a randomized controlled trial with equal fixed randomization. The developed method uses a patient's biomarkers to alter the allocation probability to each treatment, in order to emphasize the benefit to the trial population. The method starts with an initial burn-in period of a small number of patients, who with equal probability, are allocated to each treatment. We then use a regression method to predict the best outcome of the next patient, using their biomarkers and the information from the previous patients. This estimated best treatment is assigned to the next patient with high probability. A completed clinical trial for the effect of catumaxomab on the survival of cancer patients is used as an example to demonstrate the use of the method and the differences to a controlled trial with equal allocation. Different regression procedures are investigated and compared to a randomized controlled trial, using efficacy and ethical measures.

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.

δ13 C and δ18 O heterogeneities in carbonates: Nonlinear mixing in the application of dual-carbonate-clumped isotope thermometer.

RATIONALE: Dual-carbonate-clumped isotope thermometry assumes any departure from Δ47 and Δ48 co-equilibrium is due to disequilibrium processes; however, the effects of endmember mixing have not been evaluated for Δ48 . We show that variations in δ13 C and δ18 O values within a sample can lead to offsets in Δ47 and Δ48 that can be mistaken for kinetic fractionation. METHODS: A numerical mixing model was developed to calculate the Δ48 and Δ47 values of samples with heterogeneous isotope compositions. The model was used to test a variety of possible endmember mixing scenarios and produce a dataset of mixing offsets in both Δ48 and Δ47 . RESULTS: Different mixing patterns arise from endmember mixing, with different patterns between Δ48 and Δ47 . Δ47 can be both positively and negatively offset from equilibrium values by mixing; however, Δ48 can only be offset in a positive direction, producing an underestimate of formation temperature. The overall results suggest that endmember mixing can mimic kinetic fractionation caused by CO2 degassing in dual-clumped isotope measurements. CONCLUSIONS: Mixing between endmembers can result in patterns that resemble that of CO2 degassing. However, these effects require a variation of greater than 5‰ in endmember δ18 O values to have a significant effect relative to measurement errors on Δ48 with the detection limits of modern mass spectrometers. Δ47 remains more sensitive to endmember mixing effects and will display measurable mixing effects at 2‰ variation or less in endmember isotopic values.

Intraoperative physiology augments atlas-based data in awake deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) is commonly performed with patients awake to perform intraoperative microelectrode recordings and/or macrostimulation testing to guide final electrode placement. Supplemental information from atlas-based databases derived from prior patient data and visualised as efficacy heat maps transformed and overlaid onto preoperative MRIs can be used to guide preoperative target planning and intraoperative final positioning. Our quantitative analysis of intraoperative testing and corresponding changes made to final electrode positioning aims to highlight the value of intraoperative neurophysiological testing paired with image-based data to optimise final electrode positioning in a large patient cohort. METHODS: Data from 451 patients with movement disorders treated with 822 individual DBS leads at a single institution from 2011 to 2021 were included. Atlas-based data was used to guide surgical targeting. Intraoperative testing data and coordinate data were retrospectively obtained from a large patient database. Medical records were reviewed to obtain active contact usage and neurologist-defined outcomes at 1 year. RESULTS: Microelectrode recording firing profiles differ per track, per target and inform the locations where macrostimulation testing is performed. Macrostimulation performance correlates with the final electrode track chosen. Centroids of atlas-based efficacy heat maps per target were close in proximity to and may predict active contact usage at 1 year. Overall, patient outcomes at 1 year were improved for patients with better macrostimulation response. CONCLUSIONS: Atlas-based imaging data is beneficial for target planning and intraoperative guidance, and in conjunction with intraoperative neurophysiological testing during awake DBS can be used to individualize and optimise final electrode positioning, resulting in favourable outcomes.

Arrest of mouse preterm labor until term delivery by combination therapy with atosiban and mundulone, a natural product with tocolytic efficacy.

There is a lack of FDA-approved tocolytics for the management of preterm labor (PL). In prior drug discovery efforts, we identified mundulone and mundulone acetate (MA) as inhibitors of in vitro intracellular Ca2+-regulated myometrial contractility. In this study, we probed the tocolytic potential of these compounds using human myometrial samples and a mouse model of preterm birth. In a phenotypic assay, mundulone displayed greater efficacy, while MA showed greater potency and uterine-selectivity in the inhibition of intracellular-Ca2+ mobilization. Cell viability assays revealed that MA was significantly less cytotoxic. Organ bath and vessel myography studies showed that only mundulone exerted inhibition of myometrial contractions and that neither compounds affected vasoreactivity of ductus arteriosus. A high-throughput combination screen identified that mundulone exhibits synergism with two clinical-tocolytics (atosiban and nifedipine), and MA displayed synergistic efficacy with nifedipine. Of these combinations, mundulone+atosiban demonstrated a significant improvement in the in vitro therapeutic index compared to mundulone alone. The ex vivo and in vivo synergism of mundulone+atosiban was substantiated, yielding greater tocolytic efficacy and potency on myometrial tissue and reduced preterm birth rates in a mouse model of PL compared to each single agent. Treatment with mundulone after mifepristone administration dose-dependently delayed the timing of delivery. Importantly, mundulone+atosiban permitted long-term management of PL, allowing 71% dams to deliver viable pups at term (>day 19, 4-5 days post-mifepristone exposure) without visible maternal and fetal consequences. Collectively, these studies provide a strong foundation for the development of mundulone as a single or combination tocolytic for management of PL.

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

COVID-19 Vaccine Seroresponse Based on The Timing of The Primary Series; Pre- versus Post-Renal Transplantation.

BACKGROUND: Coronavirus disease 2019 (COVID-19) poses a serious risk to patients with chronic kidney disease (CKD) and renal transplant. While COVID-19 vaccination is recommended before transplant, there are limited data comparing vaccine timing. Our aim is to evaluate serological responses to COVID-19 vaccines pre- and post-renal transplant and the durability of antibody levels. METHODS: We retrospectively evaluated the antibody response of adult renal transplant recipients who had received at least a primary series of the COVID-19 vaccine. The patients were divided into two groups based on the timing; pre- or post-transplant. Antibody titer levels were evaluated at least 4 weeks after vaccination for each group. Titer durability was assessed by calculating the median titer level of individuals. RESULTS: A total of 139 patients were identified between January 2019 and April 2022. Twenty-nine patients were excluded because of previous COVID-19 infection, and 15 patients were excluded each for insufficient vaccine doses and lack of titer data. Forty patients were included for the pre-transplant group and 40 for post-transplant. The number of pre-transplant patients who developed antibodies (39 patients, 97.5%) was significantly greater than the number of post-transplant patients (21 patients, 52.5%) with p < .01. The median post-vaccination titer levels were significantly greater in the pre-transplant group up to 5 months after vaccination (p < .05). The pre-transplant group's titers seemed sustained even after renal transplantation. CONCLUSION: Vaccinating renal transplant patients before transplant results in increased achievement of seroresponse, higher levels of antibody titers, and sustained titers following transplant. Larger and prospective studies are warranted to confirm the findings.

Arrest of mouse preterm labor until term delivery by combination therapy with atosiban and mundulone, a natural product with tocolytic efficacy.

Currently, there is a lack of FDA-approved tocolytics for the management of preterm labor (PL). In prior drug discovery efforts, we identified mundulone and its analog mundulone acetate (MA) as inhibitors of in vitro intracellular Ca 2+ -regulated myometrial contractility. In this study, we probed the tocolytic and therapeutic potential of these small molecules using myometrial cells and tissues obtained from patients receiving cesarean deliveries, as well as a mouse model of PL resulting in preterm birth. In a phenotypic assay, mundulone displayed greater efficacy in the inhibition of intracellular-Ca 2+ from myometrial cells; however, MA showed greater potency and uterine-selectivity, based IC 50 and E max values between myometrial cells compared to aorta vascular smooth muscle cells, a major maternal off-target site of current tocolytics. Cell viability assays revealed that MA was significantly less cytotoxic. Organ bath and vessel myography studies showed that only mundulone exerted concentration-dependent inhibition of ex vivo myometrial contractions and that neither mundulone or MA affected vasoreactivity of ductus arteriosus, a major fetal off-target of current tocolytics. A high-throughput combination screen of in vitro intracellular Ca 2+ -mobilization identified that mundulone exhibits synergism with two clinical-tocolytics (atosiban and nifedipine), and MA displayed synergistic efficacy with nifedipine. Of these synergistic combinations, mundulone + atosiban demonstrated a favorable in vitro therapeutic index (TI)=10, a substantial improvement compared to TI=0.8 for mundulone alone. The ex vivo and in vivo synergism of mundulone and atosiban was substantiated, yielding greater tocolytic efficacy and potency on isolated mouse and human myometrial tissue and reduced preterm birth rates in a mouse model of PL compared to each single agent. Treatment with mundulone 5hrs after mifepristone administration (and PL induction) dose-dependently delayed the timing of delivery. Importantly, mundulone in combination with atosiban (FR 3.7:1, 6.5mg/kg + 1.75mg/kg) permitted long-term management of PL after induction with 30 µg mifepristone, allowing 71% dams to deliver viable pups at term (> day 19, 4-5 days post-mifepristone exposure) without any visible maternal and fetal consequences. Collectively, these studies provide a strong foundation for the future development of mundulone as a stand-alone single- and/or combination-tocolytic therapy for management of PL.

Amphiphilic silicones for the facile dispersion of carbon nanotubes and formation of soft skin electrodes.

Flexible, dry skin electrodes represent a potentially superior alternative to standard Ag/AgCl metal electrodes for wearable devices used in long-term monitoring. Herein, such electrodes were formed using a facile method for dispersing carbon nanotubes (CNTs) in a silicone matrix using custom amphiphilic dispersive additives (DSPAs). Using only brief mixing and without the use of solvents or surface modification of CNTs, twelve poly(ethylene oxide)-silanes (PEO-SAs) of varying crosslinkability, architecture, siloxane tether length, and molar ratio of siloxane:PEO were combined with an addition cure silicone and CNTs. Nearly all PEO-SA modified silicone-CNT composites demonstrated improved conductivity compared to the unmodified composite. Best conductivities correlated to composites prepared with PEO-SAs that formed micelles of particular sizes (d ~ 200 - 300 nm) and coincided to PEO-SAs with a siloxane:PEO molar ratio of ~ 0.75 - 3.00. Superior dispersion of CNT by such PEO-SAs was exemplified by scanning electron microscopy (SEM). Advantageously, modified composites retained their moduli, rather than becoming more rigid. Resultant electrodes fabricated with modified composites showed skin-electrode impedance comparable to that of Ag/AgCl electrodes. Combined, these results demonstrate the potential of silicone-CNT composites prepared with PEO-SA DSPAs as flexible, dry electrodes as a superior alternative to traditional electrodes.

Predicting early versus late recovery from sport-related concussion using decision tree analysis.

OBJECTIVE: Accurately predicting early (≤ 14 days) versus typical (15-27 days) or delayed (≥ 28 days) recovery from sport-related concussion (SRC) may allow for improved resource utilization and precision in planning and carrying out rehabilitation. In this study, the authors sought to develop an algorithm that enables accurate differentiation of recovery periods and duration after SRC. The authors hypothesized that data regarding initial symptom burden as quantified by a Post-Concussion Symptom Scale (PCSS) score, time to presentation, and number of prior concussions would be the most useful for analyzing predictive factors for concussion recovery duration. METHODS: A retrospective case-control study was conducted to assess the primary outcome of days to clinical recovery following SRC in pediatric patients. Data from patients 12-18 years old presenting within 28 days of injury to an SRC clinic between November 11, 2017, and October 10, 2020, were analyzed. Patients with positive evidence of injury on head imaging or incomplete records were excluded. The primary outcome was duration of clinical recovery, grouped as early (≤ 14 days), typical (15-27 days), or delayed (≥ 28 days). Recovery was defined as follows: 1) symptom resolution or return to baseline, or 2) initiation of graduated return to play. CHAID (chi-square automatic interaction detection) analysis was used to optimize a decision tree based on 16 input factors, including age, sex, initial PCSS score, time to clinic presentation, number of prior concussions, and presence of defined symptom clusters. The cohort was randomized into training (70%) and test (30%) samples for algorithm validation. RESULTS: A total of 493 patients met the inclusion criteria (mean age 15.7 ± 1.5 years, 68.2% male, 70.0% White). The median time to presentation was 5 days (IQR 2-10 days). Most patients (52.3%) recovered within 14 days of injury, 21.5% recovered within 15-27 days, and 26.2% had a recovery period of 28 days or longer. The variables most predictive of recovery were initial PCSS score (cutoffs ≤ 6, 7-28, or ≥ 29), time to presentation (≤ 7 vs > 7 days), or prior concussions (0 vs ≥ 1). The model accurately discriminated between early versus typical or delayed recovery duration groupings (area under the curve 0.80, Youden index 0.44), and correctly classified > 90% of patients who recovered early. CONCLUSIONS: This novel three-factor predictive tool enabled accurate discrimination of early versus typical or delayed SRC recovery to better allocate resources, counsel patients, and make timely referrals.

Mechanisms underlying thermal breadth differ by species in insects from adjacent but thermally distinct streams - A test of the climate variability hypothesis.

The Climate Variability Hypothesis (CVH) predicts that ectotherms from thermally variable climates should have wider thermal tolerances than their counterparts living in stable climates. Although the CVH has been widely supported, the mechanisms underlying wider tolerance traits remain unclear. We test the CVH along with three mechanistic hypotheses that may explain how differences in tolerance limits arise: 1) Short-term Acclimation Hypothesis (mechanism: rapid, reversible plasticity), 2) Long-term Effects Hypothesis (mechanisms: developmental plasticity, epigenetics, maternal effects, or adaptation), and 3) Trade-off Hypothesis (mechanism: trade-off between short- and long-term responses). We tested these hypotheses by measuring CTMIN, CTMAX, and thermal breadths (CTMAX - CTMIN) of aquatic mayfly and stonefly nymphs from adjacent streams with distinctly different levels of thermal variation following acclimation to either cool, control, and warm conditions. In one stream, daily mean temperature varied by about 5 °C annually, whereas in the other, it varied by more than 25 °C. In support of the CVH, we found that mayfly and stonefly nymphs from the thermally variable stream had broader thermal tolerances than those from the thermally stable stream. However, support for the mechanistic hypotheses differed by species. Mayflies appear to rely on long-term strategies for maintaining broader thermal limits, whereas stoneflies achieve broader thermal limits via short-term plasticity. We found no support for the Trade-off Hypothesis.

Going with the flow - how a stream insect, Pteronarcys californica, exploits local flows to increase oxygen availability.

For insects, life in water is challenging because oxygen supply is typically low compared with in air. Oxygen limitation may occur when oxygen levels or water flows are low or when warm temperatures stimulate metabolic demand for oxygen. A potential mechanism for mitigating oxygen shortages is behavior - moving to cooler, more oxygenated or faster flowing microhabitats. Whether stream insects can make meaningful choices, however, depends on: (i) how temperature, oxygen and flow vary at microspatial scales and (ii) the ability of insects to sense and exploit that variation. To assess the extent of microspatial variation in conditions, we measured temperature, oxygen saturation and flow velocity within riffles of two streams in Montana, USA. In the lab, we then examined preferences of nymphs of the stonefly Pteronarcys californica to experimental gradients based on field-measured values. Temperature and oxygen level varied only slightly within stream riffles. By contrast, flow velocity was highly heterogeneous, often varying by more than 125 cm s-1 within riffles and 44 cm s-1 around individual cobbles. Exploiting micro-variation in flow may thus be the most reliable option for altering rates of oxygen transport. In support of this prediction, P. californica showed little ability to exploit gradients in temperature and oxygen but readily exploited micro-variation in flow - consistently choosing higher flows when conditions were warm or hypoxic. These behaviors may help stream insects mitigate low-oxygen stress from climate change and other anthropogenic disturbances.

Pediatric spinal injury patterns and management in all-terrain vehicle and dirt bike crashes, 2010-2019.

OBJECTIVE: Pediatric spinal injuries in all-terrain vehicle (ATV) and dirt bike crashes are relatively uncommon but may be associated with significant morbidity. There are no recent studies examining these injuries, their management, and outcomes. Therefore, a retrospective study was performed to characterize pediatric spinal injuries related to ATV and dirt bike crashes over the last decade. METHODS: Data on all patients involved in ATV or dirt bike crashes evaluated at a regional level 1 pediatric trauma center over a 10-year period (2010-2019) were analyzed. Descriptive statistics were analyzed and chi-square, Fisher exact, and Mann-Whitney U-tests were performed comparing the demographics, injury characteristics, and clinical outcomes in patients with versus those without spinal injuries. RESULTS: Of 680 patients evaluated, 35 (5.1%) were diagnosed with spinal injuries. Over the study period, both spinal injuries and emergency department visits related to ATV or dirt bike crashes increased in frequency. All spinal injuries were initially diagnosed on CT scans, and 57.9% underwent spinal MRI. Injuries were most commonly thoracic (50%), followed by cervical (36.8%). The injuries of most patients were classified as American Spinal Injury Association (ASIA) grade E on presentation (86.8%), while 2 (5.3%) had complete spinal cord injuries (ASIA grade A) and 3 patients (8.6%) were ASIA grade B-D. Operative management was required for 13 patients (28.9%). Nonoperative management was used in 71.1% of injuries, including bracing in 33% of all injuries. Patients with spinal injuries were older than those without (13.4 ± 3.35 vs 11.5 ± 3.79 years, p = 0.003). Spinal injuries occurred via similar crash mechanisms (p = 0.48) and in similar locations (p = 0.29) to nonspinal injuries. Patients with spinal injuries more frequently required admission to the intensive care unit (ICU; 34.2% vs 14.6%, p = 0.011) and had longer hospital stays (mean 4.7 ± 5.5 vs 2.7 ± 4.0 days, p = 0.0025). CONCLUSIONS: Although infrequent among young ATV and dirt bike riders, spinal injuries are associated with longer hospital stays, increased ICU use, and required operative intervention in 29%. Increasing awareness among ATV and dirt bike riders about the severity of riding-related injuries may encourage safer riding behaviors.

Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Socioeconomic factors associated with helmet use in pediatric ATV and dirt bike trauma.

Objectives: Recreational off-road vehicle crashes can produce severe injury and death among children, often from head trauma sustained while riding unhelmeted. Although required for competition, recreational riders commonly forego helmets. This study aimed to identify socioeconomic factors associated with unhelmeted injuries among children riding all-terrain vehicles (ATVs) and dirt bikes recreationally, thus informing injury prevention efforts. Methods: A retrospective review was completed of patients younger than 18 years who presented after recreational ATV or dirt bike crash to a single American College of Surgeons-verified level 1 pediatric trauma center (2010-2019). Demographic, injury, and outcome data were collected. US Census data regarding median and per capita income, poverty prevalence, and scholastic graduation rates were recorded for each patient's home county. Relationships between helmet use at the time of injury, demographics, and socioeconomic variables were examined. Results: The cohort comprised 680 injured recreational ATV (n=510; 75%) and dirt bike (170; 25%) riders. Unhelmeted riders (n=450) were significantly older (median age 13 vs 11 years; p=0.008) and more often rode ATVs (n=399). Significantly greater percentages of females (77.9%; p<0.001) and passengers (89.5%; p<0.001) were unhelmeted at the time of injury. Residents of counties with lower median and per capita income, higher poverty prevalence, and lower high school and college graduation rates were significantly more likely to be unhelmeted at the time of their crash (p=0.003). In multivariable analysis, unhelmeted injuries were independently associated with ATV use (OR=6.757; p<0.0001), passenger status (OR=6.457; p<0.0001), and older age (OR=1.219; p<0.0001). Conclusion: In children, ATV use, passenger status, and older age associated independently with unhelmeted riding in recreational vehicle crash. Residence in a county with both lower median income and scholastic graduation rates associated with unhelmeted crashes, and lower median income significantly predicted unhelmeted crashes. This study revealed socioeconomic factors that identify communities with greatest need for injury prevention initiatives. Level of evidence: III-retrospective comparative epidemiological study.

Amphiphilic silicones to mitigate lens epithelial cell growth on intraocular lenses.

Silicone intraocular lenses (IOLs) that resist lens epithelial cell (LEC) growth would greatly improve patient outcomes. Herein, amphiphilic surface modifying additives (SMAs) were incorporated into an IOL-type diphenyl silicone to reduce LEC growth without compromising opto-mechanical properties. The SMAs were poly(ethylene oxide)-silane amphiphiles (PEO-SAs) [H-Si-ODMSm-block-PEO8-OCH3], comprised of a PEO segment and siloxane tether of varying lengths (m = 0, 13, and 30). These three SMAs were each blended into the addition cure diphenyl silicone at varying concentrations (5, 10, 15, 20, and 25 µmol g-1) wherein the wt% of PEO was maintained for all SMAs at a given molar concentration. The chemical crosslinking and subsequent retention of SMAs in modified silicones was confirmed. Key material properties were assessed following equilibration in both air and aqueous environments. Silicones modified with SMAs having longer tethers (m = 13 and 30) underwent rapid and substantial water-driven restructuring of PEO to the surface to form highly hydrophilic surfaces, especially as SMA concentration increased. The % transmittance was also maintained for silicones modified with these particular SMAs. The moduli of the modified silicones were largely unchanged by the SMA and remained in the typical range for silicone IOLs. When the three SMAs were introduced at the highest concentration, modified silicones remained non-cytotoxic and LEC count and associated alpha-smooth muscle actin (α-SMA) expression decreased with increasing tether length. These results demonstrate the potential of silicones modified with PEO-SA SMAs to produce LEC-resistant IOLs.

Effects of Solvents, Emulsions, Cosolvents, and Complexions on Ex Vivo Mouse Myometrial Contractility.

A great need exists to develop tocolytic and uterotonic drugs that combat poor, labor-related maternal and fetal outcomes. A widely utilized method to assess novel compounds for their tocolytic and uterotonic efficacy is the isometric organ bath contractility assay. Unfortunately, water-insoluble compounds can be difficult to test using the physiological, buffer-based, organ bath assay. Common methods for overcoming solubility issues include solvent variation, cosolvency, surfactant or complexion use, and emulsification. However, these options for drug delivery or formulation can impact tissue function. Therefore, the goal of this study was to evaluate the ability of common solvents, surfactants, cosolvents, and emulsions to adequately solubilize compounds in the organ bath assay without affecting mouse myometrial contractility. We found that acetone, acetonitrile, and ethanol had the least effect, while dimethylacetamide, ethyl acetate, and isopropanol displayed the greatest inhibition of myometrial contractility based on area under the contractile curve analyses. The minimum concentration of surfactants, cosolvents, and human serum albumin required to solubilize nifedipine, a current tocolytic drug, resulted in extensive bubbling in the organ bath assay, precluding their use. Finally, we report that an oil-in-water base emulsion containing no drug has no statistical effect beyond the control (water), while the drug emulsion yielded the same potency and efficacy as the freely solubilized drug.

The impact of helmet use on neurosurgical care and outcomes after pediatric all-terrain vehicle and dirt bike crashes: a 10-year single-center experience.

OBJECTIVE: All-terrain vehicle (ATV) and dirt bike crashes frequently result in traumatic brain injury. The authors performed a retrospective study to evaluate the role of helmets in the neurosurgical outcomes of pediatric patients involved in ATV and dirt bike crashes who were treated at their institution during the last decade. METHODS: The authors analyzed data on all pediatric patients involved in ATV or dirt bike crashes who were evaluated at a single regional level I pediatric trauma center between 2010 and 2019. Patients were excluded if the crash occurred in a competition (n = 70) or if helmet status could not be determined (n = 18). Multivariable logistic regression was used to analyze the association of helmet status with the primary outcomes of 1) neurosurgical consultation, 2) intracranial injury (including skull fracture), and 3) moderate or severe traumatic brain injury (MSTBI) and to control for literature-based, potentially confounding variables. RESULTS: In total, 680 patients were included (230 [34%] helmeted patients and 450 [66%] unhelmeted patients). Helmeted patients were more frequently male (81% vs 66%). Drivers were more frequently helmeted (44.3%) than passengers (10.5%, p < 0.001). Head imaging was performed to evaluate 70.9% of unhelmeted patients and 48.3% of helmeted patients (p < 0.001). MSTBI (8.0% vs 1.7%, p = 0.001) and neurosurgical consultation (26.2% vs 9.1%, p < 0.001) were more frequent among unhelmeted patients. Neurosurgical injuries, including intracranial hemorrhage (16% vs 4%, p < 0.001) and skull fracture (18% vs 4%, p < 0.001), were more common in unhelmeted patients. Neurosurgical procedures were required by 2.7% of unhelmeted patients. One helmeted patient (0.4%) required placement of an intracranial pressure monitor, and no other helmeted patients required neurosurgical procedures. After adjustment for age, sex, driver status, vehicle type, and injury mechanism, helmet use significantly reduced the odds of neurosurgical consultation (OR 0.250, 95% CI 0.140-0.447, p < 0.001), intracranial injury (OR 0.172, 95% CI 0.087-0.337, p < 0.001), and MSTBI (OR 0.244, 95% CI 0.079-0.758, p = 0.015). The unadjusted absolute risk reduction provided by helmet use equated to a number-needed-to-helmet of 6 riders to prevent 1 neurosurgical consultation, 4 riders to prevent 1 intracranial injury, and 16 riders to prevent 1 MSTBI. CONCLUSIONS: Helmet use remains problematically low among young ATV and dirt bike riders, especially passengers. Expanding helmet use among these children could significantly reduce the rates of intracranial injury and MSTBI, as well as the subsequent need for neurosurgical procedures. Promoting helmet use among recreational ATV and dirt bike riders must remain a priority for neurosurgeons, public health officials, and injury prevention professionals.