Search

Abstract Childhood abuse represents one of the most potent risk factors for the development of psychopathology during childhood, accounting for 30–60% of the risk for onset. While previous studies have separately associated reductions in gray matter volume (GMV) with childhood abuse and internalizing psychopathology (IP), it is unclear whether abuse and IP differ in their structural abnormalities, and which GMV features are related to abuse and IP at the individual level. In a pooled multisite, multi-investigator sample, 246 child and adolescent females between the ages of 8–18 were recruited into studies of interpersonal violence (IPV) and/or IP (i.e. posttraumatic stress disorder (PTSD), depression, and/or anxiety). Youth completed assessments for IP, childhood abuse history, and underwent high resolution T1 structural MRI. First, we characterized how differences in GMV associated with childhood abuse exposure depend on the presence or absence of IP using voxel-based morphometry (VBM). Next, we trained convolutional neural networks to predict individual psychopathology and abuse experience and estimated the strength and direction of importance of each structural feature in making individual-level predictions using Shapley values. Shapley values were aggregated across the entire cohort, and the top 1% of feature clusters with the highest importance are reported. At a group-level, VBM analyses identified widespread decreases in GMV across the prefrontal cortex, insula, and hippocampus in youth with IP, while abuse experience was specifically associated with increased GMV in the cingulate cortex and supramarginal gyrus. Further, interactions between IP and severity of abuse were identified in the ventral and dorsal prefrontal cortex, anterior cingulate cortex, and thalamus. After extensive training, model tuning, and model evaluation, the neural networks performed above chance when predicting IP (63% accuracy) and abuse experiences (71% accuracy) at the level of the individual. Interestingly, structural regions with the highest importance in making individual IP predictions had a high degree of overlap with group-level patterns. We have identified unique structural correlates of childhood abuse and IP on both the group and individual level with a high degree of overlap, providing evidence that IP and trauma exposure may uniquely and jointly impact child and adolescent structural neurodevelopment. Feature learning may offer power and novelty above and beyond traditional group-level approaches to the identification of biomarkers and a movement towards individualized diagnosis and treatment.

Abstract Amblyomma maculatum sensu lato (s.l.) is an ixodid tick found in the semi-arid southwestern United States and northern Mexico where it is a parasite of medical and veterinary significance, including as a vector for Rickettsia parkeri, a cause of spotted fever rickettsiosis in the Americas. To describe the comprehensive natural history of this tick, monthly small mammal trapping and avian mist netting sessions were conducted at sites in Cochise County Arizona, within the Madrean Archipelago region where human cases of R. parkeri rickettsiosis and adult stages of A. maculatum s.l. were previously documented. A total of 1949 larvae and nymphs were removed from nine taxonomic groups of rodents and ten species of birds and were used in combination with records for adult stages collected both from vegetation and hunter-harvested animals to model seasonal activity patterns. A univoltine phenology was observed, initiated by the onset of the annual North American monsoon and ceasing during the hot, dry conditions preceding the following monsoon season. Cotton rats (Sigmodon spp.) were significantly more likely to be infested than other rodent taxa and carried the highest tick loads, reflecting a mutual affinity of host and ectoparasite for microhabitats dominated by grass.

Abstract An unusual pattern among the scaling laws in nature is that the fastest animals are neither the largest, nor the smallest, but rather intermediately sized. Because of the enormous diversity in animal shape, the mechanisms underlying this have long been difficult to determine. To address this, we challenge predictive human musculoskeletal simulations, scaled in mass from the size of a mouse (0.1 kg) to the size of an elephant (2000 kg), to move as fast as possible. Our models replicate patterns observed across extant animals including: (i) an intermediate optimal body mass for speed; (ii) a reduction in the cost of transport with increasing size; and (iii) crouched postures at smaller body masses and upright postures at larger body masses. Finally, we use our models to determine the mechanical limitations of speed with size, showing larger animals may be limited by their ability to produce muscular force while smaller animals are likely limited by their ability to produce larger ground reaction forces. Despite their bipedal gait, our models replicate patterns observed across quadrupedal animals, suggesting these biological phenomena likely represent general rules and are not the result of phylogenetic or other ecological factors that typically hinder comparative studies.

Transcutaneous osseointegration for amputees (TOFA), an alternative approach to limb-loss rehabilitation, offers an enhanced quality of life and mobility, overcoming some challenges associated with amputation. This review presents evolution, surgical techniques, patient selection principles, and outcomes associated with TOFA. Notable points include the recognition that press-fit osseointegration techniques and implants achieve the quality of life and mobility improvements with a single surgical episode. Infection remains the most common adverse event, but uncommonly requires additional surgery, and rarely requires implant removal. Press-fit osseointegration has proven suitable for rehabilitating a broad range of patients with pelvic, transfemoral, or transtibial amputation performed to manage trauma, cancer, infection, chronic pain, and deformity. This technigue is safe for patients with vascular disease, diabetes mellitus, short residual bones, and osteoporotic residual bones. This article serves as a central resource for understanding the principles and techniques of osseointegration.

GJ 1214b is the archetype sub-Neptune for which thick aerosols have prevented us from constraining its atmospheric properties for over a decade. In this study, we leverage the panchromatic transmission spectrum of GJ 1214b established by the Hubble Space Telescope (HST) and JWST to investigate its atmospheric properties using a suite of atmospheric radiative transfer, photochemistry, and aerosol microphysical models. We find that the combined HST, JWST/NIRSpec, and JWST/MIRI spectrum can be well explained by atmospheric models with an extremely high metallicity of [M/H] ∼ 3.5 and an extremely high haze production rate of F _haze ∼ 10 ^−8 to 10 ^−7 g cm ^−2 s ^−1 . Such high atmospheric metallicity is suggested by the relatively strong CO _2 feature compared to the haze absorption feature or the CH _4 feature in the NIRSpec-G395H bandpass of 2.5–5 μ m. The flat 5–12 μ m MIRI spectrum also suggests a small scale height with a high atmospheric metallicity that is needed to suppress a prominent ∼6 μ m haze feature. We tested the sensitivity of our interpretation to various assumptions for uncertain haze properties, such as optical constants and production rate, and all models tested here consistently suggest extremely high metallicity. Thus, we conclude that GJ 1214b likely has a metal-dominated atmosphere where hydrogen is no longer the main atmospheric constituent. We also find that different assumptions for the haze production rate lead to distinct inferences for the atmospheric C/O ratio. We stress the importance of high-precision follow-up observations to confirm the metal-dominated atmosphere, as it challenges the conventional understanding of interior structure and evolution of sub-Neptunes.

Minimally invasive surgical techniques, such as MR-guided laser interstitial thermal therapy (LITT), have emerged as promising alternatives to open disconnective surgeries in drug-resistant epilepsy (DRE). This review synthesizes current literature on the application of LITT for corpus callosal disconnection and functional hemispheric disconnection. Studies highlight LITT's effectiveness for achieving seizure control and functional outcomes, often with reduced complications compared to traditional open procedures. Challenges include technical limitations to achieving total disconnection and adequate assessment of disconnection postoperatively. The literature is largely composed of observational studies and there is a need for rigorous, multi-center trials to establish robust guidelines and improve generalizability in clinical practice. There is also a need for a more robust exploration of how patient-specific factors contribute to response or nonresponse to intervention.

The present studies were undertaken to understand the effects of the commonly used nutraceutical PEA on brain function and lipid chemistry. These studies using MRI and broad-scale lipidomics are without precedent in animal or human research. During the MRI scanning session awake rats were given one of three doses of PEA (3, 10, or 30 mg/kg) or vehicle and imaged for changes in BOLD signal and functional connectivity. There was an inverse dose–response for negative BOLD suggesting a decrease in brain activity affecting the prefrontal ctx, sensorimotor cortices, basal ganglia and thalamus. However, there was a dose-dependent increase in functional connectivity in these same brain areas. Plasma and CNS levels of PEA and over 80 endogenous lipids (endolipids) were determined post treatment. While levels of PEA in the CNS were significantly higher after 30 mg/kg treatment, levels of the endocannabinoid, Anandamide, and at least 20 additional endolipids, were significantly lower across the CNS. Of the 78 endolipids that were detected in all CNS regions evaluated, 51 of them were modulated in at least one of the regions. Taken together, the functional connectivity and lipidomics changes provide evidence that PEA treatment drives substantial changes in CNS activity.

Background: Mohs micrographic surgeries (MMSs) vary in complexity and corresponding procedural duration. Preoperative triage of MMS cases enables physicians to estimate procedure duration and create an efficient schedule. The Webb and Rivera (WAR) score is a quantitative formula developed to predict complexity in Mohs cases based on tumor diameter, history of recurrence, location, and aggressiveness. Patients are given a score between 0 and 5 based on this information, with increasing surgical complexity for higher scores. Purpose: We aim to assess the association between WAR score, the number of stages, and repair type used in MMS to determine its value for clinical practice. Methods: Data for WAR score calculation were collected and analyzed for patients with squamous cell carcinoma and/or basal cell carcinoma treated with MMS between 2019 and 2023. Analyses were performed to determine if there was significant heterogeneity across WAR score groups. The Mantel–Haenszel Chi-square tests were performed for ordered categorical variables (Mohs stage), and Chi-square tests were performed for nonordered categorical variables. The results were verified using Fisher’s exact test when more than 25% of cells had an expected count of

Abstract Objective Nicotine‐containing products have historically been tobacco derivatives like cigarettes, cigars, and dip. Recently, tobacco‐free nicotine (TFN) products have been marketed as a healthy alternative. TFN pouches are small, discreet, flavored pouches containing nicotine designed to be placed between the gum and lip. This product does not fit a conventional tobacco category, leading to inaccurate reporting. This study aims to investigate discrepancies in physician documentation of TFN pouches. Methods A retrospective chart review was conducted on TFN users. Setting Single Health Care System. Methods Statistical analyses assessed TFN documentation concordance between social history templates and physician notes. Results There were 150 patients who used TFN and 841 patients who vaped. Concordance was higher for vape documentation than TFN pouch documentation (55.9%, 470/841 vs 25.3%, 38/150; P

Formation kinetics of metal nanoparticles are generally described via mass transport and thermodynamics‐based models, such as diffusion‐limited growth and classical nucleation theory (CNT). However, metal monomers are commonly assumed as precursors, leaving the identity of molecular intermediates and their contribution to nanoparticle formation unclear. Herein, liquid phase transmission electron microscopy (LPTEM) and reaction kinetic modeling are utilized to establish the nucleation and growth mechanisms and discover molecular intermediates during silver nanoparticle formation. Quantitative LPTEM measurements show that their nucleation rate decreases while growth rate is nearly invariant with electron dose rate. Reaction kinetic simulations show that Ag4 and Ag− follow a statistically similar dose rate dependence as the experimentally determined growth rate. We show that experimental growth rates are consistent with diffusion‐limited growth via the attachment of these species to nanoparticles. The dose rate dependence of nucleation rate is inconsistent with CNT. A reaction‐limited nucleation mechanism is proposed and it is demonstrated that experimental nucleation kinetics are consistent with Ag42+ aggregation rates at millisecond time scales. Reaction throughput analysis of the kinetic simulations uncovered formation and decay pathways mediating intermediate concentrations. We demonstrate the power of quantitative LPTEM combined with kinetic modeling for establishing nanoparticle formation mechanisms and principal intermediates.

Clinical management of non-small cell lung cancer (NSCLC) requires accurate identification of tumor-specific genetic alterations to inform treatment options. Historically, providers have relied on single-gene testing (SGT) for actionable variants due to a perception of cost-effectiveness and/or efficient turnaround time compared to next-generation sequencing (NGS). However, not all actionable variants may be evaluated through SGT modalities, and an SGT approach can exhaust valuable tissue needed for more comprehensive analyses. In contrast, comprehensive genomic profiling (CGP) tests employ NGS to sequence megabases of DNA and RNA to evaluate all relevant molecular alterations, providing a broader genetic profile to identify actionable alterations that SGT may not accurately or efficiently assess. Here, we briefly describe four cases from a large reference laboratory in which actionable alterations were identified by CGP but not SGT. The discussion highlights the utility and advantages of using CGP to provide complete and timely treatment options and clinical trial opportunities for patients with NSCLC.

The shape of skeletal muscle varies remarkably—with important implications for locomotor performance. In many muscles, the fibres are arranged at an angle relative to the tendons’ line of action, termed the pennation angle. These pennate muscles allow more sarcomeres to be packed side by side, enabling the muscle to generate higher maximum forces for a given muscle size. Historically, the physiological cross-sectional area (PCSA) has been used to capture both the size and arrangement of muscle fibres, and is one of the best predictors of a muscles capacity to produce force. However, the anatomical and mechanical implications of PCSA remain ambiguous as misinterpretations have limited our ability to understand the mechanical advantage of pennate muscle designs. We developed geometric models to resolve the mechanistic and functional impacts of pennation angle across a range of muscle shapes and sizes. Comparisons among model predictions and empirical data on human lower limb muscles demonstrated how a pennate arrangement of fibres allows muscles to produce up to six times more isometric force when compared with non-pennate muscles of the same volume. We show that in muscles much longer than thick, an optimal pennation angle exists at which isometric force is maximized. Using empirically informed geometric models we demonstrate the functional significance of a pennate muscle design and provide a new parameter, pennation mechanical advantage, which quantifies this performance improvement.

Abstract Introduction Degenerative disc disease (DDD) is accompanied by structural changes in the intervertebral discs (IVD). Extra‐cellular matrix degradation of the annulus fibrosus (AF) has been linked with degeneration of the IVD. Collagen is a vital component of the IVD. Collagen hybridizing peptide (CHP) is an engineered protein that binds to degraded collagen, which we used to quantify collagen damage in AF. This method was used to compare AF samples obtained from donors with no DDD to AF samples from patients undergoing surgery for symptomatic DDD. Methods Fresh AF tissue was embedded in an optimal cutting temperature compound and cryosectioned at a thickness of 8 μm. Hematoxylin and Eosin staining was performed on sections for general histomorphological assessment. Serial sections were stained with Cy3‐conjugated CHP and the mean fluorescence intensity and areal fraction of Cy3‐positive staining were averaged for three regions of interest (ROI) on each CHP‐stained section. Results Increases in mean fluorescence intensity (p = 0.0004) and percentage of positively stained area (p = 0.00008) with CHP were detected in DDD samples compared to the non‐DDD samples. Significant correlations were observed between mean fluorescence intensity and percentage of positively stained area for both non‐DDD (R = 0.98, p = 5E‐8) and DDD (R = 0.79, p = 0.0012) samples. No significant differences were detected between sex and the lumbar disc level subgroups of the non‐DDD and DDD groups. Only tissue pathology (non‐DDD versus DDD) influenced the measured parameters. No three‐way interactions between tissue pathology, sex, and lumbar disc level were observed. Discussion and Conclusions These findings suggest that AF collagen degradation is greater in DDD samples compared to non‐DDD samples, as evidenced by the increased CHP staining. Strong positive correlations between the two measured parameters suggest that when collagen degradation occurs, it is detected by this technique and is widespread throughout the tissue. This study provides new insights into the structural alterations associated with collagen degradation in the AF that occur during DDD.

Background: There is an imminent need to identify neural markers during preadolescence that are linked to developing depression during adolescence, especially among youth at elevated familial risk. However, longitudinal studies remain scarce and exhibit mixed findings. Here we aimed to elucidate functional connectivity (FC) patterns among preadolescents that interact with familial depression risk to predict depression two years later. Methods: 9–10 year-olds in the Adolescent Brain Cognitive Development (ABCD) Study were classified as healthy (i.e., no lifetime psychiatric diagnoses) at high familial risk for depression (HR; n=559) or at low familial risk for psychopathology (LR; n=1203). Whole-brain seed-to-voxel resting-state FC patterns with the amygdala, putamen, nucleus accumbens, and caudate were calculated. Multi-level, mixed-effects regression analyses were conducted to test whether FC at ages 9–10 interacted with familial risk to predict depression symptoms at ages 11–12. Results: HR youth demonstrated stronger associations between preadolescent FC and adolescent depression symptoms (ps0.001), primarily among amygdala/striatal FC with visual and sensory/somatomotor networks. Conclusions: Preadolescent amygdala and striatal FC may be useful biomarkers of adolescent-onset depression, particularly for youth with family histories of depression. This research may point to neurobiologically-informed approaches to prevention and intervention for depression in adolescents.

Background Immune checkpoint protein V-domain immunoglobulin suppressor of T cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. Previous mechanistic studies have indicated that VISTA impairs the toll-like receptor (TLR)-mediated activation of myeloid antigen-presenting cells, promoting the expansion of myeloid-derived suppressor cells, and suppressing tumor-reactive cytotoxic T cell function.Methods The aim of this study was to develop a dual-action lipid nanoparticle (dual-LNP) coloaded with VISTA-specific siRNA and TLR9 agonist CpG oligonucleotide. We used three murine preclinical tumor models, melanoma YUMM1.7, melanoma B16F10, and colon carcinoma MC38 to assess the functional synergy of the two cargoes of the dual LNP and therapeutic efficacy.Results The dual-LNP synergistically augmented antitumor immune responses and rejected large established tumors whereas LNPs containing VISTA siRNA or CpG alone were ineffective. In comparison with therapies using the soluble CpG and a VISTA-specific monoclonal antibody, the dual-LNP demonstrated superior therapeutic efficacy yet with reduced systemic inflammatory cytokine production. In three murine models, the dual-LNP treatment achieved a high cure rate. Tumor rejection was associated with influx of immune cells to tumor tissues, augmented dendritic cell activation, production of proinflammatory cytokines, and improved function of cytotoxic T cells.Conclusions Our studies show the dual-LNP ensured codelivery of its synergistic cargoes to tumor-infiltrating myeloid cells, leading to simultaneous silencing of VISTA and stimulation of TLR9. As a result, the dual-LNP drove a highly potent antitumor immune response that rejected large aggressive tumors, thus may be a promising therapeutic platform for treating immune-cold tumors.

Abstract Neuromodulation via Responsive Neurostimulation (RNS) or Deep Brain Stimulation (DBS) is an emerging treatment strategy for pediatric drug‐resistant epilepsy (DRE). Knowledge gaps exist in patient selection, surgical technique, and perioperative care. Here, we use an expert survey to clarify practices. Thirty‐two members of the Pediatric Epilepsy Research Consortium were surveyed using REDCap. Respondents were from 17 pediatric epilepsy centers (missing data in one): Four centers implant RNS only while 13 implant both RNS and DBS. Thirteen RNS programs commenced in or before 2020, and 10 of 12 DBS programs began thereafter. The busiest six centers implant 6–10 new RNS devices per year; all DBS programs implant 50%) was reported by 81% (13/16) of centers. RNS and DBS are rapidly evolving treatment modalities for safe and effective treatment of pediatric DRE. There is increasing interest in multicenter collaboration to gain knowledge and facilitate dialogue. Plain language summary We surveyed 32 pediatric epilepsy centers in USA to highlight current practices of intracranial neuromodulation. Of the 17 that replied, we found that most centers are implanting thalamic targets in pediatric drug‐resistant epilepsy using the RNS device. DBS device is starting to be used in pediatric epilepsy, especially after 2020. Different strategies for target identification are enumerated. This study serves as a starting point for future collaborative research.

Abstract Respiratory Syncytial Virus (RSV) is a leading cause of acute respiratory tract infection, with the greatest impact on infants, immunocompromised individuals, and older adults. RSV prevalence decreased substantially in the United States (US) following the implementation of COVID-19-related non-pharmaceutical interventions but later rebounded with abnormal seasonality. The biological and epidemiological factors underlying this altered behavior remain poorly defined. In this retrospective cohort study from 2009 to 2023 in Chicago, Illinois, US, we examined RSV epidemiology, clinical severity, and genetic diversity. We found that changes in RSV diagnostic platforms drove increased detections in outpatient settings post-2020 and that hospitalized adults infected with RSV-A were at higher risk of intensive care admission than those with RSV-B. While population structures of RSV-A remained unchanged, RSV-B exhibited a genetic shift into geographically distinct clusters. Mutations in the antigenic regions of the fusion protein suggest convergent evolution with potential implications for vaccine and therapeutic development.

The objectives of the present study were to describe civic attitudes and behaviors among Latinx child farmworkers in North Carolina, examine civic outcomes across relevant demographic characteristics, and discuss the implications for research on sociopolitical development among Latinx child farmworkers and for developmental theory. Descriptive statistics (count, percent, or mean, standard deviation as appropriate) were calculated for demographic and civic variables. Associations between the demographic variables and the four civic summary variables were calculated using Generalized Linear Models, the Kruskal–Wallis test, t-tests, or Chi-Square tests. Latinx child farmworkers in North Carolina (N = 169; ages 11–19, Mage = 15.8, 62.7% boys) endorsed relatively high levels of beliefs that society is fair and connections/efficacy in their communities. They reported relatively low involvement in volunteering and political activity. Future work should examine how the daily lives and experiences of child farmworkers inform their developing ideas about civic life in the US and their behavioral participation as they mature.

Abstract Animal performance fundamentally influences behaviour, ecology, and evolution. It typically varies monotonously with size. A notable exception is maximum running speed; the fastest animals are of intermediate size. Here we show that this peculiar allometry results from the competition between two musculoskeletal constraints: the kinetic energy capacity, which dominates in small animals, and the work capacity, which reigns supreme in large animals. The ratio of both capacities defines the physiological similarity index Γ, a dimensionless number akin to the Reynolds number in fluid mechanics. The scaling of Γ indicates a transition from a dominance of muscle forces to a dominance of inertial forces as animals grow in size; its magnitude defines conditions of “dynamic similarity“ that enable comparison and estimates of locomotor performance across extant and extinct animals; and the physical parameters that define it highlight opportunities for adaptations in musculoskeletal “design” that depart from the eternal null hypothesis of geometric similarity. The physiological similarity index challenges the Froude number as prevailing dynamic similarity condition, reveals that the differential growth of muscle and weight forces central to classic scaling theory is of secondary importance for the majority of terrestrial animals, and suggests avenues for comparative analyses of locomotor systems.

Introduction: Maxillary ameloblastoma is a rare, slow-growing odontogenic tumor that can recur after surgical excision, be locally aggressive, and rarely develop systemic metastases. We describe the course and management of a patient with recurrent maxillary ameloblastoma with orbital invasion and systemic metastases, the fourth case of its kind to be described in the literature. Case Presentation: A 50-year-old female presented with left hyperglobus. A diagnosis of maxillary ameloblastoma was made based on biopsy and neuroimaging with MRI and CT. Surgical management included partial maxillectomy with orbital floor reconstruction, given the orbital invasion. Three years later, left hyperglobus recurred, and the patient was found to have orbital recurrence and lung metastases on PET imaging. The lung and orbital lesions have responded well to chemoradiation therapy without surgical intervention. Conclusion: Maxillary ameloblastoma is a rare tumor that typically arises from odontogenic tissues. Though considered benign, they can recur and in the case of our patient, metastasize. Complete surgical excision with wide surgical margins is associated with a shorter average time to recurrence and a lower incidence of metastasis. Cases of metastasis are managed with chemotherapy with or without adjuvant radiotherapy. Precision medicine may play a role in managing this entity in the future, given the discovery of differing profiles of maxillary ameloblastoma compared to mandibular. Ophthalmologists should be aware of this tumor as it can invade the orbit, resulting in significant ocular morbidity and mortality.

Abstract Low‐grade epilepsy‐associated tumors (LEATs) are a common cause of drug‐resistant epilepsy in children. Herein, we demonstrate the feasibility of using tumor tissue derived from stereoelectroencephalography (sEEG) electrodes upon removal to molecularly characterize tumors and aid in diagnosis. An 18‐year‐old male with focal epilepsy and MRI suggestive of a dysembryoplastic neuroepithelial tumor (DNET) in the left posterior temporal lobe underwent implantation of seven peri‐tumoral sEEG electrodes for peri‐operative language mapping and demarcation of the peri‐tumoral ictal zone prior to DNET resection. Using electrodes that passed through tumor tissue, we show successful isolation of tumor DNA and subsequent analysis using standard methods for tumor classification by DNA, including Glioseq targeted sequencing and DNA methylation array analysis. This study provides preliminary evidence for the feasibility of molecular diagnosis of LEATs or other lesions using a minimally invasive method with microscopic tissue volumes. The implications of sEEG electrodes in tumor characterization are broad but would aid in diagnosis and subsequent targeted therapeutic strategies.

Abstract Objective Corpus callosotomy (CC) is an important treatment for atonic seizures in patients with generalized or multifocal drug‐resistant epilepsy (DRE). Traditionally, CC is performed via an open microsurgical approach, but more recently, MR‐guided stereotactic laser interstitial thermal therapy (LITT) corpus callosum ablation (CCA) has been developed to leverage the safety and minimally invasive nature of LITT. Given the recent adoption of CCA at select centers, how CCA compares to CC is unknown. We aim to compare the clinical seizure outcomes of CCA and CC after extended follow‐up. Methods We performed a retrospective cohort study to compare the effectiveness and safety of CC to CCA from 1994 to 2022. The primary outcome was a 50% reduction in target seizure. Secondary outcome measures were postoperative length of stay, adverse events, and other effectiveness metrics. Comparative statistics were executed using Stata. Normality for continuous variables was assessed, and parametric statistics were utilized as needed. Frequency was compared with chi‐squared or Fischer's exact tests, when applicable. Results Data from 47 operations performed on 36 patients were included in this study, of which 13 (36%) patients underwent 17 CCA. Patients who received CCA had similar rates of meaningful reduction (>50%) of atonic seizures as their CC counterparts (55% vs 70% P = 0.15). Patients undergoing CCA had significantly shorter hospitalizations than those receiving CC (2.5 vs 6.0 days P

Abstract The medial entorhinal cortex (MEC) is hypothesized to function as a cognitive map for memory-guided navigation. How this map develops during learning and influences memory remains unclear. By imaging MEC calcium dynamics while mice successfully learned a novel virtual environment over ten days, we discovered that the dynamics gradually became more spatially consistent and then stabilized. Additionally, grid cells in the MEC not only exhibited improved spatial tuning consistency, but also maintained stable phase relationships, suggesting a network mechanism involving synaptic plasticity and rigid recurrent connectivity to shape grid cell activity during learning. Increased c-Fos expression in the MEC in novel environments further supports the induction of synaptic plasticity. Unsuccessful learning lacked these activity features, indicating that a consistent map is specific for effective spatial memory. Finally, optogenetically disrupting spatial consistency of the map impaired memory-guided navigation in a well-learned environment. Thus, we demonstrate that the establishment of a spatially consistent MEC map across learning both correlates with, and is necessary for, successful spatial memory.

Abstract Background Cancer-testis antigens (CTAs) are tumor antigens that are normally expressed in the testes but are aberrantly expressed in several cancers. CTA overexpression drives the metastasis and progression of lung cancer, and is associated with poor prognosis. To improve lung cancer diagnosis, prognostic prediction, and drug discovery, robust CTA identification and quantitation is needed. In this study, we examined and quantified the co-expression of CTAs in lung cancer to derive cancer testis antigen burden (CTAB), a novel biomarker of immunotherapy response. Methods Formalin fixed paraffin embedded (FFPE) tumor samples in discovery cohort (n = 5250) and immunotherapy and combination therapy treated non-small cell lung cancer (NSCLC) retrospective (n = 250) cohorts were tested by comprehensive genomic and immune profiling (CGIP), including tumor mutational burden (TMB) and the mRNA expression of 17 CTAs. PD-L1 expression was evaluated by IHC. CTA expression was summed to derive the CTAB score. The median CTAB score for the discovery cohort of 170 was applied to the retrospective cohort as cutoff for CTAB “high” and “low”. Biomarker and gene expression correlation was measured by Spearman correlation. Kaplan–Meier survival analyses were used to detect overall survival (OS) differences, and objective response rate (ORR) based on RECIST criteria was compared using Fisher’s exact test. Results The CTAs were highly co-expressed (p

Introduction: Skin ulcers can be challenging to diagnose and manage, particularly with comorbid autoimmune and gastrointestinal diseases. Occam’s razor encourages the simplest explanation to guide care, but reconsideration must occur when intervention proves futile. Case Presentation: We report the case of a 70-year-old male, with a 17-year history of expanding pretibial skin ulcer, presumed by prior care providers to be pyoderma gangrenosum related to Crohn’s disease. A surgical biopsy performed upon presentation to our institution revealed basal cell carcinoma of the skin, invasive to the proximal tibia with associated deep infection, prompting transfemoral amputation. Conclusion: This report is written as a reminder to reconsider a diagnosis and consider seeking additional expertise when a patient’s condition progressively worsens despite intervention. Earlier diagnosis likely would have facilitated therapeutic limb salvage care.

IntroductionYounger patients with non-small cell lung cancer (NSCLC) (

Wearable robotic exoskeletons designed to assist human movement should integrate with the neuromusculoskeletal system. This means assisting movement while not perturbing motor control. We sought to test if passive ankle exoskeletons, which have been shown to successfully assist human gait, affect neuromuscular control of an exaggerated anterior–posterior standing sway task. Participants actively swayed while wearing an ankle exoskeleton that provided 0, 42 or 85 Nm rad−1 of additional stiffness to the ankle joint in resistance to dorsiflexion. Sway amplitude was controlled via biofeedback to elicit similar ankle angle displacements across conditions. With greater exoskeleton stiffness, participants swayed at lower sway-cycle frequencies and slower centre of pressure speeds. Furthermore, increasing exoskeleton stiffness resulted in longer operating lengths of the medial gastrocnemius and overall reduced plantar flexor muscle activation. For the soleus, there was also a temporal shift in the cross-correlation of its electromyogram with the centre of pressure displacement, meaning that muscle activation peaked later than anterior sway displacement. Together, these data suggest that assistive ankle exoskeletons influence neuromuscular control of ankle-based sway tasks. Changes in fascicle lengths could influence afferent feedback signals and the short-range stiffness of ankle muscles, while shifts in muscle activation timing suggest changes in neural control. The observed neuromuscular adaptations to exoskeleton assistance demonstrate the potential implications for standing balance and overall movement control, prompting future investigations.

Abstract Background Opioid use remains a major public health issue, especially among young adults. Despite investment in harm reduction and supply-side strategies such as reducing overprescribing and safe medication disposal, little is known about demand-side issues, such as reasons for use and pathways to opioid use. Adolescents and young adults who struggle with opioid use disorder (OUD) are multifaceted individuals with varied individual histories, experiences, challenges, skills, relationships, and lives. Methods To inform the development of prevention strategies that hold promise for addressing opioid use, this study employs brief structured surveys and semi-structured in-depth interviews with 30 young adults (ages 18–29; 19 female, 23 White, 16 from Suburban areas) in recovery from OUD. For survey data, we used descriptive statistics to summarize the means and variance of retrospectively reported risk and protective factors associated with opioid use. For in-depth interview data, we used a combination of thematic analysis and codebook approaches to generate common themes and experiences shared by participants. Results Surveys revealed that the most endorsed risk factors pertained to emotions (emotional neglect and emotional abuse) followed by sexual abuse, physical abuse, and physical neglect. Themes generated from qualitative analyses reveal challenging experiences during adolescence, such as unaddressed mental health, social, and emotional needs, which were often reported as reasons for opioid initiation and use. Through surveys and interviews, we also identified positive assets, such as skills and social relationships that were present for many participants during adolescence. Conclusion Implications include the need for universal prevention strategies that include emotion-focused interventions and supports alongside current harm reduction and environmental strategies to regulate prescriptions; the potential utility of more emotion-focused items being included on screening tools; and more voices of young people in recovery.

Abstract Atomically precise hydrogen desorption lithography using scanning tunnelling microscopy (STM) has enabled the development of single-atom, quantum-electronic devices on a laboratory scale. Scaling up this technology to mass-produce these devices requires bridging the gap between the precision of STM and the processes used in next-generation semiconductor manufacturing. Here, we demonstrate the ability to remove hydrogen from a monohydride Si(001):H surface using extreme ultraviolet (EUV) light. We quantify the desorption characteristics using various techniques, including STM, X-ray photoelectron spectroscopy (XPS), and photoemission electron microscopy (XPEEM). Our results show that desorption is induced by secondary electrons from valence band excitations, consistent with an exactly solvable non-linear differential equation and compatible with the current 13.5 nm (~92 eV) EUV standard for photolithography; the data imply useful exposure times of order minutes for the 300 W sources characteristic of EUV infrastructure. This is an important step towards the EUV patterning of silicon surfaces without traditional resists, by offering the possibility for parallel processing in the fabrication of classical and quantum devices through deterministic doping.

Abstract Epilepsy affects 1% of the US population. Healthcare disparities are well-studied among adults with epilepsy but less so among children. We examined whether children with epilepsy (1) have lower income than or (2) utilize the emergency department (ED) differently from children without epilepsy, and (3) if income moderates ED utilization. Data from the 2016–2019 National Survey of Children’s Health were used to identify children with active “epilepsy or seizure disorder”. Children with versus without epilepsy were compared. Income and ED visits were modeled with logistic and Poisson regressions. This analysis included 131,326 children; 835 were diagnosed with epilepsy. Estimated population prevalence of epilepsy was 0.6%. Children from higher-income-households were less likely to have epilepsy (aOR: 0.7). Children with epilepsy were more likely to visit EDs (aOR = 10.2), see healthcare professionals (aOR: 2.7), and receive care from specialists (aOR: 10.3). Income moderated the relationship between having epilepsy and ED visits. 7.7% of children with epilepsy did not receive needed healthcare. Some barriers were acquiring appointments (aOR: 3.9) and transportation (aOR: 4.7). In conclusion, children with epilepsy were more likely than children without epilepsy to live in lower-income-households, visit EDs, see healthcare professionals, and not receive needed healthcare. Barrier-specific policy interventions may improve medical access for children with epilepsy.

Abstract The Aerosol Cloud meTeorology Interactions oVer the western ATlantic Experiment (ACTIVATE) field campaign provides accurate data for aerosol characterization and trace gas profiles, and establishes knowledge of the relationships between aerosols and water. The dropsonde dataset provides an in situ characterization of the vertical thermodynamic structure of the atmosphere during 165 research flights by NASA Langley’s King Air research aircraft between February 2020 and June 2022 and four test flights between December 2019 and November 2021. The research flights covered the western North Atlantic region, off the coast of the Eastern United States and around Bermuda and covered all seasons. The dropsonde profiles provide observations of temperature, pressure, relative humidity, and horizontal and vertical winds between the surface and about 9 km. 801 dropsondes were released, of which 796 were processed and 788 provide complete profiles of all parameters between the flight level and the surface with normal parachute performance. Here, we describe the dataset, the processing of the measurements, general statistics, and applications of this rich dataset.

Background: Exercise can promote sustainable protection against cold and warm liver ischemia–reperfusion injury (IRI) and tumor metastases. We have shown that this protection is by the induction of hepatic mitochondrial biogenesis pathway. In this study, we hypothesize that ZLN005, a PGC-1α activator, can be utilized as an alternative therapeutic strategy. Methods: Eight-week-old mice were pretreated with ZLN005 and subjected to liver warm IRI. To establish a liver metastatic model, MC38 cancer cells (1 × 106) were injected into the spleen, followed by splenectomy and liver IRI. Results: ZLN005-pretreated mice showed a significant decrease in IRI-induced tissue injury as measured by serum ALT/AST/LDH levels and tissue necrosis. ZLN005 pretreatment decreased ROS generation and cell apoptosis at the site of injury, with a significant decrease in serum pro-inflammatory cytokines, innate immune cells infiltration, and intrahepatic neutrophil extracellular trap (NET) formation. Moreover, mitochondrial mass was significantly upregulated in hepatocytes and maintained after IRI. This was confirmed in murine and human hepatocytes treated with ZLN005 in vitro under normoxic and hypoxic conditions. Additionally, ZLN005 preconditioning significantly attenuated tumor burden and increased the percentage of intratumoral cytotoxic T cells. Conclusions: Our study highlights the effective protection of ZLN005 pretreatment as a therapeutic alternative in terms of acute liver injury and tumor metastases.

Abstract Objectives Type 1 laryngeal clefts (LC1) and deep interarytenoid grooves contribute to pediatric feeding disorders. Management of these defects remains heterogeneous among surgeons and interarytenoid injection augmentation (IIA) is not always offered as a treatment option. This study evaluated IIA outcomes among a pediatric patient cohort comprised mostly of those with deep interarytenoid grooves. Methods A single‐institution retrospective chart review featured children under the age of 5 years presenting for aspiration, dysphagia, or choking. Over the period of 7 years (January 2014–October 2021), 39 met inclusion criteria and had sufficient follow‐up data. Descriptive statistics and subgroup analyses were performed. Results Of the 39 included patients, 76.92% had clinical improvement post‐injection, with the mean time to follow‐up being 47 days. Within the deep interarytenoid groove group, improvement rates were 82.76%. Bronchoscopy findings revealed 29 (74.36%) patients with a DIG, 3 (7.69%) with LC1, 3 (7.69%) with no anatomic abnormality, and 4 (10.26%) with vocal cord paralysis. There were no adverse events. There were no associations with the outcomes based on subgroup analysis and logistic regression. Conclusions IIA is an effective and safe treatment for pediatric feeding disorders. No covariates were associated with symptom improvement. Within the deep interarytenoid groove diagnosis subgroup, IIA effectively improved symptoms. Further investigations are needed to explore predictors of success with IIA in this population. Level of Evidence VI.

Abstract Granulomas often form around pathogens that cause chronic infections. Here, we discover an innate granuloma model in mice with an environmental bacterium called Chromobacterium violaceum. Granuloma formation not only successfully walls off, but also clears, the infection. The infected lesion can arise from a single bacterium that replicates despite the presence of a neutrophil swarm. Bacterial replication ceases when macrophages organize around the infection and form a granuloma. This granuloma response is accomplished independently of adaptive immunity that is typically required to organize granulomas. The C. violaceum-induced granuloma requires at least two separate defense pathways, gasdermin D and iNOS, to maintain the integrity of the granuloma architecture. This innate granuloma successfully eradicates C. violaceum infection. Therefore, this C. violaceum-induced granuloma model demonstrates that innate immune cells successfully organize a granuloma and thereby resolve infection by an environmental pathogen.

Abstract Background Delayed access to care may contribute to disparities in prostate cancer (PCa). The Affordable Care Act (ACA) aimed at increasing access and reducing healthcare disparities, but its impact on timely treatment initiation for PCa men is unknown. Methods Men with intermediate‐ and high‐risk PCa diagnosed 2010–2016 and treated with curative surgery or radiotherapy were identified in the National Cancer Database. Multivariable logistic regression modeled the effect of race and insurance type on treatment delay >180 days after diagnosis. Cochran–Armitage test measured annual trends in delays, and joinpoint regression assessed if 2014, the year the ACA became fully operationalized, was significant for inflection in crude rates of major delays. Results Of 422,506 eligible men, 18,720 (4.4%) experienced >180‐day delay in treatment initiation. Compared to White patients, Black (OR 1.79, 95% CI 1.72–1.87, p

Abstract Background A prospective observational cohort study of COVID-19 patients in a single Emergency Department (ED) showed that sTREM-1- and IL-6-based algorithms were highly predictive of adverse outcome (Van Singer et al. J Allergy Clin Immunol 2021). We aim to validate the performance of these algorithms at ED presentation. Methods This multicentric prospective observational study of PCR-confirmed COVID-19 adult patients was conducted in the ED of three Swiss hospitals. Data of the three centers were retrospectively completed and merged. We determined the predictive accuracy of the sTREM-1-based algorithm for 30-day intubation/mortality. We also determined the performance of the IL-6-based algorithm using data from one center for 30-day oxygen requirement. Results 373 patients were included in the validation cohort, 139 (37%) in Lausanne, 93 (25%) in St.Gallen and 141 (38%) in EOC. Overall, 18% (93/373) patients died or were intubated by day 30. In Lausanne, 66% (92/139) patients required oxygen by day 30. The predictive accuracy of sTREM-1 and IL-6 were similar compared to the derivation cohort. The sTREM-1-based algorithm confirmed excellent sensitivity (90% versus 100% in the derivation cohort) and negative predictive value (94% versus 100%) for 30-day intubation/mortality. The IL-6-based algorithm performance was acceptable with a sensitivity of 85% versus 98% in the derivation cohort and a negative predictive value of 60% versus 92%. Conclusion The sTREM-1 algorithm demonstrated good reproducibility. A prospective randomized controlled trial, comparing outcomes with and without the algorithm, is necessary to assess its safety and impact on hospital and ICU admission rates. The IL-6 algorithm showed acceptable validity in a single center and need additional validation before widespread implementation.

Abstract Background ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes. Methods Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs—one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)—on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe. Results A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC. Conclusions The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures.

Lennox Gastaut Syndrome (LGS) is characterized by drug-resistant epilepsy that typically leads to decreased quality of life and deleterious neurodevelopmental comorbidities from medically refractory seizures. In recent years there has been a dramatic increase in the development and availability of novel treatment strategies for Lennox Gastaut Syndrome patient to improve seizure. Recent advances in neuromodulation and minimally invasive magnetic resonance guided laser interstitial thermal therapy (MRgLITT) have paved the way for new treatments strategies including deep brain stimulation (DBS), responsive neurostimulation (RNS), and MRgLITT corpus callosum ablation. These new strategies offer hope for children with drug-resistant generalized epilepsies, but important questions remain about the safety and effectiveness of these new approaches. In this review, we describe the opportunities presented by these new strategies and how each treatment strategy is currently being employed. Next, we will critically assess available evidence for these new approaches compared to traditional palliative epilepsy surgery approaches, such as vagus nerve stimulation (VNS) and open microsurgical corpus callosotomy (CC). Finally, we will describe future directions that would help define which of the available strategies should be employed and when.

Background:. Perioperative data are essential to improve the safety of surgical care. However, surgical outcome research (SOR) from low- and middle-income countries (LMICs) is disproportionately sparse. We aimed to assess practices, barriers, facilitators, and perceptions influencing the collection and use of surgical outcome data (SOD) in LMICs. Methods:. An internet-based survey was developed and disseminated to stakeholders involved in the care of surgical patients in LMICs. The Performance of Routine Information Systems Management framework was used to explore the frequency and relative importance of organizational, technical, and behavioral barriers. Associations were determined using χ2 and ANOVA analyses. Results:. Final analysis included 229 surgeons, anesthesia providers, nurses, and administrators from 36 separate LMICs. A total of 58.1% of individuals reported that their institution had experience with collection of SOD and 73% of these reported a positive impact on patient care. Mentorship and research training was available in

Abstract Background When lengthening the tibia segment using motorized internal lengthening nails (MILN), undesired distal migration of the proximal fibula segment is prevented by tibiofibular stabilization, traditionally using a screw. A tightened cortical suspensory fixation rope (tether) is an alternative option, but its appropriateness has never been studied. The primary outcome was comparing the amount of proximal fibular migration between patients who were stabilized with either a tether or a screw. The secondary outcome was to evaluate the effect of fibular migration on the clinical outcome between both groups. Methods A retrospective study was conducted on patients who underwent tibial lengthening with MILN between April 2016 and June 2022. Two cohorts were compared: 18 limbs with tether fixation versus 29 limbs with screw fixation. Data on the patient's age, sex, etiologies, and clinical outcomes were collected. Radiographic measurements included the lengthening distance and the amount of proximal fibular migration. Results In total, 47 limbs from 41 patients, with average age 35.01 ± 13.72 years old. There were 28 males (68.29%) and 13 females (31.71%). The tether group demonstrated a statistically significant greater distance of migration than the screw group (p

Abstract In-situ marine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to expanding the available data in these difficult-to-reach regions of the Earth and improving our understanding of aerosol-cloud interactions. The data collection includes particle composition and continental tracers to identify potential contributing CCN sources. Several of these campaigns include High Spectral Resolution Lidar (HSRL) and polarimetric imaging measurements and retrievals that will be the basis for the next generation of space-based remote sensors and, thus, can be utilized as satellite surrogates.

Abstract Aims Heart failure (HF) is one of the leading causes of cardiovascular morbidity and mortality. HF with preserved ejection fraction (HFpEF), or diastolic failure, accounts for half of all HF cases and differs from HF with reduced ejection fraction (HFrEF). Patients with HFpEF are typically older, female, and commonly seen with chronic kidney disease (CKD), one of the leading independent risk factors for mortality in these patients. Unfortunately, drugs that had shown significant improvements in mortality in HFrEF have not shown similar benefits in HFpEF. Recently, sodium glucose transporter 2 inhibitors (SGLT2i) have been shown to reduce cardiovascular morbidity and mortality in HFrEF patients and slow down CKD progression. This study aimed to elucidate the impact of this drug class on mortality and risk of end stage renal disease in patients with HFpEF, which is currently unclear. Methods and results We retrospectively analysed the Research Data Warehouse containing electronic health records from de‐identified patients (n = 1 266 290) from the University of Mississippi Medical Center from 2013 to 2022. HFpEF patients had an average follow‐up of 4 ± 2 years. Factors associated with increased all‐cause mortality during HFpEF included age, male sex, and CKD. Interestingly, the only treatments associated with significant improvements in survival were angiotensin converting enzyme inhibitors/angiotensin receptor blockers and SGLT2i, regardless of CKD or diabetes status. Additionally, SGLT2i use was also associated with significant decrease in the risk of end stage renal disease. Conclusions Our results support the use of SGLT2i in an HFpEF population with relatively high rates of hypertension, CKD, and black race and suggests that improvements in mortality may be through preserving kidney function.

Chagas disease is an inflammatory parasitic infection caused by Trypanosoma cruzi (T. cruzi). Early diagnosis is crucial in guiding treatment and slowing disease progression; however, current diagnostic methods have insufficient detection limits and often require skilled technicians. Molecular tests, especially isothermal nucleic acid assays, are advantageous due to their excellent sensitivity, specificity, speed, and simplicity. Here, we optimized a colorimetric loop-mediated isothermal amplification (LAMP) assay for T. cruzi. We can detect as few as 2 genomic copies/reaction using three different T. cruzi strains. We examined selectivity using other parasitic protozoans and successfully detected T. cruzi DNA extracted from parasites in human whole blood down to 1.2 parasite equivalents/reaction. We also performed a blinded study using canine blood samples and established a 100% sensitivity, specificity, and accuracy for the colorimetric LAMP assay. Finally, we used a heated 3D printer bed and an insulated thermos cup to demonstrate that the LAMP incubation step could be performed with accessible, low-cost materials. Altogether, we have developed a high-performing assay for T. cruzi with a simple colorimetric output that would be ideal for rapid, low-cost screening at the point of use.

Telomeres, potential biomarkers of aging, are known to shorten with continued cigarette smoke exposure. In order to further investigate this process and its impact on cellular stress and inflammation, we used an in vitro model with cigarette smoke extract (CSE) and observed the downregulation of telomere stabilizing TRF2 and POT1 genes after CSE treatment. hTERT is a subunit of telomerase and a well-known oncogenic marker, which is overexpressed in over 85% of cancers and may contribute to lung cancer development in smokers. We also observed an increase in hTERT and ISG15 expression levels after CSE treatment, as well as increased protein levels revealed by immunohistochemical staining in smokers’ lung tissue samples compared to non-smokers. The effects of ISG15 overexpression were further studied by quantifying IFN-γ, an inflammatory protein induced by ISG15, which showed greater upregulation in smokers compared to non-smokers. Similar changes in gene expression patterns for TRF2, POT1, hTERT, and ISG15 were observed in blood and buccal swab samples from smokers compared to non-smokers. The results from this study provide insight into the mechanisms behind smoking causing telomere shortening and how this may contribute to the induction of inflammation and/or tumorigenesis, which may lead to comorbidities in smokers.

Summary: Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Summary: Skeletal muscle protein levels are governed by the relative rates of muscle protein synthesis (MPS) and breakdown (MPB). The mechanisms controlling these rates are complex, and their integrated behaviors are challenging to study through experiments alone. The purpose of this study was to develop and analyze a kinetic model of leucine-mediated mTOR signaling and protein metabolism in the skeletal muscle of young adults. Our model amalgamates published cellular-level models of the IRS1-PI3K-Akt-mTORC1 signaling system and of skeletal-muscle leucine kinetics with physiological-level models of leucine digestion and transport and insulin dynamics. The model satisfactorily predicts experimental data from diverse leucine feeding protocols. Model analysis revealed that total levels of p70S6K are a primary determinant of MPS, insulin signaling substantially affects muscle net protein balance via its effects on MPB, and p70S6K-mediated feedback of mTORC1 signaling reduces MPS in a dose-dependent manner.

The human voice is a critical stimulus for the auditory system that promotes social connection, informs the listener about identity and emotion, and acts as the carrier for spoken language. Research on voice processing in adults has informed our understanding of the unique status of the human voice in the mature auditory cortex and provided potential explanations for mechanisms that underly voice selectivity and identity processing. There is evidence that voice perception undergoes developmental change starting in infancy and extending through early adolescence. While even young infants recognize the voice of their mother, there is an apparent protracted course of development to reach adult-like selectivity for human voice over other sound categories and recognition of other talkers by voice. Gaps in the literature do not allow for an exact mapping of this trajectory or an adequate description of how voice processing and its neural underpinnings abilities evolve. This review provides a comprehensive account of developmental voice processing research published to date and discusses how this evidence fits with and contributes to current theoretical models proposed in the adult literature. We discuss how factors such as cognitive development, neural plasticity, perceptual narrowing, and language acquisition may contribute to the development of voice processing and its investigation in children. We also review evidence of voice processing abilities in premature birth, autism spectrum disorder, and phonagnosia to examine where and how deviations from the typical trajectory of development may manifest.