Overview of Unilateral and Bilateral Pediatric Facial Paralysis: Workup, Treatment, and Frontiers.

Pediatric facial nerve paralysis can present significant challenges based on its various etiologies, unique approach to treatment options, and overall outcomes. It can impact both the child and parent when regarding function, appearance, and psychosocial implications. The etiology of facial nerve palsy can include congenital, traumatic, iatrogenic, and idiopathic causes. In some, the paralysis is transient while others have permanent loss of function. A thorough evaluation and differential diagnosis are essential to guide treatment planning. The purpose of this paper is to review facial paralysis in children with a focus on surgical management.

Vitamin D and Toxic Metals in Pregnancy - a Biological Perspective.

Purpose of Review: To discuss the potential biological mechanisms between vitamin D and toxic metals and summarize epidemiological studies examining this association in pregnant women. Recent Findings: We identified four plausible mechanisms whereby vitamin D and toxic metals may interact: nephrotoxicity, intestinal absorption of metals, endocrine disruption, and oxidative stress. Few studies have examined the association between vitamin D and toxic metals in pregnant women. North American studies suggest that higher vitamin D status early in pregnancy are associated with lower blood metals later in pregnancy. However, a trial of vitamin D supplementation in a pregnant population, with higher metal exposures and lower overall nutritional status, does not corroborate these findings. Summary: Given ubiquitous exposure to many toxic metals, nutritional intervention could be a means for prevention of adverse outcomes. Future prospective studies are needed to establish a causal relationship and clarify the directionality of vitamin D and metals. Supplementary Information: The online version contains supplementary material available at 10.1007/s40471-024-00348-0.

Biohacking Nerve Repair: Novel Biomaterials, Local Drug Delivery, Electrical Stimulation, and Allografts to Aid Surgical Repair.

The regenerative capacity of the peripheral nervous system is limited, and peripheral nerve injuries often result in incomplete healing and poor outcomes even after repair. Transection injuries that induce a nerve gap necessitate microsurgical intervention; however, even the current gold standard of repair, autologous nerve graft, frequently results in poor functional recovery. Several interventions have been developed to augment the surgical repair of peripheral nerves, and the application of functional biomaterials, local delivery of bioactive substances, electrical stimulation, and allografts are among the most promising approaches to enhance innate healing across a nerve gap. Biocompatible polymers with optimized degradation rates, topographic features, and other functions provided by their composition have been incorporated into novel nerve conduits (NCs). Many of these allow for the delivery of drugs, neurotrophic factors, and whole cells locally to nerve repair sites, mitigating adverse effects that limit their systemic use. The electrical stimulation of repaired nerves in the perioperative period has shown benefits to healing and recovery in human trials, and novel biomaterials to enhance these effects show promise in preclinical models. The use of acellular nerve allografts (ANAs) circumvents the morbidity of donor nerve harvest necessitated by the use of autografts, and improvements in tissue-processing techniques may allow for more readily available and cost-effective options. Each of these interventions aid in neural regeneration after repair when applied independently, and their differing forms, benefits, and methods of application present ample opportunity for synergistic effects when applied in combination.

Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies.

Neurofibromatosis type 1 (NF1), Noonan syndrome and related syndromes, grouped as the RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together the RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared to the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the last decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multi-disciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 AACR Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.

A Quantitative Analysis of Publication Trends in Vascular Surgery and a Comparative Analysis with Interventional Radiology.

BACKGROUND: Since its recognition as an independent surgical subspecialty, vascular surgery has experienced rapid growth in both surgical volume and research productivity. Trends in vascular surgery research have not been well characterized. Understanding how research in the field has evolved in comparison to interventional radiology can offer insights into evolving interests and discrepancies between the specialties. METHODS: Primary and secondary research publications indexed in the MEDLINE database from 1992 to 2023 were analyzed using a novel text mining algorithm. Eight high-impact vascular surgery journals and 6 interventional radiology journals were included. Articles were categorized based on treatment modalities, pathologies, and other subgroup analyses. Temporal trends were assessed using linear regression and correlation analysis. A comparative analysis was performed assessing publication trends by broad pathology groups between vascular surgery and interventional radiology journals. A further subgroup analysis was conducted comparing publication trends by endovascular treatment modality for peripheral arterial disease (PAD). RESULTS: 28,931 vascular surgery publications and 13,094 interventional radiology publications met the inclusion criteria. Publication volume grew exponentially, with over 50% emerging in the last decade. Publications exploring endovascular interventions have increasingly exceeded those focused on exclusively open interventions in research volume since 2006. Aortic pathology, carotid disease, PAD, and venous pathology represented the vast majority of vascular surgery research output, with PAD exhibiting the fastest growth. Comparative analysis revealed a number of key differences in research focus and treatment modalities between vascular surgery and interventional radiology, including a greater emphasis on venous pathology in interventional radiology journals and fewer relative publications on carotid artery pathology (P < 0.001). When comparing endovascular treatments for PAD, interventional radiology journals published more frequently on endovascular brachytherapy (8.73% vs 1.02%, P < 0.001) and less frequently on atherectomy (4.29% vs 6.50%, P = 0.035) as compared to the vascular surgery journals. CONCLUSIONS: Our findings demonstrate increasing emphasis on endovascular interventions and specific pathologies in vascular surgery research. Despite some key differences, there is notable overlap in interests between vascular surgery and interventional radiology, which may represent promising opportunities for collaboration in advancing endovascular procedures. Differences in research focus may stem from specialty perspectives and be perpetuated by differences in training.

Patterns of Locoregional Pancreatic Cancer Recurrence After Total Neoadjuvant Therapy and Implications on Optimal Neoadjuvant Radiation Treatment Volumes.

PURPOSE: To generate a map of local recurrences after neoadjuvant chemotherapy and radiation (total neoadjuvant therapy or TNT) followed by surgical resection for pancreatic ductal adenocarcinoma (PDAC). Such recurrence patterns will serve to inform radiation treatment planning volumes that should be given in the neoadjuvant setting. METHODS: Locoregional recurrences following TNT followed by surgery treated between 2009-2022 were radiologically identified. Recurrences were individually segmented using MIM software and complied in a single base scan. All contour compilations were used to create a threshold contour encompassing 80% of recurrences among all patients, head only, and body/tail only. The distance between organs at risk and the threshold contour were measured to design an optimal clinical target volume (CTV) contour for patients treated with TNT. Recurrence patterns were also compared to existing adjuvant guidelines to assess coverage. RESULTS: A database of 484 patients managed with TNT for PDAC was queried. While locoregional recurrences were rare in this cohort, we identified eighty patients with either isolated locoregional or simultaneous local and distant recurrences. Patients with diagnostic imaging at the time of recurrence were identified. The majority of recurrences were partially in the field of published contouring guidelines or volumetric expansions off of vessels, and volumetric coverage was low for all. Common areas of recurrence include the aortico-diaphragmatic junction, retro-pancreatic duodenal nodal basin, and the region to the right of the superior mesenteric artery. A novel set of proposed neoadjuvant contours was designed to cover the central-most 80% of recurrences. CONCLUSIONS: This is the largest collection of local/regional PDAC recurrences from a cohort of patients treated exclusively with TNT. Patterns of local/regional recurrence using TNT in PDAC vary significantly from those patients with PDAC treated with a surgery-first approach. Novel contouring guidelines presented herein can help to ensure optimal coverage of high risk regions and avoid reliance on the current adjuvant guidelines to guide treatment planning.

Programmable responsive metamaterials for mechanical computing and robotics.

Unconventional computing based on mechanical metamaterials has been of growing interest, including how such metamaterials might process information via autonomous interactions with their environment. Here we describe recent efforts to combine responsive materials with nonlinear mechanical metamaterials to achieve stimuli-responsive mechanical logic and computation. We also describe some key challenges and opportunities in the design and construction of these devices, including the lack of comprehensive computational tools, and the challenges associated with patterning multi-material mechanisms.

Comments and Controversies in Oncology: The Tribulations of Trials Developing ONC201.

Our international team highlights issues with efficacy reports in several studies on DMG with the new drug ONC201.

Apple Vision Pro Augmented Reality-Assisted Minimally Invasive Surgical Treatment of Spinal Dural Arteriovenous Fistula.

This report outlines the innovative use of augmented reality (AR) in the surgical planning and treatment of a spinal dural arteriovenous fistula (dAVF) via a minimally invasive technique. AR technology by way of an Apple Vision Pro headset was employed to enhance preoperative visualization and understanding of the pathology, leading to successful surgical ligation of the AVF. This case describes a 56-year-old male presenting with progressive weakness and thoracic myelopathy who showed marked improvement postoperatively, highlighting AR's potential to improve surgical approach and outcomes.

EphA3-targeted chimeric antigen receptor T cells are effective in glioma and generate curative memory T cell responses.

BACKGROUND: High-grade gliomas including glioblastoma (GBM) and diffuse midline gliomas (DMG) represent the most lethal and aggressive brain cancers where current treatment modalities offer limited efficacy. Chimeric antigen receptor (CAR) T cell therapies have emerged as a promising strategy, boasting tumor-specific targeting and the unique ability to penetrate the blood-brain barrier. However, the effective clinical application hinges on the optimal choice of antigen, with a limited number, currently under investigation. METHODS: We employed cell surface proteomic analysis of primary human high-grade glioma samples from both adult and pediatric patients. This led to the identification of Ephrin type-A receptor 3 (EphA3) as a prevalently expressed target. We engineered a second-generation EphA3-targeted CAR T cell and assessed function using in vitro and in vivo models of GBM and DMG. RESULTS: EphA3-targeted CAR T cells demonstrated robust antigen-specific killing of human GBM and DMG cell lines in vitro. In an orthotopic xenograft NSG mouse model, EphA3-targeted CAR T cells not only effectively eradicated tumors but also established a functional T cell population protective on rechallenge. Remarkably, mice rechallenged with a second contralateral orthotopic tumor implantation achieved complete tumor clearance and maintained a sustained complete response 6 months following initial treatment. CONCLUSION: Building on the proven safety profile of EphA3 antibodies in clinical settings, our study provides compelling preclinical evidence supporting the efficacy of EphA3-targeted CAR T cells against high-grade gliomas. These findings underscore the potential for transitioning this innovative therapy into clinical trials, aiming to revolutionize the treatment landscape for patients afflicted with these formidable brain cancers.

Preclinical development of a stabilized RH5 virus-like particle vaccine that induces improved antimalarial antibodies.

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage malaria vaccine antigen target, currently in a phase 2b clinical trial as a full-length soluble protein/adjuvant vaccine candidate called RH5.1/Matrix-M. We identify that disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees and that a re-engineered and stabilized immunogen (including just the alpha-helical core of RH5) induces a qualitatively superior growth inhibitory antibody response in rats vaccinated with this protein formulated in Matrix-M adjuvant. In parallel, bioconjugation of this immunogen, termed "RH5.2," to hepatitis B surface antigen virus-like particles (VLPs) using the "plug-and-display" SpyTag-SpyCatcher platform technology also enables superior quantitative antibody immunogenicity over soluble protein/adjuvant in vaccinated mice and rats. These studies identify a blood-stage malaria vaccine candidate that may improve upon the current leading soluble protein vaccine candidate RH5.1/Matrix-M. The RH5.2-VLP/Matrix-M vaccine candidate is now under evaluation in phase 1a/b clinical trials.

Neurovascular coupling, functional connectivity, and cerebrovascular endothelial extracellular vesicles as biomarkers of mild cognitive impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.

Patient Interest in Quadriceps Autograft Anterior Cruciate Ligament Reconstruction Is Increasing Over Other Autograft Options: A 12-Year Google Trends Analysis.

Purpose: To use Google trends to explore differences in public interest among types of anterior cruciate ligament (ACL) autografts, specifically quadriceps tendon, patellar tendon, and hamstring tendon autografts, between 2008 and 2019. Methods: Data were obtained by querying Google Trends for key terms and phrases for online search data ranging from January 2008 to December 2019. Relative search volumes were created based on searches related to ACL reconstruction with comparative analysis generated for search terms related to quadriceps ACL, patellar tendon ACL, and hamstring ACL autografts. Statistical analysis included linear regression analysis, comparison of quarterly search volume trends over time, and comparison of cumulative annual search volumes for 2008 versus 2019. Results: Linear models for respective search terms were statistically significant for the quadriceps (P < .001) and patellar (P = .007) tendon autograft groups but not the hamstring group (P = .129). The quadriceps autograft group demonstrated a 12-year search volume trend change of 0.56, which was significantly greater than the hamstring (0.07; P < .001) and patellar tendon (0.168; P < .001) groups. There was no significant difference in the trend change between hamstring and patellar tendon groups (P = .20). Percent change in cumulative relative annual search volumes between 2008 and 2019 was 112% for the quadriceps tendon group, 12.9% for the hamstring group, and 18.6% for the patellar tendon group. Conclusions: This study indicates a consistently increasing public interest in quadriceps tendon autograft for ACL reconstruction. The quadriceps autograft group demonstrated a significantly greater 12-year online search volume, greater linear correlation, and larger percent change between 2008 and 2019 compared with patellar tendon or hamstring autograft groups. Clinical Relevance: Awareness of patient perceptions has value in informing shared decision-making, aligning patient expectations, and guiding areas of future research. Each of these has an impact on patient care. Being aware of patient interest and expectations is particularly important in areas with controversial or emerging research.

Consensus Statement: Technical Standards for Thoracoabdominal Normothermic Regional Perfusion.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a powerful technique for optimizing organ procurement from donation after circulatory death donors. Despite its rapid adoption, standardized guidelines for TA-NRP implementation are lacking, prompting the need for consensus recommendations to ensure safe and effective utilization of this technique. METHODS: A working group composed of members from The American Society of Transplant Surgeons, The International Society of Heart and Lung Transplantation, The Society of Thoracic Surgeons, and The American Association for Thoracic Surgery was convened to develop technical guidelines for TA-NRP. The group systematically reviewed existing literature, consensus statements, and expert opinions to identify key areas requiring standardization, including predonation evaluation, intraoperative management, postdonation procedures, and future research directions. RESULTS: The working group formulated recommendations encompassing donor evaluation and selection criteria, premortem testing and therapeutic interventions, communication protocols, and procedural guidelines for TA-NRP implementation. These recommendations aim to facilitate coordination among transplant teams, minimize variability in practice, and promote transparency and accountability throughout the TA-NRP process. CONCLUSIONS: The consensus guidelines presented herein serve as a comprehensive framework for the successful and ethical implementation of TA-NRP programs in organ procurement from donation after circulatory death donors. By providing standardized recommendations and addressing areas of uncertainty, these guidelines aim to enhance the quality, safety, and efficiency of TA-NRP procedures, ultimately contributing to improved outcomes for transplant recipients.

Automatic Speech Recognition of Conversational Speech in Individuals With Disordered Speech.

PURPOSE: This study examines the effectiveness of automatic speech recognition (ASR) for individuals with speech disorders, addressing the gap in performance between read and conversational ASR. We analyze the factors influencing this disparity and the effect of speech mode-specific training on ASR accuracy. METHOD: Recordings of read and conversational speech from 27 individuals with various speech disorders were analyzed using both (a) one speaker-independent ASR system trained and optimized for typical speech and (b) multiple ASR models that were personalized to the speech of the participants with disordered speech. Word error rates were calculated for each speech model, read versus conversational, and subject. Linear mixed-effects models were used to assess the impact of speech mode and disorder severity on ASR accuracy. We investigated nine variables, classified as technical, linguistic, or speech impairment factors, for their potential influence on the performance gap. RESULTS: We found a significant performance gap between read and conversational speech in both personalized and unadapted ASR models. Speech impairment severity notably impacted recognition accuracy in unadapted models for both speech modes and in personalized models for read speech. Linguistic attributes of utterances were the most influential on accuracy, though atypical speech characteristics also played a role. Including conversational speech samples in model training notably improved recognition accuracy. CONCLUSIONS: We observed a significant performance gap in ASR accuracy between read and conversational speech for individuals with speech disorders. This gap was largely due to the linguistic complexity and unique characteristics of speech disorders in conversational speech. Training personalized ASR models using conversational speech significantly improved recognition accuracy, demonstrating the importance of domain-specific training and highlighting the need for further research into ASR systems capable of handling disordered conversational speech effectively.

Central nervous system active medication use in Medicare enrollees receiving home health care: association with chronic pain and anxiety level.

ABSTRACT: No comparative effectiveness data exist on nonopioid analgesics and nonbenzodiazepine anxiolytics to treat pain with anxiety. We examined the relationship between drug class and central nervous system (CNS) active drug polypharmacy on pain and anxiety levels in Medicare enrollees receiving home health (HH) care. This retrospective cohort study included enrollees with diagnoses and 2+ assessments of pain and anxiety between HH admission and discharge. Three sets of linear regression difference-in-reduction analyses assessed the association of pain or anxiety reduction with number of drugs; drug type; and drug combinations in those with daily pain and daily anxiety. Logistic regression analysis assessed the effect of medication number and class on less-than-daily pain or anxiety at HH discharge. A sensitivity analysis using multinomial regression was conducted with a three-level improvement to further determine clinical significance. Of 85,403 HH patients, 43% received opioids, 27% benzodiazepines, 26% gabapentinoids, 32% selective serotonin reuptake inhibitors, and 8% serotonin and norepinephrine reuptake inhibitors (SNRI). Furthermore, 75% had depression, 40% had substance use disorder diagnoses, and 6.9% had PTSD diagnoses. At HH admission, 83%, 35%, and 30% of patients reported daily pain, daily anxiety, and both, respectively. Central nervous system polypharmacy was associated with worse pain control and had no significant effect on anxiety. For patients with daily pain plus anxiety, pain was best reduced with one medication or any drug combination without opioid/benzodiazepine; anxiety was best reduced with combinations other than opiate/benzodiazepine. Gabapentinoids or SNRI achieved clinically meaningful pain control. Selective serotonin reuptake inhibitors provided clinically meaningful anxiety relief.

Insect Flight: State of the Field and Future Directions.

The evolution of flight in an early winged insect ancestral lineage is recognized as a key adaptation explaining the unparalleled success and diversification of insects. Subsequent transitions and modifications to flight machinery, including secondary reductions and losses, also play a central role in shaping the impacts of insects on broadscale geographic and ecological processes and patterns in the present and future. Given the importance of insect flight, there has been a centuries-long history of research and debate on the evolutionary origins and biological mechanisms of flight. Here, we revisit this history from an interdisciplinary perspective, discussing recent discoveries regarding the developmental origins, physiology, biomechanics, and neurobiology and sensory control of flight in a diverse set of insect models. We also identify major outstanding questions yet to be addressed and provide recommendations for overcoming current methodological challenges faced when studying insect flight, which will allow the field to continue to move forward in new and exciting directions. By integrating mechanistic work into ecological and evolutionary contexts, we hope that this synthesis promotes and stimulates new interdisciplinary research efforts necessary to close the many existing gaps about the causes and consequences of insect flight evolution.

Atrioventricular Synchrony Delivered by a Dual-Chamber Leadless Pacemaker System.

BACKGROUND: A dual-chamber leadless pacemaker system has been designed for atrioventricular synchronous pacing using wireless, beat-to-beat, implant-to-implant (i2i) communication between distinct atrial and ventricular leadless pacemakers. The atrioventricular synchrony achieved across various ambulatory scenarios has yet to be systematically evaluated. METHODS: A prospective, single-arm, unblinded, multicenter, international clinical trial of the leadless pacemaker system was conducted in patients with a conventional dual-chamber pacing indication enrolled from February 2022 to March 2023. Leadless pacemaker systems were implanted, and 12-lead Holter electrocardiographic recordings were collected 3 months after implantation over various postures/activities: sitting, supine, left lateral recumbent, right lateral recumbent, standing, normal walk, and fast walk. An independent Holter core laboratory performed a manual adjudication of the percent of atrioventricular synchronous beats using the standard 300-millisecond PR interval limit. Atrium-to-ventricle and ventricle-to-atrium i2i communication success rates were also assessed. Post hoc summary statistics describing the relationships between atrioventricular synchrony and i2i success, posture/activity, implantation indication, atrioventricular event, and heart rate were calculated. RESULTS: In the evaluable population (n=384 of 464 enrolled [83%]; 61% male; age, 70 years; weight, 82 kg; 60% ejection fraction; 95% of beats evaluable), the mean atrioventricular synchrony of 98% of beats observed across all postures using the standard 300-millisecond limit was greater than both atrial-to-ventricular i2i (94%) and ventricular-to-atrial i2i (94%; P<0.001), exceeding both i2i values in 95% of patients. Atrioventricular synchrony was achieved in >95% of evaluable beats across all postures/activities, implantation indications, atrioventricular paced/sensed event combinations, and heart rate ranges (including >100 bpm). CONCLUSIONS: This dual-chamber leadless pacemaker system demonstrated atrioventricular synchrony in 98% of evaluable beats at 3 months after implantation. Atrioventricular synchrony was maintained across postures/activities and remained robust for heart rates >100 bpm.

Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype.

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.