Laryngoscopy Grade Improvement and Difficult Airway Resolution in Infants With Robin Sequence Undergoing Mandibular Distraction Osteogenesis: A Multi-Institutional Study.

OBJECTIVE: Mandibular distraction osteogenesis (MDO) aims to relieve tongue-based airway obstruction in Robin Sequence (RS). We investigated direct laryngoscopy grade (DLG) improvement and difficult airway (DA) resolution following MDO. DESIGN: Retrospective cohort analysis. SETTING: Three tertiary care institutions. PATIENTS: Sixty-four infants with RS who underwent a single MDO procedure in their first year of life were identified from January 2010 to January 2019. MAIN OUTCOME MEASURES: The primary outcome was DLG pre- and post-MDO. Secondary outcomes included DA designation, pre- and post-MDO polysomnographic assessment for obstructive sleep apnea (OSA), length of stay, need for gastrostomy, and major/minor adverse events. RESULTS: Median DLG improved from II pre-MDO to I at the time of distractor removal (n = 43, P < .001). No significant change was seen in patients with a third recorded time point (eg, palatoplasty; n = 78, P = .52). Twenty-six (47%) of 55 patients were designated as DA pre-MDO, and 10 (18%) of 55 patients retained the label post-MDO (P < .01). Five (50%) of these 10 patients appeared to be inappropriately retained. Median obstructive apnea-hypopnea index improved from 38.6 (range 31.2-62.8) pre-MDO to 2.9 (range 1-3.9) post-MDO (n = 12; P = .002). CONCLUSION: Mandibular distraction osteogenesis allowed for DLG improvement that was stably maintained as well as functional improvement in OSA, with minimal morbidity. Difficult airway designation persisted in the electronic record of some infants despite clinical resolution.

Highly scalable, closed-loop synthesis of drug-loaded, layer-by-layer nanoparticles.

Layer-by-layer (LbL) self-assembly is a versatile technique from which multicomponent and stimuli-responsive nanoscale drug carriers can be constructed. Despite the benefits of LbL assembly, the conventional synthetic approach for fabricating LbL nanoparticles requires numerous purification steps that limit scale, yield, efficiency, and potential for clinical translation. In this report, we describe a generalizable method for increasing throughput with LbL assembly by using highly scalable, closed-loop diafiltration to manage intermediate purification steps. This method facilitates highly controlled fabrication of diverse nanoscale LbL formulations smaller than 150 nm composed from solid-polymer, mesoporous silica, and liposomal vesicles. The technique allows for the deposition of a broad range of polyelectrolytes that included native polysaccharides, linear polypeptides, and synthetic polymers. We also explore the cytotoxicity, shelf life and long-term storage of LbL nanoparticles produced using this approach. We find that LbL coated systems can be reliably and rapidly produced: specifically, LbL-modified liposomes could be lyophilized, stored at room temperature, and reconstituted without compromising drug encapsulation or particle stability, thereby facilitating large scale applications. Overall, this report describes an accessible approach that significantly improves the throughput of nanoscale LbL drug-carriers that show low toxicity and are amenable to clinically relevant storage conditions.

SARS-CoV-2 serology testing: Progress and challenges.

The coronavirus disease 2019 (COVID-19) pandemic has caused the most devasting social and economic impact of this century. The current pandemic will end only after a safe, effective vaccine becomes available and protective herd immunity has been achieved through vaccination. The key parameter to gauge protective immunity is neutralizing antibody levels. Thus, reliable serology testing is essential to diagnose whether an individual has been previously infected, as a large proportion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is asymptomatic. For both naturally infected and vaccinated individuals, it is critical to monitor their neutralizing antibody titers over time. This is because, when neutralizing antibody levels wane below a threshold which remains to be determined, they become vulnerable to reinfection. Due to the importance of serology testing, academia and industry have developed different platforms for serological diagnosis, many of which have achieved the Food and Drug Administration (FDA) Emergency Use Authorizations (EUA). Here we summarize the status of COVID-19 serology testing, discuss challenges, and provide future directions for improvement.

Making sense of spike D614G in SARS-CoV-2 transmission.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the current coronavirus disease 2019 (COVID-19) pandemic, has evolved to adapt to human host and transmission over the past 12 months. One prominent adaptive mutation is the asparagine-to-glycine substitution at amino acid position 614 in the viral spike protein (D614G), which has become dominant in the currently circulating virus strains. Since spike protein determines host ranges, tissue tropism, and pathogenesis through binding to the cellular receptor of angiotensin converting enzyme 2 (ACE2), the D614G mutation is hypothesized to enhance viral fitness in human host, leading to increased transmission during the global pandemic. Here we summarize the recent progress on the role of the D614G mutation in viral replication, pathogenesis, transmission, and vaccine and therapeutic antibody development. These findings underscore the importance in closely monitoring viral evolution and defining their functions to ensure countermeasure efficacy against newly emerging variants.

Microglial Metabolism After Pediatric Traumatic Brain Injury - Overlooked Bystanders or Active Participants?

Microglia play an integral role in brain development but are also crucial for repair and recovery after traumatic brain injury (TBI). TBI induces an intense innate immune response in the immature, developing brain that is associated with acute and chronic changes in microglial function. These changes contribute to long-lasting consequences on development, neurologic function, and behavior. Although alterations in glucose metabolism are well-described after TBI, the bulk of the data is focused on metabolic alterations in astrocytes and neurons. To date, the interplay between alterations in intracellular metabolic pathways in microglia and the innate immune response in the brain following an injury is not well-studied. In this review, we broadly discuss the microglial responses after TBI. In addition, we highlight reported metabolic alterations in microglia and macrophages, and provide perspective on how changes in glucose, fatty acid, and amino acid metabolism can influence and modulate the microglial phenotype and response to injury.

Tuning Nanoparticle Interactions with Ovarian Cancer through Layer-by-Layer Modification of Surface Chemistry.

Nanoparticle surface chemistry is a fundamental engineering parameter that governs tumor-targeting activity. Electrostatic assembly generates controlled polyelectrolyte complexes through the process of adsorption and charge overcompensation utilizing synthetic polyions and natural biomacromolecules; it can yield films with distinctive hydration, charge, and presentation of functional groups. Here, we used electrostatic layer-by-layer (LbL) assembly to screen 10 different surface chemistries for their ability to preferentially target human ovarian cancer in vitro. Our screen identified that poly-l-aspartate, poly-l-glutamate, and hyaluronate-coated LbL nanoparticles have striking specificity for ovarian cancer, while sulfated poly(ß-cyclodextrin) nanoparticles target noncancerous stromal cells. We validated top candidates for tumor-homing ability with a murine model of metastatic disease and with patient-derived ovarian cancer spheroids. Nanoparticle surface chemistry also influenced subcellular trafficking, indicating strategies to target the cell membrane, caveolae, and perinuclear vesicles. Our results confirm LbL is a powerful tool to systematically engineer nanoparticles and achieve specific targeting.

RNA-Peptide nanoplexes drug DNA damage pathways in high-grade serous ovarian tumors.

DNA damaging chemotherapy is a cornerstone of current front-line treatments for advanced ovarian cancer (OC). Despite the fact that a majority of these patients initially respond to therapy, most will relapse with chemo-resistant disease; therefore, adjuvant treatments that synergize with DNA-damaging chemotherapy could improve treatment outcomes and survival in patients with this deadly disease. Here, we report the development of a nanoscale peptide-nucleic acid complex that facilitates tumor-specific RNA interference therapy to chemosensitize advanced ovarian tumors to frontline platinum/taxane therapy. We found that the nanoplex-mediated silencing of the protein kinase, MK2, profoundly sensitized mouse models of high-grade serous OC to cytotoxic chemotherapy by blocking p38/MK2-dependent cell cycle checkpoint maintenance. Combined RNAi therapy improved overall survival by 37% compared with platinum/taxane chemotherapy alone and decreased metastatic spread to the lungs without observable toxic side effects. These findings suggest (a) that peptide nanoplexes can serve as safe and effective delivery vectors for siRNA and (b) that combined inhibition of MK2 could improve treatment outcomes in patients currently receiving frontline chemotherapy for advanced OC.