Combinatorial design of ionizable lipid nanoparticles for muscle-selective mRNA delivery with minimized off-target effects.

Ionizable lipid nanoparticles (LNPs) pivotal to the success of COVID-19 mRNA (messenger RNA) vaccines hold substantial promise for expanding the landscape of mRNA-based therapies. Nevertheless, the risk of mRNA delivery to off-target tissues highlights the necessity for LNPs with enhanced tissue selectivity. The intricate nature of biological systems and inadequate knowledge of lipid structure-activity relationships emphasize the significance of high-throughput methods to produce chemically diverse lipid libraries for mRNA delivery screening. Here, we introduce a streamlined approach for the rapid design and synthesis of combinatorial libraries of biodegradable ionizable lipids. This led to the identification of iso-A11B5C1, an ionizable lipid uniquely apt for muscle-specific mRNA delivery. It manifested high transfection efficiencies in muscle tissues, while significantly diminishing off-targeting in organs like the liver and spleen. Moreover, iso-A11B5C1 also exhibited reduced mRNA transfection potency in lymph nodes and antigen-presenting cells, prompting investigation into the influence of direct immune cell transfection via LNPs on mRNA vaccine effectiveness. In comparison with SM-102, while iso-A11B5C1's limited immune transfection attenuated its ability to elicit humoral immunity, it remained highly effective in triggering cellular immune responses after intramuscular administration, which is further corroborated by its strong therapeutic performance as cancer vaccine in a melanoma model. Collectively, our study not only enriches the high-throughput toolkit for generating tissue-specific ionizable lipids but also encourages a reassessment of prevailing paradigms in mRNA vaccine design. This study encourages rethinking of mRNA vaccine design principles, suggesting that achieving high immune cell transfection might not be the sole criterion for developing effective mRNA vaccines.

AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery.

Ionizable lipid nanoparticles (LNPs) are seeing widespread use in mRNA delivery, notably in SARS-CoV-2 mRNA vaccines. However, the expansion of mRNA therapies beyond COVID-19 is impeded by the absence of LNPs tailored for diverse cell types. In this study, we present the AI-Guided Ionizable Lipid Engineering (AGILE) platform, a synergistic combination of deep learning and combinatorial chemistry. AGILE streamlines ionizable lipid development with efficient library design, in silico lipid screening via deep neural networks, and adaptability to diverse cell lines. Using AGILE, we rapidly design, synthesize, and evaluate ionizable lipids for mRNA delivery, selecting from a vast library. Intriguingly, AGILE reveals cell-specific preferences for ionizable lipids, indicating tailoring for optimal delivery to varying cell types. These highlight AGILE's potential in expediting the development of customized LNPs, addressing the complex needs of mRNA delivery in clinical practice, thereby broadening the scope and efficacy of mRNA therapies.

The Matthew Effect: Prevalence of Doctor and Physician Parents among Ophthalmology Applicants.

Objective This article determines the prevalence of physician parents among ophthalmology residency applications. Design Retrospective, single-center cohort study. Subjects All applicants to the University of Kentucky Ophthalmology Residency between 2018 and 2023. Methods Residency applications were reviewed, with data collection including applicant gender, self-identified Under-Represented in Medicine (URiM) status, United States Medical Licensing Examination (USMLE) Step 1 score, USMLE Step 2 score, and whether the application identified a doctor or physician as a parent. Doctor was defined as a profession requiring a doctorate degree, and similarly, physician as a profession requiring a medical degree. Results A total of 2,057 applications were reviewed, representing 54% of all match participants during the study period. Fourteen percent (296) of applications indicated a parent was a doctor and 12% (253) a parent was a physician. There were no differences between gender, URiM, USMLE Step 1, and Step 2 scores between applicants indicating a doctor or physician as a parent and those that did not ( p all > 0.4 and Cohen's d all < 0.02). Of the type of doctors, 85% (253) were physicians, 6% (17) optometrists, 6% (17) Doctors of Philosophy, 3% (8) dentists, 1% (1) pharmacist, and 1% (1) veterinarian. Eighty-six percent (217) of applications with a physician parent provided the type of physician, with ophthalmologist the most common (93, 43%). Ninety-eight percent (249) of applications with a physician parent provided the gender of the parent, with father (168, 68%) more common than mother (42, 17%) or both parents (39, 16%). Conclusion Physician parents are substantially overrepresented in ophthalmology residency applicants. This raises concerns regarding diversity and inclusion efforts for recruitment in medicine.

Oral inflammatory load predicts vascular function in a young adult population: a pilot study.

Background: The periodontium is a highly vascularized area of the mouth, and periodontitis initiates negative functional and structural changes in the vasculature. However, mild oral inflammation, including levels experienced by many apparently healthy individuals, has an unclear impact on cardiovascular function. The purpose of this pilot study is to investigate the effects of objectively measured whole mouth oral inflammatory load (OIL) on vascular function in apparently healthy individuals. Methods: In this cross-sectional and correlational analysis, we recruited 28 young (18-30 years) and systemically healthy participants (16 male, 12 female). Using oral neutrophil counts, a validated measure for OIL, we collected participant's mouth rinse samples and quantified OIL. Blood pressure, arterial stiffness (pulse-wave velocity) and endothelial function (brachial artery flow-mediated dilation) were also measured. Results: Only oral neutrophil count significantly predicted flow-mediated dilation % (p = 0.04; R2 = 0.16, ß = - 1.05) and those with OIL levels associated with >2.5 × 105 neutrophil counts (n = 8) had a lower flow-mediated dilation % (6.0 ± 2.3%) than those with counts associated with gingival health with less than 2.5 × 105 neutrophil counts (10.0 ± 5.2%, p = 0.05). There were no significant predictors for arterial stiffness. Conclusion: We found that OIL was a predictor of reduced flow-mediated dilation. An impairment in flow-mediated dilation is an indicator of future possible risk of cardiovascular disease-one of the leading causes of death in North America. Therefore, this study provides evidence for the importance of oral health and that OIL may impact endothelial function.

Diagnostic Pathway of Oral Cavity Cancer in an Integrated Health Care System.

CONTEXT: Survival for patients with oral cavity squamous cell carcinoma (OCSCC) has remained relatively stagnant despite advances in treatment. Few studies have examined why advanced-stage disease is diagnosed in 40% of patients with OCSCC nationally. OBJECTIVE: To characterize the diagnostic pathway of OCSCC in an integrated health care system. DESIGN: Retrospective study of patients with OCSCC (2007-2010). MAIN OUTCOME MEASURES: Referral patterns and demographic, clinical, and tumor characteristics associated with time to diagnosis (diagnostic interval). RESULTS: Of 247 patients, 167 (68%) had early-stage (I/II) disease, 86 (35%) were referred by dentists, and 70 (28%) had a history of premalignancy. The median time (interquartile range) from symptom onset to care sought from a primary care physician (patient interval), from primary care physician to otolaryngologist, and from otolaryngologist to diagnosis was 8.6 (4.0-25.8), 1.0 (0.6-3.1), 0.0 (0.0-3.0) weeks, respectively. These intervals did not differ by demographic characteristics, clinical factors, or tumor stage. Prolonged diagnostic intervals were observed among patients with premalignant lesions. CONCLUSION: The patient interval was the largest component of the total diagnostic interval. The subsequent professional workup proceeded relatively efficiently. Prolonged diagnostic interval in patients with premalignant lesions may reflect the natural history of malignant transformation rather than a delay in diagnosis. However, nearly one-fourth of these cases were diagnosed at an advanced stage; closer surveillance may represent an opportunity for diagnosis at an earlier stage. Surveillance for premalignant lesions and facilitating referrals from dentists may expedite the diagnosis and treatment of OCSCC. Further investigation is warranted.

Effects of Cementing on Ligament Balance During Total Knee Arthroplasty.

Complications related to joint imbalance may contribute to some of the most predominant modes of failure in total knee arthroplasty (TKA). These complications include instability, aseptic loosening, asymmetric component wear, and idiopathic pain. Fixation may represent a step that introduces unchecked variability into the procedure and may contribute to the incidence of joint imbalance-related complications. The ability to quantify in vivo loading in the medial and lateral compartments would allow for the ability to confirm balance after fixation and prior to wound closure. This retrospective study sought to capture any variability and imbalance associated with cementing technique. A total of 93 patients underwent sensor-assisted TKA. All patients were confirmed to have quantifiably balanced joints prior to cementation. After cementing and final component placement, the sensor was reinserted into the joint to capture any cementation-induced changes in loading. Imbalance was observed in 44% of patients after cementation. There was no difference in the proportion of imbalance due to surgeon experience (P=.456), cement type (P=.429), or knee system (P=.792). A majority of knees exhibited loading increase in the medial compartment. It was concluded that cementation technique contributes to a significant amount of balance-related variability at the fixation stage of the procedure. The use of the sensor in this study allowed for the correction of all instances of imbalance prior to closure. More objective methods of balance verification may be important for ensuring optimal surgical outcomes. [Orthopedics. 2017; 40(3):e455-e459.].

Odontogenic sinusitis: a case series studying diagnosis and management.

BACKGROUND: Odontogenic sinusitis is a well-recognized, but understudied form of sinusitis. Odontogenic sinusitis requires unique diagnostic criteria and a treatment regimen that differs from non-odontogenic sinusitis. The purpose of this article is to present a case series of patients with odontogenic sinusitis in order to clarify key disease characteristics and management techniques. METHODS: Retrospective case series of 55 patients with odontogenic sinusitis. Each patient underwent chart and imaging review to analyze demographic factors, diagnostic criteria, clinical course, and management. RESULTS: Fifty-five patients were identified retrospectively. Forty-four were diagnosed at initial visit. Twenty-eight (64%) of these patients were diagnosed by computed tomography (CT) scan showing dental pathology, 11 (25%) by known temporal relationship to a dental procedure, and 5 (11%) by presentation with oral-antral fistula. Only 65% of radiology reports for all patients mentioned dental pathology. Overall, 21 (38%) patients had disease resolution. Of these, 7 (33%) resolved with endoscopic sinus surgery (ESS) alone, 7 (33%) resolved with concurrent ESS and dental surgery, 2 (10%) resolved with dental surgery alone, 2 (10%) resolved with ESS after failing dental surgery, 2 (10%) resolved with medical management alone, and 1 (5%) resolved with medical management after failing dental surgery. Forty-six (84%) patients had unilateral odontogenic sinusitis. The Lund-Mackay score for all patients was (mean ± standard deviation [SD]) 4.0 ± 3.2. CONCLUSION: Odontogenic sinusitis is often misdiagnosed. Radiology reports commonly do not mention dental pathology. Management of odontogenic sinusitis needs to be tailored to each individual patient and involves varying combinations of medical management, dental surgery, and ESS.

Modern concepts in mandibular reconstruction in oral and oropharyngeal cancer.

PURPOSE OF REVIEW: This article reviews literature pertaining to advances in oromandibular reconstruction in the context of a 30-year background of microvascular free tissue transfer, which still represents the current standard of care. RECENT FINDINGS: Most literature reiterates established patterns of reconstruction. Notable exceptions address these key areas: the use of computer-assisted modeling to more closely and efficiently design the excision of the mandible, to produce the template and to contour the fibula bone to fit the defect; the evolution of plating techniques to maximize the bony repair; distraction osteogenesis; tissue engineering; and optimal techniques for dealing with osteonecrosis, from both radiation and bisphosphonate use. SUMMARY: Osteocutaneous free flaps remain the standard of care. The fibula flap has emerged as the accepted favorite among these flaps. Evolution of fibula flap reconstruction constitutes a major portion of the current literature. Improvements upon free tissue transfer are currently elusive, largely due to associated radiation. Tissue engineering holds promise as the next plateau but is not yet readily applicable.

Engineered multifunctional nanotools for biological applications.

Smart multifunctional magnetic nanoparticles are popular candidates for several biological applications owing to their intrinsic magnetic property and diverse applications that range from rare protein separation and biomedical utilization to cancer therapy and diagnostics. A universal protocol, for the development of such nanocarriers, is highly desirable for scientists with different backgrounds so that custom-made multifunctional nanoparticles can be developed to address their needs, among which are the superparamagnetic iron oxide and manganese oxide nanoparticles that are synthesized through high temperature decomposition reactions. However, an interface is needed to present these inorganic materials to biomolecules to enhance their application for different biological use. This compatibility is achieved by introducing a class of multifunctional copolymers. Magnetic nanoparticles are elaborately decorated with copolymers that carry three principle functionalities as follows: (1) dopamine moieties for surface anchorage of metal oxides; (2) dyes for optical detection; and (3) a large variety of functional molecules such as amines or carboxylates for conjugation of various biomolecules (i.e., proteins, nucleic acids, enzymes, etc.). These copolymers, in combination with nanoparticles, serve as a tool box that results in engineered nanotools with customized modifications and functionalities for applications in fields ranging from proteomics -bioseparation to tumor therapy.

Flexible nerve stimulation electrode with iridium oxide sputtered on liquid crystal polymer.

Current electrode designs require flexible substrates that absorb little moisture and provide large charge injection capability. Sputtered iridium oxide films have superior charge injection capabilities versus noble metals and can adhere to various substrates. Liquid crystal polymers (LCPs) have very little water absorption compared to other flexible substrates. Therefore, the combination of sputtered iridium oxide film on LCP substrate was studied using 50 Hz, 100 micros duration, and 10 mA biphasic current waveforms for 700 h at 67 degrees C in bicarbonate buffer saline. Scanning electron micrograph analysis showed no delamination and approximately 1% of electrode material was lost to the bicarbonate buffer. The charge injection limit and the cathodic charge storage capacity within the water window were 4.6 +/- 1.0 and 31.5 +/-6.6 mC/cm2, respectively. Additional electrochemical analysis revealed significant charge imbalance attributed to oxygen reduction within the water window. These results, along with the flexible, chemically inert, and biocompatible substrate, indicate that sputtered iridium oxide films on LCP could become the method of choice for flexible substrate nerve electrodes.