Comparison of the immunogenicity of mRNA-encoded and protein HIV-1 Env-ferritin nanoparticle designs.

Nucleoside-modified mRNA technology has revolutionized vaccine development with the success of mRNA COVID-19 vaccines. We used modified mRNA technology for the design of envelopes (Env) to induce HIV-1 broadly neutralizing antibodies (bnAbs). However, unlike SARS-CoV-2 neutralizing antibodies that are readily made, HIV-1 bnAb induction is disfavored by the immune system because of the rarity of bnAb B cell precursors and the cross-reactivity of bnAbs targeting certain Env epitopes with host molecules, thus requiring optimized immunogen design. The use of protein nanoparticles (NPs) has been reported to enhance B cell germinal center responses to HIV-1 Env. Here, we report our experience with the expression of Env-ferritin NPs compared with membrane-bound Env gp160 when encoded by modified mRNA. We found that well-folded Env-ferritin NPs were a minority of the protein expressed by an mRNA design and were immunogenic at 20 µg but minimally immunogenic in mice at 1 µg dose in vivo and were not expressed well in draining lymph nodes (LNs) following intramuscular immunization. In contrast, mRNA encoding gp160 was more immunogenic than mRNA encoding Env-NP at 1 µg dose and was expressed well in draining LN following intramuscular immunization. Thus, analysis of mRNA expression in vitro and immunogenicity at low doses in vivo are critical for the evaluation of mRNA designs for optimal immunogenicity of HIV-1 immunogens.IMPORTANCEAn effective HIV-1 vaccine that induces protective antibody responses remains elusive. We have used mRNA technology for designs of HIV-1 immunogens in the forms of membrane-bound full-length envelope gp160 and envelope ferritin nanoparticle. Here, we demonstrated in a mouse model that the membrane-bound form induced a better response than envelope ferritin nanoparticle because of higher in vivo protein expression. The significance of our research is in highlighting the importance of analysis of mRNA design expression and low-dose immunogenicity studies for HIV-1 immunogens before moving to vaccine clinical trials.

Adverse events associated with Vibrant Soundbridge: A MAUDE study.

OBJECTIVE: To summarize adverse events and their root causes reported to the United States Food and Drug Administration (FDA) on Vibrant Soundbridge (VSB) hearing device (Med-El, Innsbruck, Austria), an active middle ear implant for patients with moderate to severe hearing loss. MATERIALS AND METHODS: The FDA's Manufacturer and User Facility Device Experience (MAUDE) database was queried for reports of VSB adverse events from January 1, 2012, to July 27, 2022. RESULTS: Six hundred sixty-three total medical device reports were identified, from which 913 adverse events were extracted. Of these, 498 (54.5 %) were adverse events to patients (AEPs), while 415 (45.5 %) were device malfunctions (DMs). The most common AEPs were hearing performance issues 428 (85.9 %). The most common DMs were compromised conductive link 125 (30.1 %). Root causes identified for DMs were iatrogenic 85 (58.6 %), patient-related 28 (19.3 %), and trauma and external causes 32 (22.1 %). The most common iatrogenic root cause 12 (14.1 %) involved damage to the conductive link during revision surgery. The most common patient-related causes of DMs were excessive middle ear tissue growth 16 (57 %), and abrupt body movements 5 (28.6 %). The most common external cause of DM was cleaning of the ear canal or mastoid cavity 20 (62.5 %). CONCLUSIONS: Despite its well-known limitations, the MAUDE database provides valuable information on possible complications of VSB as it relates to device malfunction or adverse events for patients. Implementation of standardized reports with relevant and well-defined categories could certainly allow for a more meaningful analysis.

Reframing reentry: Understanding how reentry programming affects the well-being and quality of life of returning citizens.

This study examined the experiences returning citizens (RCs) have in participating in different reentry programs and how these experiences may lead to improved well-being and quality of life (QOL). We conducted 14 semi-structured interviews with RCs participating in employment-oriented reentry programs. The interviews focused on participants' reentry programming experience and areas affecting their well-being (e.g., housing, education, financial stability). QOL was enhanced for RCs when they were able to access stable housing, develop supportive relationships, have a job that permitted them the resources needed to live independently, and increase their perceptions of self-efficacy and social capital. While reentry programs maintain a focus on employment for RCs, housing, healthy relationships, and opportunities for increasing self-efficacy and social capital are tied to well-being and QOL among RCs. Reentry programs have the potential to influence a variety of factors at multiple levels that shape well-being and QOL, and in turn employment and recidivism, among RCs.

Utilization of submandibular ultrasound in assessing upper airway changes following the administration of propofol.

Background and Aims: Our study aimed to use submandibular ultrasound to measure upper airway parameters before and after induction dose of propofol in order to further understand upper airway changes that occur during induction of anesthesia. Measuring the changes that occur in airway anatomy due to the hypotonic effects of induction agents will allow for a deeper understanding of airway management. Material and Methods: We enrolled 39 patients between November 2021 and January 2022. Submandibular ultrasound was used to measure tongue thickness, geniohyoid muscle thickness, the distance between the lingual arteries (DLA), lateral pharyngeal wall thickness, and hyomental distance before and after administration of induction doses of the commonly used, sedative-hypnotic agent, propofol. Results: The mean DLA increased significantly after propofol administration, from 3.62 ± 0.63 cm to 3.79 ± 0.56 cm (P < 0.001). The mean tongue thickness was 4.89 ± 0.51 cm and decreased significantly to a mean of 4.62 ± 0.50 cm after propofol administration (P < 0.001). The change in DLA measurements after propofol administration decreased significantly as STOP-BANG score increased (r = -0.344, P = 0.037). However, DLA measurements when patients were awake increased significantly with an increase in the STOP-BANG score (r = 0.351, P = 0.031). Conclusion: These findings suggest that propofol widens and flattens the tongue, which are changes that may contribute to difficult airway management. Given the quick and non-invasive nature of ultrasound, further studies should evaluate the role of submandibular ultrasound for understanding the upper airway and airway management in various populations.

Communication in disasters to support families with children with medical complexity and special healthcare needs: a rapid scoping review.

Disasters can disrupt normal healthcare processes, with serious effects on children who depend upon regular access to the health care system. Children with medical complexity (CMC) are especially at risk. These children have chronic medical conditions, and may depend on medical technology, like feeding tubes. Without clear, evidence-based processes to connect with healthcare teams, families may struggle to access the services and supports they need during disasters. There is limited research about this topic, which has been pushed forward in importance as a result of the COVID-19 pandemic. The authors therefore conducted a rapid scoping review on this topic, with the intention to inform policy processes. Both the peer-reviewed and gray literatures on disaster, CMC, and communication were searched in summer 2020 and spring 2021. Twenty six relevant articles were identified, from which four main themes were extracted: 1. Cooperative and collaborative planning. 2. Proactive outreach, engagement, and response. 3. Use of existing social networks to connect with families. 4. Return to usual routines. Based on this review, good practices appear to involve including families, professionals, other stakeholders, and children themselves in pre-disaster planning; service providers using proactive outreach at the outset of a crisis event; working with existing peer and neighborhood networks for support; employing multiple and two-way communication channels, including social media, to connect with families; re-establishing care processes as soon as possible, which may include virtual connections; addressing mental health issues as well as physical functioning; and prioritizing the resumption of daily routines. Above all, a well-established and ongoing relationship among children, their caregivers, and healthcare teams could reduce disruptions when disaster strikes.

Synthetic lethality: targeting SMARCA2 ATPase in SMARCA4-deficient tumors - a review of patent literature from 2019-30 June 2023.

INTRODUCTION: The multi-subunit SWI/SNF chromatin remodeling complex is a key epigenetic regulator for many cellular processes, and several subunits are found to be mutated in human cancers. The inactivating mutations of SMARCA4, the ATPase subunit of the complex, result in cellular dependency on the paralog SMARCA2 for survival. This observed synthetic lethal relationship posits targeting SMARCA2 in SMARCA4-deficient settings as an attractive therapeutic target in oncology. AREAS COVERED: This review covers patent literature disclosed during the 2019-30 June 2023 period which claim ATPase inhibitors and PROTAC degraders that bind to the ATPase domain of SMARCA2 and/or SMARCA4. A total of 16 documents from 6 applicants are presented. EXPERT OPINION: The demonstration of cellular dependence on SMARCA2 ATPase activity in SMARCA4-deficient settings has prompted substantial research toward SMARCA2-targeting therapies. Although selectively targeting the ATPase domain of SMARCA2 is viewed as challenging, several ATPase inhibitor scaffolds have been disclosed within the last five years. Most early compounds are weakly selective, but these efforts have culminated in the first dual SMARCA2/SMARCA4 ATPase inhibitor to enter clinical trials. Data from the ongoing clinical trials, as well as continued advancement of SMARCA2-selective ATPase inhibitors, are anticipated to significantly impact the field of therapies, targeting SMARCA4-deficient tumors.

Synthetic lethality: targeting the SMARCA2 bromodomain for degradation in SMARCA4-deficient tumors - a review of patent literature from 2019-June 2023.

INTRODUCTION: SMARCA2 and SMARCA4 are subunits of the SWI/SNF complex which is a chromatin remodeling complex and a key epigenetic regulator that facilitates gene expression. Tumors with loss of function mutations in SMARCA4 rely on SMARCA2 for cell survival and this synthetic lethality is a potential therapeutic strategy to treat cancer. AREAS COVERED: The current review focuses on patent applications that claim proteolysis-targeting chimeras (PROTAC) degraders that bind the bromodomain site of SMARCA2 and are published between January 2019-June 2023. A total of 29 applications from 9 different applicants were evaluated. EXPERT OPINION: SMARCA2/4 bromodomain inhibitors do not lead to desired effects on cancer proliferation; however, companies have converted bromodomain binders into PROTACs to degrade the protein, with a preference for SMARCA2 over SMARCA4. Selective degradation of SMARCA2 is most likely required to be efficacious in the SMARCA4-deficient setting, while allowing for sufficient safety margin in normal tissues. With several patent applications disclosed recently, interest in targeting SMARCA2 should continue, especially with a selective SMARCA2 PROTAC now in the clinic from Prelude Therapeutics. The outcome of the clinical trials will influence the evolution of selective SMARCA2 PROTACs development.

The utility of ultrasonographic surveillance in management of a presumed branchial cleft cyst later confirmed HPV-associated oropharyngeal cancer.

While branchial cleft cysts are often considered benign pathologies, the literature discusses cases of squamous cell carcinoma (SCC) arising from these cystic lesions as either a primary or metastatic tumor. We illustrate our institutional experience and review the current literature to identify recommendations for best diagnostic, surveillance, and treatment guidelines for SCC identified in a branchial cleft cyst. A 61-year-old male presented with a right sided neck mass, with suspicion of a branchial cleft cyst due to benign findings on fine needle aspiration. Following surgical excision, a focus of SCC was found on surgical pathology. Despite PET/CT and flexible laryngoscopy, no primary tumor was identified prompting routine surveillance every 3 months with cervical ultrasonography and flexible nasolaryngoscopy. Two and a half years following his initial presentation, pathologic right level II lymphadenopathy was detected on ultrasound without evidence of primary tumor. Subsequent transoral robotic surgery with right tonsillectomy and partial pharyngectomy, with right lateral neck dissection revealed a diagnosis of pT1N1 HPV-HNSCC and he was referred for adjuvant chemotherapy and radiation. To our knowledge there are less than 10 cases of confirmed HPV-associated oropharyngeal SCC arising from a branchial cleft cyst. Here we demonstrate the utility of ultrasound as a surveillance tool and emphasize a higher index of suspicion for carcinoma in adult patients with cystic neck masses.

Impact of COVID-19 on Perinatal Outcomes and Birth Locations in a Large US Metropolitan Area.

This was a population-based study to determine the impact of COVID-19 on birth outcomes in the Chicago metropolitan area, comparing pre-pandemic (April-September 2019) versus pandemic (April-September 2020) births. Multivariable regression models that adjusted for demographic and neighborhood characteristics were used to estimate the marginal effects of COVID-19 on intrauterine fetal demise (IUFD)/stillbirth, preterm birth, birth hospital designation, and maternal and infant hospital length of stay (LOS). There were no differences in IUFD/stillbirths or preterm births between eras. Commercially insured preterm and term infants were 4.8 percentage points (2.3, 7.4) and 3.4 percentage points (2.5, 4.2) more likely to be born in an academic medical center during the pandemic, while Medicaid-insured preterm and term infants were 3.6 percentage points less likely (-6.5, -0.7) and 1.8 percentage points less likely (-2.8, -0.9) to be born in an academic medical center compared to the pre-pandemic era. Infant LOS decreased from 2.4 to 2.2 days (-0.35, -0.20), maternal LOS for indicated PTBs decreased from 5.6 to 5.0 days (-0.94, -0.19), and term births decreased from 2.5 to 2.3 days (-0.21, -0.17). The pandemic had a significant effect on the location of births that may have exacerbated health inequities that continue into childhood.

In-office Transoral Hilar Sialolithotomy: A Cost-Effective and Patient-Centered Procedure.

Transoral sialolithotomy performed in-office under local anesthesia is routinely performed for distal submandibular stones. We demonstrate the senior author's novel practice of in-office transoral sialolithotomy for hilar and intraglandular stones. A review of cases performed by the senior author revealed similar rates of complication and stone recurrence as those reported in the literature from removal under general anesthesia. Laryngoscope, 134:4042-4044, 2024.

Race and Ethnicity Independently Predict Adverse Outcomes Following Head and Neck Autograft Surgery.

OBJECTIVE: There is growing attention toward the implications of race and ethnicity on health disparities within otolaryngology. While race is an established predictor of adverse head and neck oncologic outcomes, there is paucity in the literature on studies employing national, multi-institutional data to assess the impact of race and ethnicity on head and neck autograft surgery. METHODS: Using the National Surgical Quality Improvement Program (NSQIP) database, trends in 30 days outcomes were assessed. Patients with ICD-10 codes for malignant head and neck neoplasms were isolated. Autograft surgeries were selected using Current Procedural Terminology (CPT) codes for free flap and pedicled flap reconstruction. Primary outcomes included surgical complications, reoperation, readmission, extended length of stay and operation time. Each binary categorical variable was compared to racial/ethnic identity via binary logistic regression. RESULTS: The study cohort consisted of 2447 patients who underwent head and neck autograft surgery (80.71% free flap reconstruction and 19.39% pedicled flap reconstruction). Black patients had significantly higher odds of overall surgical complications (odds ratio [OR] 1.583, 95% confidence interval [CI] 1.091, 2.298, p = 0.016) with much higher odds of perioperative blood transfusions (OR 2.291, 95% CI 1.532, 3.426, p = <.001). Hispanic patients were more likely to undergo reoperation within 30 days after surgery and were more likely to be hospitalized for more than 30 days post-operatively (OR 1.566, 95% CI 1.015, 2.418, p = 0.043 and OR 12.224, 95% CI 2.698, 55.377, p = 0.001, respectively). CONCLUSIONS: Race and ethnicity serve as independent predictors of complications in the post-operative period following head and neck autograft surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3595-3603, 2024.

Trends of female authorship in head and neck surgery publications over the last decade.

BACKGROUND: While other otolaryngology subspecialties have established female authorship trends, there is no comprehensive study within head and neck surgery (HNS). METHODS: Five researchers recorded the gender identity of first and senior authors from HNS subspecialty papers (head and neck oncology, endocrine surgery, salivary gland pathology, and microsurgery) derived from 10 journals in otolaryngology and oncology in the years 2013, 2016, 2019, and 2022. RESULTS: From 3457 articles, 6901 unique author identities were analyzed. Female authors represented 32% (N = 1103) of first authors and 20% (N = 690) of senior authors. Female authors were less likely to publish in microvascular and reconstructive surgery. Senior female authors were more likely to publish in higher impact journals than male senior authors, and first female authors had an increased likelihood of funding compared to their male counterparts. CONCLUSIONS: While female authors remain underrepresented in certain literature, we illustrate promising trends in productivity, funding allocation, and impact.

Knockdowns of CD3zeta Chain in Primary NK Cells Illustrate Modulation of Antibody-Dependent Cellular Cytotoxicity Against Human Immunodeficiency Virus-1.

Multifaceted natural killer (NK) cell activities are indispensable for controlling human immunodeficiency virus (HIV)-1 transmission and pathogenesis. Among the diverse functions of NK cells, antibody-dependent cellular cytotoxicity (ADCC) has been shown to predict better HIV-1 protection. ADCC is initiated by the engagement of an Fc γ receptor CD16 with an Fc portion of the antibody, leading to phosphorylation of the CD3 ζ chain (CD3ζ) and Fc receptor γ chain (FcRγ) as well as downstream signaling activation. Though CD3ζ and FcRγ were thought to have overlapping roles in NK cell ADCC, several groups have reported that CD3ζ-mediated signals trigger a more robust ADCC. However, few studies have illustrated the direct contribution of CD3ζ in HIV-1-specific ADCC. To further understand the roles played by CD3ζ in HIV-1-specific ADCC, we developed a CD3ζ knockdown system in primary human NK cells. We observed that HIV-1-specific ADCC was inhibited by CD3ζ perturbation. In summary, we demonstrated that CD3ζ is important for eliciting HIV-1-specific ADCC, and this dynamic can be utilized for NK cell immunotherapeutics against HIV-1 infection and other diseases.

Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity.

Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.

The current status of Korean native pig production.

Korean native pigs (KNPs) have been one of the traditional livestock primarily raised in rural areas of Korea for centuries. KNPs have adapted to the climate and geography of the Korean Peninsula for a long time, exhibiting excellent adaptability even in challenging environments. For these reasons, the preservation and purification of KNPs are crucial in securing unique genetic resources. Therefore, this review covers the characteristics, production status, commercial value and potential breeding directions of KNPs. Unfortunately, there is still a long way to go for the improvement of KNPs. It is crucial to acknowledge the current challenges, identify the issues, and dedicate efforts to the breed's improvement. Each section of this comprehensive review will play an important role in integrating related research and data into the overall findings. In-depth discussions on the genetic diversity, productivity, genetic conservation, ecological roles, and sustainability of KNPs will be crucial components in the future of KNP business.

Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates.

Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs.

Impact of COVID-19 specific simulation training in improving intubators' level of comfort during intubations of COVID-19 patients - Results from a USA national survey.

Background: Tracheal intubation is a hazardous aerosolizing procedure with a potential risk of spreading SAR-CoV-2 between patients and physicians. Aim: The purpose of this study was to explore the impact of COVID-19 specific simulation training in improving provider level of comfort during the intubation of COVID-19 patients. Methods: In this cross-sectional national study, an electronic survey was disseminated using a snowball sample approach to intubators from 55 hospitals across the United States. The survey assessed providers' comfort of intubating and fear of contracting the virus during COVID-19 intubations. Results: A total of 329 surveys from 55 hospitals were analyzed. Of 329 providers, 111 providers (33.7%) reported participating in simulation training. Of those, 86 (77.5%) reported that the simulation training helped reduce their fear of intubating COVID-19 patients. Providers in the simulation training group also reported a higher level of comfort level with intubating both general patients (median [range] no-simulation training group 9 [3-10], simulation training group 9 [6-10]; p = 0.015) and COVID-19 patients (no-ST 8 [1-10], ST group 9 [4-10]; p < 0.0005) than providers in the no-simulation training group. Conclusions: Our study suggests that COVID-19 specific intubation simulation training promotes provider comfort. Simulation training may be implemented as part of airway management training during the current and novel pandemic situations.