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Background: Metatarsalgia and plantar plate tears are characterized by forefoot pain and toe deformity in severe cases. Conservative management may slow progression of symptoms; however, definitive treatment often requires operative intervention. The purpose of this observational study was to evaluate the combination of plantar condylectomy and surgical imbrication of the plantar plate to the metatarsal neck to repair grade 0 plantar plate injuries., Methods: We retrospectively identified 22 patients with metatarsalgia and low-grade plantar plate lesions (grade 0), operated between 2018 and 2021, who underwent operative repair involving plantar metatarsal condylectomy and proximal surgical imbrication of the plantar plate to the metatarsal neck. Fourteen patients underwent concomitant hallux valgus correction. Data collection was performed preoperatively and postoperatively and included Patient-Reported Outcomes Measurement Information System (PROMIS) physical function (PF) and pain interference (PI) scores. Paired Wilcoxon signed-rank tests compared PROMIS PF and PI scores at patients' preoperative, 6-9-week, 3-4-month, 5-6-month, and ≥9-month follow-up evaluations ( P  < .05)., Results: Compared to their preoperative visit, patients demonstrated modest improvement in their PROMIS (pain and physical function) scores over the first ≥9 months postoperatively (median 13.0 months). Median preoperative and most recent PROMIS physical function scores were 40.5 (95% CI: 36-49) and 44.5 (95% CI: 40-52), respectively. Median PROMIS pain interference scores changed from 62.5 (95% CI: 56-67) to 56.0 (95% CI: 51-62). Improvement in pain and function was sustained in patients available for postoperative follow-up., Conclusion: In this small, early follow-up series, we found that plantar condylectomy and surgical imbrication of the plantar plate to the metatarsal neck was modestly helpful to treat metatarsalgia and grade 0 plantar plate injuries., Level of Evidence: Level IV, retrospective case series., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online., (© The Author(s) 2023.)

Background: Hemophilia B (HB) is a bleeding disorder characterized by coagulation factor (F) IX (FIX) deficiency. The current standard-of-care for severe HB is prophylaxis with long-term repetitive intravenous (i.v.) infusions of recombinant FIX (rFIX) with standard half-life or extended half-life. Unmet needs remain regarding the development of non-invasive administration routes for coagulation factors. The aim of this study was to evaluate the effectiveness of intranasal delivery (IND) of rFIX and rFIX fused to Fc fragment (rFIX-Fc) in mice., Methods: Drops of rFIX and rFIX-Fc were deposited in the nostrils of wild-type, FcRn knock-out, FcRn humanized, and FIX knock-out mice. rFIX mucosal uptake was evaluated by measuring plasma FIX antigen and FIX activity (FIX:C) levels, and by performing histologic analysis of the nasal mucosa following IND., Results: After IND, both rFIX and rFIX-Fc were equally delivered to the blood compartment, irrespective of the mouse strain studied, mostly through a passive mechanism of transportation across the mucosal barrier, independent of FcRn receptor. Both plasma FIX antigen and FIX:C activity levels increased following IND in FIX knock-out mice., Conclusion: This proof-of-concept study describes evidence supporting the nasal route as an alternative to FIX i.v. infusion for the treatment of HB., Competing Interests: Funding This work was partly supported by a grant from “Fond de dotation France,” CSL Behring, the non-profit organization EURECa, University Claude Bernard Lyon I, the Société Française d’Oto-rhino-laryngologie et de chirurgie cervico-faciale (SFORL) and Amplifon. Relationship Disclosures S.L.Q. has received grant/research support from CSL Behring, honoraria from SOBI, Roche, LFB Biomedicaments, Octapharma, NovoNordisk, and is currently a full-time employee at CSL Behring. All other authors have no competing interests in relation to this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Vaccine technology is still facing challenges regarding some infectious diseases, which can be addressed by innovative drug delivery systems. In particular, nanoparticle-based vaccines combined with new types of adjuvants are actively explored as a platform for improving the efficacy and durability of immune protection. Here, biodegradable nanoparticles carrying an antigenic model of HIV were formulated with two combinations of poloxamers, 188/407, presenting or not presenting gelling properties, respectively. The study aimed to determine the influence of poloxamers (as a thermosensitive hydrogel or a liquid solution) on the adaptive immune response in mice. The results showed that poloxamer-based formulations were physically stable and did not induce any toxicity using a mouse dendritic cell line. Then, whole-body biodistribution studies using a fluorescent formulation highlighted that the presence of poloxamers influenced positively the dissemination profile by dragging nanoparticles through the lymphatic system until the draining and distant lymph nodes. The strong induction of specific IgG and germinal centers in distant lymph nodes in presence of poloxamers suggested that such adjuvants are promising components in vaccine development.

Objective: To describe a tumor resection using the inferior long-axis (ILA) technique for cisternal facial nerve dissection in large vestibular schwannomas (VS)., Study Design: Retrospective case series from 2018 to 2021., Setting: Tertiary academic medical center., Patients: Patients who underwent surgical resection with ILA facial nerve dissection of VS (>2.0 cm measured parallel to the petrous ridge) and had at least 3-month follow-up., Interventions: Cisternal facial nerve dissection during retrosigmoid or translabyrinthine approach using standardized ILA technique developed by author R.N., Main Outcome Measures: Immediate postoperative and last follow-up facial nerve function with House-Brackmann scores of I to II defined as "good" facial nerve function and House-Brackmann scores III to VI defined as "poor" function. Extent of resection was also assessed., Results: A total of 48 patients underwent large VS resection with ILA dissection of tumor off of the facial nerve from 2018 to 2021. Mean (standard deviation) tumor size was 3.11 (0.76) cm. Mean (standard deviation) follow-up was 9.2 (9.0) months. Gross-total resection or near-total resection were achieved in 75% (radiographic estimate) to 83% (surgeon estimate) of cases. End-of-case facial nerve stimulation at 0.05 mAmp with a response of at least 240 mV was achieved in 80.4% of patients. Good facial nerve function was observed in 72% immediately postoperatively, 70% 1-month postoperatively, and 82% of patients at last follow-up., Conclusions: The ILA technique is now the method of choice of the senior surgeon (R.N.) when performing microsurgical dissection of the cisternal facial nerve, with which he has achieved high rates of total or near-total resection with excellent facial nerve preservation., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2022, Otology & Neurotology, Inc.)

A decrease in non-emergent procedure volume was observed during the COVID-19 pandemic to conserve protective equipment, increase hospital capacity, and limit nosocomial infection. Decreasing COVID-19 infection rates, paired with increasing hospital financial pressure and concerns for patient welfare, have prompted the development of guidelines for re-introduction of medically-necessary time-sensitive (MeNTS) procedures. Such protocols have received criticism for potentially perpetuating inequities disfavoring vulnerable populations. Limited access to testing supplies and protective equipment, coupled with higher incidence of medical comorbidities attributable to social determinants of health, disadvantages vulnerable populations in seemingly objective prioritization schema. Here, we detail both an analysis of current guidelines as well as strategies aimed at mitigating these disparities (including prioritizing essential infrastructure workers, implementing questionnaires, improving scheduling communication, tracking patients via ZIP codes and insurance status, facilitating post-operative rehabilitation, acknowledging physician bias, and favoring lottery selection over first-come, first-served). These guidelines and strategies can apply to future pandemics and even routine prioritization schema.

Hepatitis B virus remains a major medical burden with more than 250 million chronically infected patients worldwide and 900,000 deaths each year, due to the disease progression towards severe complications (cirrhosis, hepatocellular carcinoma). Despite the availability of a prophylactic vaccine, this infection is still pandemic in Western Pacific and African regions, where around 6% of the adult population is infected. Among novel anti-HBV strategies, innovative drug delivery systems, such as nanoparticle platforms to deliver vaccine antigens or therapeutic molecules have been investigated. Here, we developed polylactic acid-based biodegradable nanoparticles as an innovative and efficient vaccine. They are twice functionalized by (i) the entrapment of Pam 3 CSK 4 , an immunomodulator and ligand to Toll-Like-Receptor 1/2, and by (ii) the adsorption/coating of myristoylated (2-48) derived PreS1 from the HBV surface antigen, identified as the major viral attachment site on hepatocytes. We demonstrate that such formulations mimic HBV virion with an efficient peptide recognition by the immune system, and elicit potent and durable antibody responses in naive mice during at least one year. We also show that the most efficient in vitro viral neutralization was observed with NP-Pam 3 CSK 4 -dPreS1 sera. The immunogenicity of the derived HBV antigen is modulated by the likely synergistic action of both the dPreS1 coated nanovector and the adjuvant moiety. This formulation represents a promising vaccine alternative to fight HBV infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Among mucosal administration routes for vaccines, the sublingual route has been proven capable of inducing a potent systemic and mucosal immune response. However, the absence of a simple and compliant delivery system and the lack of robust mucosal adjuvants impede the development of sublingual vaccines. Here, we describe a mucoadhesive patch made of a layer-by-layer assembly of polysaccharides, chitosan, and hyaluronic acid. The mucoadhesive patch was covered by adjuvanted nanoparticles carrying viral proteins. We showed that the nanoparticles effectively cross the outer layers of the sublingual mucosa to reach the epithelium. Furthermore, the encapsulated adjuvants, 3M-052 and mifamurtide, targeting toll-like receptor (TLR) 7/8 and nucleotide-binding oligomerization domain-2 (NOD2), respectively, remain fully active after encapsulation into nanoparticles and exhibit a cytokine/chemokine signature similar to the mucosal gold-standard adjuvant, the cholera toxin. However, the particulate adjuvants induced more moderate levels of proinflammatory interleukin (IL)-6 and keratinocyte chemoattractant (KC), suggesting a controlled activation of the innate immune response.

The sublingual mucosa is an appealing route for drug administration. However, in the context of increased use of therapeutic proteins, development of protein delivery systems that will protect the protein bioactivity is needed. As proteins are fragile and complex molecules, current sublingual formulations of proteins are in liquid dosage. Yet, protein dilution and short residence time at the sublingual mucosa are the main barriers for the control of the dose that is delivered. In this work, a simple delivery scaffold based on the assembly of two polysaccharides, chitosan and hyaluronic acid, is presented. The natural polymers were assembled by the Layer-by-Layer methodology to produce a mucoadhesive and oro-dispersible freestanding membrane, shown to be innocuous for epithelial human cells. The functionalization of the membrane with proteins led to the production of a bioactive patch with efficient loading and release of proteins, and suitable mechanical properties for manipulation. Sublingual administration of the patch in mouse evidenced the absence of inflammation and an extended time of contact between the model protein ovalbumin and the mucosa compared to liquid formulation. The delivery of fluorescent ovalbumin in mouse sublingual mucosa demonstrated the penetration of the protein in the epithelium 10 min after the patch administration. Moreover, a migration assay with a chemokine incorporated into the patch showed no decrease in bioactivity of the loaded protein after enzymatic release. This study therefore provides a promising strategy to develop a sublingual protein delivery system. STATEMENT OF SIGNIFICANCE: Although the oral route is largely used for drug delivery, it has limitations for the delivery of proteins that can be degraded by pH or gastric enzymes. The sublingual route therefore appears as an interesting approach for protein administration. In this work, a simple delivery scaffold is presented based on the assembly of two polysaccharides by the Layer-by-Layer methodology to produce a mucoadhesive patch. The produced patch allowed efficient loading and release of proteins, as well as protection of their bioactivity. An extended time of contact between the protein and the mucosa compared to liquid formulation was highlighted in mouse model. This study provides a promising strategy to develop a sublingual protein delivery system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although mesenchymal stem/stromal cells (MSCs) are being explored in numerous clinical trials as proangiogenic and proregenerative agents, the influence of tissue origin on the therapeutic qualities of these cells is poorly understood. Complicating the functional comparison of different types of MSCs are the confounding effects of donor age, genetic background, and health status of the donor. Leveraging a clinical setting where MSCs can be simultaneously isolated from discarded but healthy bone and thymus tissues from the same neonatal patients, thereby controlling for these confounding factors, we performed an in vitro and in vivo paired comparison of these cells. We found that both neonatal thymus (nt)MSCs and neonatal bone (nb)MSCs expressed different pericytic surface marker profiles. Further, ntMSCs were more potent in promoting angiogenesis in vitro and in vivo and they were also more motile and efficient at invading ECM in vitro. These functional differences were in part mediated by an increased ntMSC expression of SLIT3, a factor known to activate endothelial cells. Further, we discovered that SLIT3 stimulated MSC motility and fibrin gel invasion via ROBO1 in an autocrine fashion. Consistent with our findings in human MSCs, we found that SLIT3 and ROBO1 were expressed in the perivascular cells of the neonatal murine thymus gland and that global SLIT3 or ROBO1 deficiency resulted in decreased neonatal murine thymus gland vascular density. In conclusion, ntMSCs possess increased proangiogenic and invasive behaviors, which are in part mediated by the paracrine and autocrine effects of SLIT3., (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)