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To address the ongoing SARS-CoV-2 pandemic and prepare for future coronavirus outbreaks, understanding the protective potential of epitopes conserved across SARS-CoV-2 variants and coronavirus lineages is essential. We describe a highly conserved, conformational S2 domain epitope present only in the prefusion core of β-coronaviruses: SARS-CoV-2 S2 apex residues 980–1006 in the flexible hinge. Antibody RAY53 binds the native hinge in MERS-CoV and SARS-CoV-2 spikes on the surface of mammalian cells and mediates antibody-dependent cellular phagocytosis and cytotoxicity against SARS-CoV-2 spike in vitro. Hinge epitope mutations that ablate antibody binding compromise pseudovirus infectivity, but changes elsewhere that affect spike opening dynamics, including those found in Omicron BA.1, occlude the epitope and may evade pre-existing serum antibodies targeting the S2 core. This work defines a third class of S2 antibody while providing insights into the potency and limitations of S2 core epitope targeting.

ABSTRACT Bordetella produces an array of virulence factors, including the adenylate cyclase toxin (ACT), which is essential, immunogenic in humans, and highly conserved. Despite mediating immune-evasive functions as a leukotoxin, ACT’s potential role as a protective antigen is unclear. To better understand the contributions of humoral anti-ACT immunity, we evaluated protection against Bordetella pertussis by antibodies binding structurally defined ACT epitopes in a mouse pneumonia model. An ACT-neutralizing antibody, but not a nonneutralizing antibody or an isotype control, significantly increased mouse survival after lethal challenge with B. pertussis. When modified to impair Fc effector functions, the neutralizing antibody retained protective capabilities, indicating that protection was mediated by the blockade of the interactions of ACT with its αMβ2 integrin receptor. After infection with a lower bacterial dose, ACT neutralization synergistically reduced lung bacterial colonization levels when combined with an opsonic antibody binding the surface antigen pertactin. Notably, protection was significantly enhanced when antibodies were administered intranasally as opposed to systemically, indicating that local immune responses are key to antibody-mediated protection against ACT and pertactin. These data reconcile previous conflicting reports to indicate that neutralizing anti-ACT antibodies support the phagocytosis of opsonized B. pertussis and thereby contribute to pertussis protection in vivo. IMPORTANCE Despite high vaccine coverage in developed countries, the incidence of pertussis has increased in recent decades, often leading to severe consequences for sensitive groups, including infants. For this reason, improving the efficacy of pertussis vaccines is critical, and the addition of new antigens is a leading strategy to achieve this goal. The Bordetella pertussis adenylate cyclase toxin (ACT) acts to disarm host immunity and is considered a promising vaccine candidate since it is found in all Bordetella species. In this work, we show that antibodies neutralizing ACT offer protection against pertussis. Using a murine infection model, we show that antibodies neutralizing ACT can contribute to protection against infection through synergistic interactions with antibodies recognizing current vaccine antigens. Our data can help guide the design of future vaccines, whereby the inclusion of ACT-based immunogens might increase protection against pertussis infection.

RTX leukotoxins are a diverse family of prokaryotic virulence factors that are secreted by the type 1 secretion system (T1SS) and target leukocytes to subvert host defenses. T1SS substrates all contain a C-terminal RTX domain that mediates recruitment to the T1SS and drives secretion via a Brownian ratchet mechanism. Neutralizing antibodies against the Bordetella pertussis adenylate cyclase toxin, an RTX leukotoxin essential for B. pertussis colonization, have been shown to target the RTX domain and prevent binding to the αMβ2 integrin receptor. Knowledge of the mechanisms by which antibodies bind and neutralize RTX leukotoxins is required to inform structure-based design of bacterial vaccines, however, no structural data are available for antibody binding to any T1SS substrate. Here, we determine the crystal structure of an engineered RTX domain fragment containing the αMβ2-binding site bound to two neutralizing antibodies. Notably, the receptor-blocking antibodies bind to the linker regions of RTX blocks I-III, suggesting they are key neutralization-sensitive sites within the RTX domain and are likely involved in binding the αMβ2 receptor. As the engineered RTX fragment contained these key epitopes, we assessed its immunogenicity in mice and showed that it elicits similar neutralizing antibody titers to the full RTX domain. The results from these studies will support the development of bacterial vaccines targeting RTX leukotoxins, as well as next-generation B. pertussis vaccines.

Abstract Background Long head biceps tendon pathology is a common cause of anterior shoulder pain and is often associated with other shoulder conditions, such as rotator cuff tears and osteoarthritis. It is well accepted that older patients are at increased risk for major and minor peri- and postoperative complications. The purpose of this study is to investigate patients over 65 years old who underwent subpectoral biceps tenodesis and compare the complication rates of this group to those of patients younger than 65 years old. The hypothesis is, that there would be no difference in complication rates and that clinical outcome scores for patients over 65 were satisfying and showed improvements over time. Methods There were 337 patients who underwent open subpectoral biceps tenodesis, between January 2005 and June 2015, 23 were identified as being over the age of 65 with a minimum follow up of 12 months. All patients over the age of 65 were evaluated pre- and postoperatively using Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES), Constant-Murley (CM) and Single Assessment Numeric Evaluation (SANE). Intraoperative and postoperative adverse events (fracture, infection, wound opening, rupture/failure and neurovascular injuries) related to the tenodesis procedure and to the surgery itself were collected from all 337 patients in a routine postoperative follow-up. Results The under 65 group (range 27–64 years) at an average follow up (FU) of 30 months (range 12–91 months) showed a 5.4% (17 out of 314) post-operative complication rate related to the subpectoral tenodesis, whereas the group over 65 (range 65–77 years) at an average follow up of 33 months (range 12–79 months) showed an 8.7% (2 out of 23) complication rate. Conclusion This study demonstrates that in patients over the age of 65, biceps tenodesis is a successful procedure when performed for biceps tendinopathy and concomitantly with other surgical procedures of the shoulder, and does not result in an increased rate of complications when compared to a group of patients under the age of 65.

Category: Bunion Introduction/Purpose: Proximal opening wedge osteotomy (POWO) is an established correctional procedure for moderate to severe hallux valgus. A common concern of this procedure is that it results in lengthening of the metatarsal which could cause increased intra-articular pressure of the first metatarsophalangeal joint (MTP), and may ultimately lead to arthritis due to these altered mechanics. The purpose of this study was to use cadaveric models to compare intra-articular pressures and articulating contact properties of the MTP joint following either scarf osteotomy or POWO. These were compared to normal cadaveric specimens. Our hypothesis was that the intra-articular pressure of the first MTP joint would be greater following the POWO compared to the scarf osteotomy. Methods: Fresh-frozen cadaveric below knee specimens with pre-existing hallux valgus (n=12) and specimens without arthritis or hallux valgus (n=6, control group) were used. The hallux valgus specimens were stratified into two groups (n=6 each): POWO or scarf osteotomy. The groups were matched based on the degree of deformity. Peak intra-articular pressure, force, and area were measured in all normal, preoperative and postoperative specimens. These measurements were made with a pressure transducer (Tekscan, Boston, Massachusetts) while a 50 N dorsiflexion load was applied via a wired loop on the first toe over 5 seconds and then released. Secondary outcomes included range of motion (ROM) and radiographic measurements. ROM was measured pre and postoperatively under fluoroscopy. 1-2 intermetatarsal angle (1-2 IMA), hallux valgus angle (HVA), and metatarsal length were measured on simulated weight-bearing radiographs. Statistical analyses were performed using unpaired Student’s t-test, paired Student’s t-test, and ANOVA with Bonferroni correction for post-hoc analysis. Results: Postoperatively, although POWO group had slightly higher contact forces and pressures compared to the scarf group, they were lower than those of the normal group. These comparisons had no statistically significant differences (P>0.05). Normal specimens had significantly higher force (P=0.012) and pressure (P=0.007) but similar contact area (P>0.05) compared to the preoperative hallux valgus specimens. Contact area were similar in normal, POWO, and scarf groups. There was no significant difference in ROM between all three groups. The first metatarsal was lengthened 1.36 mm +/- 1.39 mm in the POWO group and lengthened 1.54 mm +/- 2.27 mm in the scarf osteotomy group. Conclusion: The results from this study show that after surgical correction, contact properties of the fist MTP joint among normal, POWO, and scarf osteotomy groups revealed no significant differences. First MTP joints in those with hallux valgus have significantly lower contact force and pressure compared to those without hallux valgus. Our results provide biomechanical evidence that first MTP joint biomechanics are similar after POWO and scarf osteotomy.

This article describes a participatory action research (PAR) project designed to evaluate Parent to Parent programs in five states. The process of developing a shared understanding of the program and of the purpose for evaluating them, along with an on-going willingness of parents and researchers to compromise, led to creative solutions to difficulties that arose. (Author/CR)

Describes the partnership between the early childhood program at the University of Vermont and Parent to Parent of Vermont. The partnership was designed to set a context for preparation of family-centered practitioners by modeling the qualities of a collaborative relationship between families and professionals and by developing a family-centered model for personnel preparation. (Author/CR)

This article describes the role of family members in early intervention personnel preparation efforts, provides a rationale for family involvement, and offers guidelines and strategies for facilitating the participation of families of special-needs young children in personnel preparation, in ways that model collaborative family-professional partnerships. (Author/DB)