BackgroundOtitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility.MethodsWe performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues.ResultsA large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma.ConclusionSPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.
Background Bone adhesives have been on the forefront of orthopedic surgery research for decades due to the potential benefit they may have in fracture management. Current publications and research being conducted on bone adhesive could be applied to our current hypothesis for the benefit of a novel minimally invasive treatment option for a select cohort of fractures, Jones fractures. The select fracture’s gold standard of treatment would be nonoperative, but with risk of complications including nonunion and delayed union. Presentation of hypothesis We hypothesize that percutaneous application of bone adhesive will provide an additional treatment option for fracture patterns that do not require operative fixation, but would benefit from additional stability. The primary outcome measures would be (1) duration of time required for bony consolidation (defined as 3 of 4 bridging cortices) and (2) duration of absenteeism (inability to work), and pain levels within the first week after the procedure. Secondary outcome measures would be the incidence of nonunion or delayed union. We hypothesize that the select bone adhesive would accelerate bony consolidation, decrease absenteeism, decrease pain levels within the first week after procedure, and decrease the incidence of delayed union and/or nonunion. Testing of hypothesis We propose a prospective multicenter, randomized, and open label trial clinical trial to test the bone adhesive via percutaneous injection into acute non-displaced or minimally displaced Jones fractures. Implications of hypothesis Bone adhesives are a new frontier in treatment of fractures, currently in laboratory and animal testing phases. The appropriate bone adhesive formula has not been approved for clinical trial use, but the implications of the bone adhesive may go beyond decreased complications and ease of stabilizing a select cohort of closed fractures. With the injectable compound illustrated (Fig. 1), the adhesive could be applied percutaneously in hopes of achieving improved outcomes compared to non-operative treatment. The overall goal of the clinical trial is to provide patients a safe treatment option for improved bone union rates of nonoperative fractures compared to the current gold standard management of the same fracture with earlier pain control, early bony consolidation and lower risk of delayed union/nonunion. The ideal patient population for use of a percutaneous bone adhesive in future studies would be for those with multiple medical comorbidities for whom surgical risks outweigh the benefits, in addition to patients at high risk for nonunion based on fracture pattern or systemic biology.
Arteriovenous malformations of the orbit are rare congenital hamartomas defined by a direct connection between the arterial and venous systems without an intervening capillary bed. Treatment can be challenging, as these lesions are anatomically complex, often involve multiple locations, and have a tendency to recur. A multidisciplinary approach is typically required, involving endovascular and surgical teams. The authors present a case of a 33year-old man with a complex, recurrent orbital arteriovenous malformations in the context of wider head and neck vascular anomaly syndrome involving the paranasal sinuses, deep facial tissues, and intracranial spaces. The complex and evolving clinical manifestations of this disease are presented with emphasis on the interdependence of the anomalies and biologic management strategies.
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