Faculty Bibliography

Bone grafting procedures have been widely utilized as the current state-of-the-art for bone regeneration, with autogenous bone graft being the gold-standard bone reconstructive option. However, the use of autografts may be limited by secondary donor-site comorbidities, a finite amount of donor supply, increased operating time, and healthcare cost impact. Synthetic materials, or alloplasts, such as the polymeric material, poly(lactic-co-glycolic acid) (PLGA) has previously been utilized as a transient scaffold to support healing of bone defects with the potential to locally delivery osteogenic additives. In this study a novel procedure was adopted to incorporate both the dissolved contents and mechanical components of leukocyte- and platelet-rich fibrin (L-PRF) into an PLGA scaffold through a two-step method: (a) extraction of the L-PRF membrane transudate with subsequent immersion of the PLGA scaffold in transudate followed by (b) delivering a fibrin gel as a low-viscosity component that subsequently polymerizes into a highly viscous, gel-like biological material within the pores of the PLGA scaffold. Two, ~0.40 cm³ , submandibular defects (n = 24) were created per side using rotary instrumentation under continuous irrigation in six sheep. Each site received a PLGA scaffold (Intra-Lock R&D, Boca Raton, FL), with one positive control (without L-PRF exudate addition [nL-PRF]), and one experimental (augmented with PLGA/L-PRF Blocks [L-PRF]). Animals were euthanized 6 weeks postoperatively and mandibles retrieved, en bloc, for histological analysis. Histomorphometric evaluation for bone regeneration was evaluated as bone area fraction occupancy (BAFO) within the region of interest of the cortical bone (with specific image analysis software) and data presented as mean values with the corresponding 95% confidence interval values. Qualitative evaluation of nondecalcified histologic sections revealed extensive bone formation for both groups, with substantially more bone regeneration for the L-PRF induced group relative nL-PRF group. Quantitative BAFO within the defect as function of the effect of L-PRF exudate on bone regeneration, demonstrated significantly (p = .018) higher values for the L-PRF group (38.26% ± 8.5%) relative to the nL-PRF group (~28% ± 4.0%). This in vivo study indicated that L-PRF exudate has an impact on the regeneration of bone when incorporated with the PLGA scaffold in a large translational model. Further studies are warranted in order to evaluate the L-PRF exudate added, as well as exploring the preparation methods, in order to facilitate bone regeneration.

BACKGROUND:The exophthalmos and class III malocclusion seen in Crouzon syndrome can be treated by Le Fort III advancement/distraction. However, reconstructive options for zygomatic retrusion are limited. The authors describe the repair of isolated exorbitism in a patient with Crouzon syndrome, via bilateral zygomatic rotation-advancement. METHODS:A 34-year-old woman with Crouzon syndrome complained of exorbitism and malar hypoplasia. Four years prior, she declined Le Fort III advancement and underwent orthodontic/orthognathic correction of malocclusion. Radiographs were used to develop a computerized surgical plan. Bilateral periorbital osteotomy with advancement/rotation of the zygomatic process was performed using custom osteotomy guides and plates. Images obtained immediately postoperative and 3- and 19-month postoperative were compared to assess surgical stability, accuracy, and soft tissue changes. RESULTS:Decreased globe exposure and increased malar prominence have improved facial balance. Superimposed pre- and postoperative radiographs demonstrate bilateral advancement of the zygomatic body and inferior orbital rim. Superimposition of immediate postoperative and 19-month radiographs showed no relapse. Soft tissue histogram showed increased prominence of the malar eminence, lateral orbital rim, and cheek. CONCLUSIONS:Zygomatic rotation-advancement proved a safe, effective, stable, and predictable treatment for isolated malar hypoplasia in a patient with Crouzon syndrome. Virtual planning can enhance novel complex craniofacial procedures.

PURPOSE/OBJECTIVE:There is a dearth of literature dedicated to specifically evaluating the use of free flap reconstruction in pediatric lower extremity traumas. This study aims to identify specific risk factors for flap failure in pediatric lower extremity trauma reconstruction. METHODS:Retrospective review of 53 free flaps in our lower extremity database (1979-2017) identified all free flaps performed for traumatic reconstruction in children <18 years of age at our institution. RESULTS:analysis (P = 0.041). CONCLUSION/CONCLUSIONS:Free flap reconstruction in the pediatric trauma population is safe with similar survival outcomes when compared to the adult population. Arterial injury and vessel size mismatch were associated with significantly higher flap failure rates in this population. LEVEL OF EVIDENCE/METHODS:Level III.

In India, social determinants of health, including poverty, domestic violence, and inadequate social support disproportionately affect women, leaving them more vulnerable to depression than men. We conducted a metaethnography to synthesize qualitative data from 13 studies (1987-2017) that explored women's experiences and perceptions of depression in India. We used a feminist standpoint to critically examine how gender shapes these experiences and perceptions. Indian women's experiences of depression were embedded in their social worlds. Women perceived interpersonal conflict, caregiving burden, domestic violence, financial insecurity, adverse reproductive events and widowhood as causes of depression. Women used cultural expressions to describe physical, emotional, and cognitive distress. The detrimental impact of discriminatory social conditions, gender inequalities, and traditional gender roles on Indian women's mental health highlights the need for gender-sensitive mental health research and practice that can attend to women's sociocultural context and promote values of gender equality and social justice.

As the field of vascularized composite allotransplantation (VCA) continues to evolve and technological approaches improve, VCA programs must focus on promoting greater consistency in psychosocial assessment across programs to support the equitable selection of patients. Based on a summary of published reports of VCA, we address the ethical considerations raised by the present heterogeneity of approaches to psychosocial assessment, including weighing risks and benefits, informed consent and the role of decisional capacity, and potential or perceived bias in the assessment process. We propose transparency of process across the field and encourage VCA programs to work collaboratively to share approaches to psychosocial assessment both pre- and post-transplant to promote health equity.

We sought to investigate the relationship of high life satisfaction with important physical health, mental health, social integration and perceived safety factors among midlife and older Mexican adults. We examined 2,200 midlife and older adults (aged 50-101 years) from the Mexican arm of the Study on global AGEing and adult health (SAGE) and used binary logistic regression models to identify key factors associated with high LSA. Our final logistic regression model revealed self-rated health, affect, interpersonal activities and perceived safety on street to be significantly associated with high life satisfaction. Results from this study add to the nascent literature on subjective well-being of midlife and older Mexicans. Although social work with older adults is not well established in Mexico, researchers and practitioners should collaborate on the development and implementation of social worker-led strategies for prevention and intervention to enhance well-being among midlife and older Mexicans.

Janus kinase (JAK2)V617F is the most common mutation found in patients with Philadelphia chromosome negative myeloproliferative neoplasms (Ph- MPNs). The discovery of this mutation over 15 years ago revolutionised MPN diagnosis and inspired the development of JAK inhibitors as new therapeutic interventions. However, despite extensive structural and biophysical studies using JAK2 domains in isolation, the exact molecular mechanisms of JAK2XX activation remains elusive. We have previously demonstrated that expression of the thrombopoietin (TPO) receptor, MPL, which interacts directly with JAK2, is essential for disease development in a mouse model of a JAK2XX-positiveMPN (Blood 2014 124:3956-3963). Using total internal reflection fluorescence (TIRF) microscopy, we visualized MPL interaction dynamics in live cells on single molecule level. Effective cell surface MPL fluorescence labelling and dual-color imaging allowed us to determine the level of MPL dimerization under various experimental conditions. Using this assay, we clearly established that MPL is monomeric at physiologically relevant receptor densities. However, TPO stimulation results in significant dimerization of MPL (>50%) and an equilibrium between monomers and dimers. This counters the current dogma that MPL exists at the membrane as a pre-formed dimer. Strikingly, we found that JAK2XX shifts this monomer-dimer equilibrium leading to significant TPO-independent MPL dimerization providing a novel mechanistic model of oncogenic JAK2 activation. To highlight the role of ligand-independent receptor dimerization in JAK2 activation, we compared three groups of autoactivating mutations in the PK domain covering the FERM-SH2 (FS2)-PK linker region (Group I), residues in the proximity of the alphaC helix (Group II) and at the autoinhibitory PK-TK interface (Group III). Consistent MPL dimerization was only observed for mutations in groups I and II. Mutations in these groups both localize to a potential homomeric PK/PK interface that has been implicated as a switch of JAK activation. Using MD simulations, we also found that the FERM domain of JAK2 strongly interacts with the inner leaflet of the lipid bilayer of the plasma membrane via a single hydrophobic residue (L224) surrounded by several positively charged residues that allows the region to act as a membrane anchor. This tight coupling to the membrane enforces an appropriate orientation between the JAKs within the receptor dimers required for optimal intermolecular PK/PK interaction that is critical for receptor dimerization. To interfere with membrane anchoring, we introduced a negative charge in this position (L224E). Strikingly, ligand-independent MPL dimerization and activation by JAK2XX was dramatically reduced upon introducing L224E, supporting the vital importance of L224 for orienting JAK2 at the membrane to allow productive PK-PK interactions. Here, we demonstrate that JAK2XX mutation acts by altering and strengthening the intermolecular interactions involving the PK/PK dimerization interface. In essence, these mutations drive cytoplasmic stabilization of receptor-JAK dimers, bypassing extracellular stabilization of dimers via cytokine binding. These results provide critical and entirely novel mechanistic insights into signal initiation in MPNs and readdress the roles of receptor-associated proteins. Disclosures: Hubbard: Ajax Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-Founder.XXCopyright

BACKGROUND:The principle of relative motion has allowed patients to regain a higher degree of hand function, while protecting extensor tendon repairs. The purpose of this study was to determine whether the principle of relative motion could be a viable method to protect a flexor tendon repair. METHODS:Four fresh-frozen cadaver arms were each mounted on a testing apparatus (wrist in 30° of extension, metacarpophalangeal [MCP] joints blocked to 70°-80°). A minimum of 11 N was used to cyclically load the flexor digitorum profundus and extensor digitorum communis tendons to maximum allowable flexion and extension for 25 cycles. Measurements of elongation of the tendons were obtained through the use of differential variable reluctance transducers. Testing was performed in both intact and repaired (single 6-0 nylon suture) middle finger tendons (zone 3) with and without a relative motion flexion splint (RMFS), which placed the affected finger in 15° to 25° of relative flexion at the MCP joint. RESULTS:In all 4 hands, elongation was restricted to less than 1.3 mm in repaired tendon in the RMFS compared with elongation >2 mm in the nonsplinted condition. Average elongation was 0.86 mm (SD = 0.45). Visual examination of the tendons demonstrated no gapping with the use of the RMFS in any of the hands. All repairs had suture breakage and repair rupture without the RMFS. CONCLUSIONS:This study demonstrates that the RMFS decreases elongation and eliminates tendon-repair gapping after flexion/extension cycling in a cadaver model. It provides proof of concept that the RMFS may be a viable protective mechanism for flexor tendon repairs in zone 3.

Ischemic complications after immediate breast reconstruction have devastating consequences; however, individual risk assessment remains challenging. We seek to develop an intraoperative assessment tool to assist in estimating risk of ischemic complications in immediate breast reconstruction.