Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons.

Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation.

Subjective and objective assessments of executive functions are independently predictive of aggressive tendencies in patients with substance use disorder.

BACKGROUND AND AIMS: Impairments in executive functions have been found to influence violent behavior. Executive functions are crucial in the treatment of patients with substance use disorders because substance use generally impairs cognitive processes and is therefore detrimental for executive functions thereby reducing control of behavior and thus of consumption impulses. We studied correlations between subjective, i.e. self-report, and objective, i.e. behavior-based, assessment of executive functions and the predictive validity of these measures for aggression in patients with substance use disorder. METHODS: The study included 64 patients with a diagnosed substance use disorder who were convicted according to the German Criminal Code for crimes they committed in the context of their disorder and were therefore in treatment in forensic psychiatric departments in Germany. Multiple self-report and behavior-based instruments were used to assess executive functions, appetitive and facilitative aggression as well as clinical and sociodemographic variables. RESULTS: Participants showed impaired executive functions, and measures of executive functions predicted aggressive tendencies and violent offenses. Despite ecological validity of the findings, the subjective and objective assessments of executive functions did not correlate with each other, which corroborates studies in other clinical settings. CONCLUSIONS: We discuss that this finding may be due to the conceptual differences between subjective and objective measures. Therefore, self-report and behavior-based measures should not be used as proxies of each other but as complementary measures that are useful for comprehensive diagnostics of cognitive impairments and assessment of risks for violent behavior.

Analysis of antibiotic resistant infections associated with hirudotherapy.

OBJECTIVE: Given rising concern regarding antibiotic resistance, our objective was to evaluate antibiotic-resistant infections following leech therapy and to characterize the use of prophylactic antibiotics. METHODS: All reports of adverse events involving hirudotherapy (product code "NRN") were retrieved from the U.S. Food and Drug Administration MAUDE database between 2012 and 2021. Antibiotic resistance was defined by bacterial culture or infection after antibiotic administration. RESULTS: Nineteen cases of antibiotic resistance involving hirudotherapy were identified. Only three cases of antibiotic resistance were discovered on routine testing and the remaining 16 cases were associated with patient injury. Positive blood cultures or fever were present in 26.3 % (n = 5) of cases. Cultures of the infection grew Aeromonas hydrophilia (n = 13; 68.4 %), Vibrio vulnificus (n = 3; 15.8 %), Pseudomonas aeruginosa (n = 2; 10.5 %), and Proteus vulgaris (n = 1; 5.3 %). There were nine (47.4 %) multi-drug resistant infections. Infection was most commonly resistant to fluoroquinolones (n = 9; 47.4 %), trimethoprim-sulfamethoxazole (n = 9; 47.4 %) and ertapenem (n = 4; 21.1 %). CONCLUSION: Antibiotic-resistant infections involving hirudotherapy are frequently resistant to multiple drugs, including fluoroquinolones and trimethoprim-sulfamethoxazole. Resistance to ertapenem, a drug of last resort, was also documented. The findings presented in this study support growing literature that the trend in multi-drug resistance is more severe than previously reported.

Adverse events associated with anastomotic coupling devices in microvascular reconstruction.

OBJECTIVE: In light of the recent US Food and Drug Administration (FDA) Class 2 safety recall notice for anastomotic coupling devices, it is important to understand related adverse events. The aim of this study was to characterize adverse events in anastomotic coupling devices for microvascular reconstruction. METHODS: A retrospective cross-sectional analysis using the 2011 to 2021 US FDA Manufacturer and User Facility Device Experience (MAUDE) database. All reports of adverse events involving anastomotic coupling devices were retrieved from the MAUDE database. Descriptive statistics were used to analyze categorized events. RESULTS: There were a total of 293 documented adverse events related to anastomotic coupling devices. These adverse events resulted in 91 (31.1 %) patient injuries and 239 (81.6 %) device malfunctions. The most frequent patient problems were thrombosis/hematoma (n = 38; 41.8 %), unspecified injury (n = 31; 34.1 %), and failure to anastomose (n = 13; 14.3 %). Free flap necrosis was reported in 42 % of thrombosis/hematoma cases (n = 16). The most common malfunctions were devices operating differently than expected (n = 74; 31.0 %), connection problems (n = 41; 17.2 %), and twisted/bent material (n = 19; 7.9 %). There was no significant trend in the number of adverse events over the study period (p > 0.05). CONCLUSIONS: Adverse events from anastomotic coupling devices represent an important and modifiable factor in free tissue failure. Adverse events are predominately related to devices operating differently than expected and may result in vascular compromise of the free flap. Reconstructive surgeons should be cognizant of defective anastomotic coupling devices and be prepared to utilize traditional hand-sewn anastomosis.

Neuroimaging in alcohol use disorder: From mouse to man.

This article provides an overview of recent advances in understanding the effects of alcohol use disorders (AUD) on the brain from the perspective of magnetic resonance imaging (MRI) research in preclinical models and clinical studies. As a noninvasive investigational tool permitting assessment of morphological, metabolic, and hemodynamic changes over time, MRI offers insight into the dynamic course of alcoholism beginning with initial exposure through periods of binge drinking and escalation, sobriety, and relapse and has been useful in differential diagnosis of neurological diseases associated with AUD. Structural MRI has revealed acute and chronic effects of alcohol on both white and gray matter volumes. MR Spectroscopy, able to quantify brain metabolites in vivo, has shed light on biochemical alterations associated with alcoholism. Diffusion tensor imaging permits microstructural characterization of white matter fiber tracts. Functional MRI has allowed for elucidation of hemodynamic responses at rest and during task engagement. Positron emission tomography, a non-MRI imaging tool, has led to a deeper understanding of alcohol-induced receptor and neurotransmitter changes during various stages of drinking and abstinence. Together, such in vivo imaging tools have expanded our understanding of the dynamic course of alcoholism including evidence for regional specificity of the effects of AUD, hints at mechanisms underlying the shift from casual to compulsive use of alcohol, and profound recovery with sustained abstinence.

Free vascularized fascia lata flap for total columella reconstruction.

INTRODUCTION: Despite their relatively small size, columellar defects, including both external and internal elements, are exceedingly difficult to reconstruct. Local, regional, and distant flaps have been described for reconstruction. Herein, we present a novel technique for reconstruction of the columella using vascularized free fascia lata from the anterolateral thigh with structural replacement and skin grafting. METHODS: This novel technique utilizes a small anterolateral thigh flap, formed into vascularized fascia lata without the overlying subcutaneous fat or skin. The fascia lata is inset into the columellar and caudal septal defect after a cartilage framework is constructed and is microsurgically anastomosed to either distal facial or angular vessels. A skin graft from the ALT donor site is then secured over the fascia. RESULTS: This technique has been applied successfully in patients with either isolated columella or in multi-subunit reconstruction following total rhinectomy with no flap or reconstructive failures. Given the low morbidity of flap harvest and minimal access incisions, this has been reliably accomplished with short (1-2 day) hospital stays. CONCLUSION: Rapid and aesthetically acceptable reconstruction of total nasal columella defects in isolation or with additional nasal subunit reconstruction, is possible utilizing this novel technique. Here we discuss pearls and pitfalls of its use following surgical resection of malignancy.

Successive duplication-divergence mechanisms at the RCO locus contributed to leaf shape diversity in the Brassicaceae.

Gene duplication is a major driver for the increase of biological complexity. The divergence of newly duplicated paralogs may allow novel functions to evolve, while maintaining the ancestral one. Alternatively, partitioning the ancestral function among paralogs may allow parts of that role to follow independent evolutionary trajectories. We studied the REDUCED COMPLEXITY (RCO) locus, which contains three paralogs that have evolved through two independent events of gene duplication, and which underlies repeated events of leaf shape evolution within the Brassicaceae. In particular, we took advantage of the presence of three potentially functional paralogs in Capsella to investigate the extent of functional divergence among them. We demonstrate that the RCO copies control growth in different areas of the leaf. Consequently, the copies that are retained active in the different Brassicaceae lineages contribute to define the leaf dissection pattern. Our results further illustrate how successive gene duplication events and subsequent functional divergence can increase trait evolvability by providing independent evolutionary trajectories to specialized functions that have an additive effect on a given trait.

Nearshore Zone Dynamics Determine Pathway of Organic Carbon From Eroding Permafrost Coasts.

Collapse of permafrost coasts delivers large quantities of particulate organic carbon (POC) to Arctic coastal areas. With rapidly changing environmental conditions, sediment and organic carbon (OC) mobilization and transport pathways are also changing. Here, we assess the sources and sinks of POC in the highly dynamic nearshore zone of Herschel Island-Qikiqtaruk (Yukon, Canada). Our results show that POC concentrations sharply decrease, from 15.9 to 0.3 mg L-1, within the first 100-300 m offshore. Simultaneously, radiocarbon ages of POC drop from 16,400 to 3,600 14C years, indicating rapid settling of old permafrost POC to underlying sediments. This suggests that permafrost OC is, apart from a very narrow resuspension zone (<5 m water depth), predominantly deposited in nearshore sediments. While long-term storage of permafrost OC in marine sediments potentially limits biodegradation and its subsequent release as greenhouse gas, resuspension of fine-grained, OC-rich sediments in the nearshore zone potentially enhances OC turnover.

Early discharge after free-tissue transfer does not increase adverse events.

INTRODUCTION: Demonstrate that carefully selected free flap patients may be discharged early after surgery without increasing the rates of postoperative complications or readmissions. METHODS: Based on a published article in Laryngoscope 2016 of 51 free-tissue transfers, a retrospective chart review was performed on an expanded cohort who underwent free-tissue transfer for head and neck reconstruction between February 2010 and May 2018 and discharged by postoperative day 3. RESULTS: 101 patients who underwent 104 free flaps with average age of 56 (3-84) years old were reviewed. Free flap indications included orbital and maxillary defects (n = 22), palatal defects (n = 16), nasal and septal defects (n = 16), cranioplasty and scalp defects (n = 16), mandibular defects due to osteoradionecrosis (n = 14), facial contouring and parotid defects (n = 12), and complex postsurgical and radiotherapy wounds or fistula closure (n = 8). Free flaps performed were anterolateral thigh (n = 97), radial forearm (n = 2), serratus (n = 2), latissimus (n = 1), fibula (n = 1) and supraclavicular (n = 1). The recipient vessels used via minimal access approaches were facial (n = 43), superficial temporal (n = 29), angular (n = 20) and others. There were 3 flap failures (2.9%) recognized in follow-up. No flap failures or perioperative complications were associated with early discharge. There were only 2 patients readmitted and 1 watched in observation within 30 days postoperatively. CONCLUSION: An updated review of our institutional experience with more than double the cohort size substantiates previous conclusions that early discharge after free-tissue transfer is a safe option in select patients. Moreover, earlier discharge is a critical management choice that reduces cost and decreases hospital-related adverse events.

Osseocartilaginous Rib Graft L-Strut for Nasal Framework Reconstruction.

BACKGROUND: In the setting of major nasal framework reconstruction, it is critical to create a stable, warp-resistant L-strut to resist the contractile forces of healing to achieve a durable outcome. OBJECTIVES: The authors sought to demonstrate the effectiveness of the osseocartilaginous rib graft for nasal framework reconstruction. METHODS: Retrospective analysis was performed of all patients who underwent osseocartilaginous rib graft for L-strut reconstruction from 2007 to 2017 at a tertiary care hospital. Only patients with severe framework-only defects (Type IV, Daniel Classification) or total/subtotal nasal defects (Type V, Daniel Classification) were included. Primary outcome measures were: (1) maintenance of projection; (2) graft warping; and (3) graft resorption. RESULTS: Twenty-six patients aged an average of 54.6 years underwent nasal framework reconstruction with an osseocartilaginous rib graft L-strut. Eighteen patients had framework-only deformities (Daniel Type IV) and 8 had total or subtotal nasal deformities (Daniel Type V). Twelve patients underwent reconstruction for autoimmune mediated deformity, 10 for malignancy, 3 for traumatic injury, and 1 for an iatrogenic deformity. Average follow-up was 21 months. There was no observed warping of the L-strut construct, and all but 2 patients demonstrated total maintenance of projection. Resorption of the caudal cartilage graft was identified as the etiology of partial loss of projection in 2 patients. CONCLUSIONS: The osseocartilaginous rib graft L-strut provides a stable, warp-resistant construct for patients lacking major dorsal and caudal support, which may be applied to reconstruction of defects due to malignancy, autoimmune, traumatic, or iatrogenic etiologies.

Mandibular rescue: Application of the ALT fascia free flap to arrest osteoradionecrosis of the mandible.

OBJECTIVES: To evaluate the use of the anterolateral thigh fascia free flap for use in neovascularization of mandibular bone in moderate osteoradionecrosis (ORN). All patients had ORN secondary to prior radiation therapy that was not severe enough to warrant segmental resection and reconstruction. STUDY DESIGN: Case series. SETTING: Tertiary medical center. METHODS: IRB approval was obtained, and a retrospective chart review performed of all mandibular rescue procedures performed from 2011 to 2014. Patients with a minimum of two years of follow-up were included in the study. RESULTS: All surgeries were performed by the senior surgeon (MF). Eight patients underwent the mandibular rescue procedure with resolution of pain and return to oral feeding in all patients, and no evidence of ORN progression on follow-up imaging. A total of 9 ALT free flaps were performed (one patient had 2 surgeries). Gender was distributed evenly (4 female/4 male). The average age was 66 (58-78), average length of hospitalization was 2.8 days (1-7), and average follow-up was 46.5 months (25-63). CONCLUSIONS: The mandibular rescue procedure is a novel technique using the ALT fascia lata free flap to provide coverage and nutrient blood flow to mandible devascularized secondary to radiation therapy. The flap provides the advantages of low morbidity, ease of harvest, two-team approach to ablation and reconstruction, and quick recovery resulting in 'short-stay' free flap surgery. Although conclusions must be tempered in this small case series, our early clinical experience shows the ALT fascia lata flap holds promise in halting the destructive progression of ORN that is not yet advanced enough to require a segmental resection and reconstruction.

Interferon-É£ mediated signaling in the brain endothelium is critical for inflammation-induced aversion.

Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-É£ (IFN-É£) in the aversive response to systemic inflammation induced by a low dose (10µg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-É£ expression in the blood and deletion of IFN-É£ or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-É£ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-É£ receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-É£ action. Collectively, these findings show that circulating IFN-É£ that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.

Comprehensive approach to reestablishing form and function after radical parotidectomy.

INTRODUCTION: The reconstructive goals following radical parotidectomy include restoration of symmetry, reanimation of the face, and reestablishment of oral competence. We present our experience utilizing the anterolateral thigh (ALT) free flap, orthodromic temporalis tendon transfer (OTTT), and facial nerve cable grafting to reestablish form and function. MATERIAL AND METHODS: From 2010 to 2016, 17 patients underwent radical parotidectomy followed by immediate reconstruction. An ALT was harvested to accommodate the volume and skin defect. Additional fascia lata and motor nerve to vastus lateralis (MNVL) were obtained. Anastomosis of the ALT to recipient vessels was performed, most commonly using the facial artery and internal jugular vein. OTTT was performed by securing the medial tendon of the temporalis to orbicularis oris through a nasolabial incision. Fascia lata was tunneled through the lower lip, then secured laterally to the temporalis tendon. The MNVL was cable grafted from either the proximal facial nerve or masseteric nerve to the distal facial nerve branches. ALT fascia was suspended to the superficial muscular aponeurotic system. RESULTS: Average follow up was 19 months. Only one patient failed to achieve symmetry attributed to dehiscence of OTTT. All patients achieved oral competence and dynamic smile with OTTT activation. Facial nerve recovery was seen in 8 patients. 5 reached a House Brackman Score of 3. Two donor site seromas and two wound infections occurred. CONCLUSION: Simultaneous ALT, OTTT, and facial nerve cable grafting provides early reestablishment of facial symmetry, facial reanimation, and oral competence with minimal morbidity.

Large orbital defect reconstruction in the setting of globe-sparing maxillectomy: The titanium hammock and layered fibula technique.

INTRODUCTION: The purpose of our study was to describe a novel technique for reconstruction of orbital defects after maxillectomy using a non-anatomic titanium mesh suspension of orbital contents for both support and volume correction. This construct is then articulated with a layered fibula osteocutaneous free flap that restores orbital rim, zygoma, and maxillary alveolus. We herein present our application of this technique, including refinements over time and long-term outcomes. METHODS: A retrospective review was performed on 12 patients who underwent reconstruction of Brown class III orbitopalatomaxillary defects with extensive orbital involvement (at minimum complete orbital floor and rim absent) with titanium mesh sling and a layered fibula free flap. RESULTS: Primary reconstruction was accomplished in all 12 patients. The mean postoperative length of stay was 8 days (6-14 days). There were no free flap failures or perioperative re-explorations. Patients were routinely extubated on postoperative day #1 and began oral intake by postoperative day #3. At a mean follow-up length of 48 months, unrestricted eye function was accomplished in all patients. Midfacial symmetry was accomplished in 10 of 12 patients; 2 patients had moderate asymmetry due to extirpation of facial musculature and/or soft tissue. Minor revisions were necessary for lower lid ectropion and exposure of the titanium plate. Two patients required adipofascial free flap coverage of exposed intraoral bone after radiation therapy. CONCLUSIONS: This technique provides excellent restoration of eye position and function and also allows for implant-based prosthetic rehabilitation. It has become our procedure of choice for orbitomaxillary reconstruction.

Perioperative cardiac complications in patients undergoing head and neck free flap reconstruction.

BACKGROUND: Limited data exists on cardiac complications following head and neck free flaps. DESIGN: A retrospective review was performed on patients that underwent free flap reconstruction from 2012 to 2015. RESULTS: 368 flaps were performed. 12.5% of patients experienced a cardiac event. Hypertension, coronary artery disease, heart failure, venous thromboembolism, and anticoagulation were associated with cardiac complications. ASA class was not predictive of cardiac events. 7.6% of patients required anticoagulation, which exhibited a strong association with surgical site hematoma. Cardiac complications led to a significantly increased length of stay. CONCLUSIONS: There is a significant rate of cardiac events in this cohort. When estimating risk, a patient's total burden of comorbidities is more important than any one factor. ASA Class fails to demonstrate utility in this setting. Cardiac events have implications for quality-related metrics including length of stay and hematoma rate.

Periocular Skin Cancer in Solid Organ Transplant Recipients.

PURPOSE: To determine the proportion of solid organ transplant recipients developing periocular nonmelanoma skin cancer and to describe the morbidity of these cancers in transplant recipients. DESIGN: Cohort study. PARTICIPANTS: Consecutive patients undergoing solid organ transplantation at the Cleveland Clinic between 1990 and 2008. METHODS: The charts of all patients receiving a solid organ transplant from 1990-2008 evaluated in the dermatology department for a subsequent biopsy-proven head and neck malignancy through April 2015 were reviewed. Patients with a periocular region nonmelanoma skin cancer (NMSC) or a nonperiocular NMSC causing a complication requiring eyelid surgery were included. Charts were reviewed for demographic data; transplant date, type, and source; immunosuppressive agents received at diagnosis; and type of NMSC, number of nonperiocular NMSCs, ophthalmologic findings, and periocular sequelae after the repair. MAIN OUTCOME MEASURES: Primary outcome measures included the type, location, final defect size, tumor-node-metastasis classification, presence of perineural invasion, and reconstruction technique(s) used for each periocular NMSC. Secondary outcome measures included the type and treatment of ocular sequelae due to nonperiocular facial NMSC. RESULTS: A total of 3489 patients underwent solid organ transplantation between 1990 and 2008. Of these, 420 patients were evaluated in the dermatology clinic for biopsy-proven NMSC of the head and neck during the study period, and 11 patients (15 malignancies) met inclusion criteria. Nine patients developed 12 periocular malignancies and 3 patients required eyelid surgery for facial malignancies outside the periocular zone. All 11 patients developed a squamous cell carcinoma (14 malignancies), and 1 patient (1 malignancy) also developed a periocular basal cell carcinoma. There was orbital invasion in 4 cases and paranasal and/or cavernous sinus invasion in 3 cases. Two patients underwent exenteration. Seven cases required reconstruction with a free flap or graft. Periocular sequelae included lower eyelid ectropion (6 malignancies), dry eye and/or exposure symptoms (8 malignancies), unilateral vision loss (3 malignancies), and facial nerve paresis (5 malignancies). CONCLUSIONS: Squamous cell carcinoma affecting the periocular region represents a risk of solid organ transplantation and may produce significant ocular morbidity, including the need for major eyelid reconstruction, globe loss, and disfiguring surgery.

Inferior outcomes in immunosuppressed patients with high-risk cutaneous squamous cell carcinoma of the head and neck treated with surgery and radiation therapy.

BACKGROUND: Immunosuppressed patients have higher rates of cutaneous squamous cell carcinoma of the head and neck. OBJECTIVE: This study reviews the effect of immune status on disease characteristics and treatment outcomes. METHODS: Patients with cutaneous squamous cell carcinoma of the head and neck treated with surgery and postoperative radiotherapy between 2000 and 2011 were included. Immunosuppressed patients underwent prior organ transplantation or chemotherapy. Baseline variables were compared using χ(2) and unpaired t tests. Overall survival and disease-free survival were calculated using the Kaplan-Meier method. RESULTS: In this study of 59 patients, 38 (64%) were immunocompetent and 21 (36%) were immunosuppressed. Most patients had recurrent tumors (63%) and node-positive disease (61%), which were well balanced between the groups. Poorly differentiated tumors (62% vs 21%; P = .009), lymphovascular invasion (29% vs 11%; P = .08), and extracapsular extension (57% vs 41%; P = .09) were more frequent in the immunosuppressed group. Two-year disease-free survival (45% vs 62%) and 2-year overall survival (36% vs 67%) were inferior for immunosuppressed patients. LIMITATIONS: Limitations include single institution, retrospective study with small sample size, and potential referral bias. CONCLUSIONS: Immunosuppressed patients with cutaneous squamous cell carcinoma of the head and neck more frequently present with high-risk pathologic features and inferior outcomes. Early multidisciplinary assessment and alternate management strategies merit prospective investigation.

Management of Facial Paralysis due to Extracranial Tumors.

Treatment of advanced parotid or cutaneous malignancies often requires sacrifice of the facial nerve as well as resection of the parotid gland and surrounding structures. In addition to considerations regarding reinnervation and dynamic reanimation, reconstruction in this setting must take into account unique factors such as soft tissue volume deficits and the high likelihood of adjunctive radiation therapy. Furthermore, considerations of patient comorbidities including advanced age and poor long-term prognosis often influence reconstructive modality. The optimal reconstructive technique would provide potential for restoration of facial tone and voluntary movement as well as immediate restoration of facial support and function. Beyond considerations of facial movement and rest position, restoration of lost soft tissue volume is critical to obtain facial symmetry. To control long-term volume in the setting of adjunctive radiation therapy, vascularized tissue is required. In this chapter, we describe a comprehensive approach to the management of radical parotidectomy and similar facial defects that addresses these concerns and also describes management strategies over time. Specific techniques employed include anterolateral thigh free flaps, nerve grafting utilizing motor nerves to the vastus lateralis muscle, and orthodromic temporalis tendon transfer. Further considerations relative to the eye, forehead, and long-term facial refinement are also discussed.