Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming.

Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O2) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O2 release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline. Here, we report that loss of murine erythrocyte-specific ADORA2B (eAdora2b-/-) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. eAdora2b-/- mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in eAdora2b-/- mice. Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O2 delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging. Overall, we determined that erythrocyte ADORA2B-BPGM axis is a key component for anti-aging and anti-age-related functional decline.

Operative Time Predicts Long-Term Abdominal Morbidity and Complication Requiring Treatment after DIEP Flap Breast Reconstruction.

BACKGROUND: The relationship between skin-to-skin operative time and long-term complications, as well as complications requiring treatment, after deep inferior epigastric perforator (DIEP) flap breast reconstructions has not been thoroughly investigated. The study objective was to evaluate if operative time would independently prognosticate the type and number of treated complications, as well as long-term abdominal morbidity. METHODS: Patients who underwent bilateral DIEP flaps from 2010 to 2021 by two senior surgeons with standardized surgical and postoperative protocols were retrospectively reviewed. Inclusion required at least 1 year of postoperative follow-up. Extensive multivariable regression analyses were utilized to adjust for potential confounders, including measures of intraoperative complexity. RESULTS: Three hundred thirty-five patients were entered into multivariable analyses. After risk adjustment, there was a significant increase in the risk of all treated complications per hour. Each hour of operation increased risk of complications requiring extended hospital stay for treatment by 25%, flap-site complications requiring readmission treatment by 24%, and flap-site complications requiring extended hospital stay for treatment by 26% (all p < 0.0001). Long-term abdominal morbidity (abdominal bulge) increased by 25% per hour of operative time (p < 0.0001). The number of complications requiring treatment, abdominal donor-site complications, and complications requiring extended hospital stay for treatment had statistically significant linear relationships with the duration of surgery (all p < 0.05). CONCLUSION: Operative time predicts long-term abdominal morbidity and complications requiring treatment, especially impacting the odds of developing abdominal bulges and complications requiring extended hospital stay for treatment or readmission treatment. This study emphasizes the importance of reducing operative time to improve DIEP flap breast reconstruction outcomes.

When Bell's Palsy is Cancer - Avoiding Misdiagnosis and Its Implications.

BACKGROUND: Facial paralysis due to cancer can be misdiagnosed as Bell's palsy. This study aims to clearly identify and quantify diagnostic differentiators and further evaluate prognostic implications of misdiagnosis. METHODS: Adult patients older than 18 years with facial palsy of unknown or cancerous etiology presenting between 2009 and 2023 were reviewed. Patient characteristics, exam findings, and clinical course, were compared between facial paralysis patients with cancer misdiagnosed as Bell's Palsy (Cancer-Bell's-Palsy group) and patients correctly diagnosed with Bell's Palsy (Bell's-Palsy Group). Additionally, morbidity and mortality were compared between facial paralysis patients with cancer initially misdiagnosed with Bell's Palsy to facial paralysis patients initially correctly diagnosed with cancer (Cancer-Palsy group). RESULTS: Two-hundred-forty-three patients participated including 43 Cancer-Palsy, 18 Cancer-Bell's-Palsy, and 182 Bell's-Palsy patients. Cancer-Bell's-Palsy patients were significantly less likely than Bell's-Palsy patients to develop synkinesis (Odds Ratio (OR)=0.0042, 95% Confidence Interval (CI) [0.0005, 0.0339]; p<0.0001), significantly more likely to experience gradual onset facial paralysis (OR=1004.69, 95% CI [54.40, 18555.77); p<0.0001), and significantly more likely to have additional non-facial cranial nerve neuropathies (OR=49.98, 95% CI [14.61, 170.98]; p<0.0001). Cancer-Bell's-Palsy patients were more likely than Cancer-Palsy patients to have a greater than six-month period from initial cancer-attributable symptom onset to cancer diagnosis (OR=47.62, 95% CI [9.26, 250.00]; p<0.001), stage IV cancer (OR=12.36, 95% CI [1.49, 102.71]; p=0.006), and decreased duration of life after cancer diagnosis (median [interquartile range] months, 40.0 [87.0] versus 12 [56.3] respectively; p=0.025). CONCLUSIONS: Facial paralysis related to cancer must be differentiated from Bell's palsy, as misdiagnosis leads to delayed intervention and poorer prognosis. Gradual onset facial palsy, multiple cranial nerve neuropathies, lack of synkinesis, and lack of improvement, were nearly definitive differentiators for underlying cancer.

Dual-Innervated Gracilis Free Functional Muscle Transfers in Facial Palsy Patients: Comparing Long-Term Outcomes between One- versus Two-Stage Procedures.

BACKGROUND: In facial reanimation, dual-innervated gracilis free functional muscle transfers (FFMTs) may have amalgamated increases in tone, excursion, synchroneity, and potentially spontaneity when compared with single innervation. The ideal staging of dual-innervated gracilis FFMTs has not been investigated. We aim to compare objective long-term outcomes following one- and two-stage dual-innervated gracilis FFMTs. METHODS: Included were adult patients with facial paralysis who underwent either one- (one-stage group) or two-stage (two-stage group) dual-innervated gracilis FFMT with ≥1 year of postoperative follow-up. Facial measurements were obtained from standardized photographs of patients in repose, closed-mouth smile, and open-mouth smile taken preoperatively, 1 year postoperatively, and 3 years postoperatively. Symmetry was calculated from the absolute difference between the paralyzed and healthy hemiface; a lower value indicates greater symmetry. RESULTS: Of 553 facial paralysis patients, 14 were included. Five and nine patients were in the one- and two-stage groups, with mean follow-up time, respectively, being 2.5 and 2.6 years. Within-group analysis of both groups, most paralyzed-side and symmetry measurements significantly improved over time with maintained significance at 3 years postoperatively in closed and open-mouth smile (all p ≤ 0.05). However, only the two-stage group had maintained significance in improvements at 3 years postoperatively in paralyzed-side and symmetry measurements in repose with commissure position (median change [interquartile range, IQR], 7.62 [6.00-10.56] mm), commissure angle (median change [IQR], 8.92 [6.18-13.69] degrees), commissure position symmetry (median change [IQR], -5.18 [-10.48 to -1.80] mm), commissure angle symmetry (median change [IQR], -9.78 [-11.73 to -7.32] degrees), and commissure height deviation (median change [IQR], -5.70 [-7.19 to -1.64] mm; all p ≤ 0.05). In the between-group analysis, all measurements were comparable in repose, closed-mouth smile, and open-mouth smile (all p > 0.05). CONCLUSION: Long-term outcomes demonstrate that both one- and two-stage dual-innervated gracilis FFMTs significantly improve excursion, but only two-stage reconstruction significantly improves resting tone.

p97 dysfunction underlies a loss of quality control of damaged membrane proteins and promotes oxidative stress and sickling in sickle cell disease.

Sickling is the central pathogenic process of sickle cell disease (SCD), one of the most prevalent inherited hemolytic disorders. Having no easy access to antioxidants in the cytosol, elevated levels of reactive oxygen species (ROS) residing at the plasma membrane in sickle red blood cells (sRBCs) easily oxidize membrane proteins and thus contribute to sickling. Although the ubiquitin-proteasome system (UPS) is essential to rapidly clear ROS-damaged membrane proteins and maintain cellular homeostasis, the function and regulatory mechanism of the UPS for their clearance in sRBCs remains unidentified. Elevated levels of polyubiquitinated membrane-associated proteins in human sRBCs are reported here. High throughput and untargeted proteomic analyses of membrane proteins immunoprecipitated by ubiquitin antibodies detected elevated levels of ubiquitination of a series of proteins including cytoskeletal proteins, transporters, ROS-related proteins, and UPS machinery components in sRBCs. Polyubiquitination of membrane-associated catalase was increased in sRBCs, associated with decreased catalase activity and elevated ROS. Surprisingly, shuttling of p97 (ATP-dependent valosin-containing chaperone protein), a key component of the UPS to shuttle polyubiquitinated proteins from the membrane to cytosol for proteasomal degradation, was significantly impaired, resulting in significant accumulation of p97 along with polyubiquitinated proteins in the membrane of human sRBCs. Functionally, inhibition of p97 directly promoted accumulation of polyubiquitinated membrane-associated proteins, excessive ROS levels, and sickling in response to hypoxia. Overall, we revealed that p97 dysfunction underlies impaired UPS and contributes to oxidative stress in sRBCs.

Optimizing Facial Function in Patients With High-Risk Recurrent Pleomorphic Adenoma and a History of Facial Nerve Injury.

BACKGROUND: Parotid pleomorphic adenoma (PA) patients present significant diagnostic and surgical challenges rendering them high risk for facial nerve injury. Recurrent PA patients often present with history of facial nerve injury or previous reanimations making salvage of the facial nerve or previous reanimations significantly more complex. The study aim is to share our experience with this high risk for facial nerve injury population and review the literature. METHODS: Adult patients with recurrent PA and history of facial nerve injury with at least 3 months of follow-up were analyzed for demographics, facial palsy history, previous head and neck surgeries, previous facial paralysis reconstruction, preoperative imaging, surgical approach, and postoperative outcomes. RESULTS: Four female patients were identified with an average age of 62 years. All patients underwent an initial protective dissection of the facial nerve or previous reanimation reconstruction by the facial nerve reconstructive team followed by the extirpative team. The average number of previous head and neck surgeries was 5, the number of recurrences was 2, and follow-up was 20 months. Half had prior dynamic facial reanimation. Two patients underwent complete preextirpative dissection of the facial nerve resulting in neuropraxia, which recovered completely after an average of 143 days. A third patient presented with 2 recurrences, both during and after reanimation with a dually innervated free functional muscle transfer. The reconstruction was salvaged, and motion was achieved. A fourth patient presented with benign preoperative findings, but intraoperative findings confirmed malignancy, necessitating facial nerve sacrifice, followed by immediate intratemporal grafting of the facial nerve and masseteric nerve transfer. Motion appeared 139 days postoperatively. CONCLUSIONS: A multidisciplinary effort should be implemented in this high risk for facial nerve injury population with the primary goal of protecting the facial nerve or any previous reanimation procedures, yet with preparedness to apply any reconstructive strategy based on intraoperative findings.

Global Prevalence and Preferences of Progressive Tension Suture Usage in Abdominoplasties.

BACKGROUND: Abdominoplasty is one of the most popular esthetic procedures. Seroma is the most frequent postoperative complication. Two decades of literature have described benefits of quilting sutures/progressive tension sutures (PTS) in reducing seroma rates and other complications in abdominoplasties. Despite this, PTS have not been universally adopted by plastic surgeons (ISAPS international survey on aesthetic/cosmetic procedures performed in 2020, 2021) Furthermore, PTS techniques and preferences vary widely. OBJECTIVE: The aim of this study is to determine the prevalence of PTS use, reasons for reluctance to utilize them, and variety of techniques utilized by plastic surgeons performing abdominoplasties internationally. METHODS: A 13-question survey was emailed via ISAPS to 3842 plastic surgeons internationally. Responses were collected and analyzed. RESULTS: Of the 272 respondents, the majority, 58%, currently use PTS. 46% were introduced to PTS during training. Only PTS training exposure was found to significantly correlate with current usage. Only 22% of North American trainees were exposed to PTS compared to 40-62% of trainees from other geographies. Of respondents who utilize PTS, most, 74%, combine them with drains. The majority use interrupted sutures, 65%, while 19% utilize a running suture, and the remaining 16% combine interrupted and running sutures. Of respondents who do not currently utilize PTS, the most common reason stated is that the surgeon's technique works well without them, 73%, which was significantly correlated with years in practice. CONCLUSION: Globally, most plastic surgeons currently utilize PTS (typically with drains) with training exposure being a significant predictor. There are still areas to address reluctance to implement them and use them without drains. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A Crowdsourced Evaluation of Facial Averageness and Attractiveness.

BACKGROUND: Evolutionary psychologists have demonstrated that humans are attracted to individuals who possess average anatomy for the population. OBJECTIVES: The aim of this study was to prove that a composite of average facial features would be more attractive to raters than the cohort utilized to create the composite. METHODS: The male and female cohorts each consisted of 41 standardized frontal-view monochrome photographs, with 1 composite image derived from the other 40 real images. Amazon Mechanical Turk, a widely used crowdsourcing platform, was utilized to obtain ratings of images ranging from 1 to 7, with 1 and 7 being least and most attractive, respectively. The strength of the preference for the composite over the real images was assessed by the difference between the mean rating of the composite and real images. RESULTS: In total, 870 and 876 respondents were recruited to rate the male and female cohorts, respectively. For the male and female cohorts, the composite image was rated significantly higher than the rest of the cohort overall and across all ages, genders, and countries of residence (all P < 0.0001). For both cohorts, the strength of the preference was significantly higher for European respondents and lower for South American and nonbinary respondents (all P < 0.05). CONCLUSIONS: This study reveals that average facial anatomy is perceived as most attractive across all demographics, a finding that is hoped to serve as a stepping stone for further studies leading to objective cosmetic quantifications and integrating evidence-based medicine into aesthetic surgery.

Dual Versus Single Innervation of Gracilis Free Functional Muscle Transfer in Facial Paralysis - Long-Term Resting and Dynamic Outcomes.

BACKGROUND: Comparing long-term tone and excursion between single- versus dual-innervated free functional muscle transfer (FFMT) in patients with longstanding facial paralysis. METHODS: Longstanding facial palsy patients treated with a FFMT innervated either by a nerve-to-masseter (single-innervation group) or by nerve-to-masseter and cross-facial-nerve graft (dual-innervation group) were included. One year minimal follow up was required. Outcome measures, based on standardized photos, included excursion, smile angle, teeth exposure, commissure height deviation, and upper lip height deviation in repose and in closed and open teeth smile preoperatively, and at 3-months, 1-year, and 3-years postoperatively. Emotrics software (Massachusetts Eye and Ear Infirmary, Boston, MA) and ImageJ (Rasband, W.S., ImageJ, U.S, National Institutes of Health, Bethesda, MD) were used for measurements. Between group and within group longitudinal comparisons were analyzed. RESULTS: At three years (single=24, dual=13), significance was found between groups in commissure position (single=26.42mm, dual=31.51mm, p<0.0001) and excursion with open mouth smile (single=31.32mm, dual=26.59mm, p<0.001). Single-innervation FFMT within group analysis lacked significant improvement in commissure height deviation and upper lip height deviation at 3 years in repose, while dual-innervation group revealed significant improvements (3.67mm and p<0.001, 3.17mm and p<0.001 respectively). Teeth exposure revealed an increase in the dual-innervation group (single=35.753 mm 2, dual=64.177 mm 2), albeit significance was not observed. CONCLUSIONS: Dually innervated FFMT revealed improvements in resting tone and teeth exposure with minimal decrease in smile excursion compared with single innervated FFMT.

Operative Time Predicts Postoperative Outcomes in Bilateral DIEP Flap Reconstruction: Multivariate 1000 Flap Analysis.

Skin-to-skin operative time (OT) as a risk factor for adverse postoperative outcomes in microvascular breast reconstruction has not been thoroughly investigated. This study evaluates OT's impact on length of stay (LOS), overall morbidity, individual complications, and unplanned reoperation (UR) in deep inferior epigastric artery perforator (DIEP) flaps, with a primary objective of identifying a clinically relevant time of decreased odds. Methods: Patients who underwent bilateral DIEP flaps from 2010 to 2021 by two senior surgeons (N.T.H. and S.S.T.) with standardized surgical and postoperative protocols were retrospectively reviewed. One thousand flaps (500 patients) were analyzed with extensive multivariate regression equations to adjust for potential confounders, including intraoperative complexity. The odds of postoperative complication, extended LOS (eLOS, defined as ≥5 days) were compared across OT per hour and OT intervals. Results: After risk-adjustment, each hour of OT increased morbidity by 19%, UR by 8.7%, and LOS by 6.5 hours (all P < 0.001). For eLOS, procedures ≤5 hours had 9.5 times lower odds than ≥5 hours (P = 0.050), 5-7 hours had comparable odds (P = 0.540), and 7-9 hours had 5.5 times lower odds than procedures ≥ 9 hours (P < 0.001). Last, a multivariate linear regression showed that LOS can be calculated from OT: LOS (days) =1.527 + 0.272 × OT (hours) (R2 = 0.308; P < 0.001). Conclusions: OT (per hour) independently predicts morbidity, UR and LOS in DIEP flaps. Furthermore, 5 and 9 hours are critical cutoffs for eLOS. These findings emphasize the benefits of decreasing OT through efficiency models, such as process analysis, team-based intraoperative protocols, and co-surgery model.

Overview of Biologic Agents Used in Skin and Soft Tissue Reconstruction.

Wound healing is a highly complex process mediated by cellular interactions at the microscopic level. Increased understanding of wound healing physiology has served as the foundation for translational research to develop biologic wound care technologies that have profoundly affected patient care. As the reader will see throughout this series in Seminars in Plastic Surgery , biologic wound technologies have broad applications and have greatly impacted the reconstructive ladder. Despite their frequent use, many surgeons lack familiarity with the myriad of products available on the market along with each product's relative advantages and shortcomings. This overview will discuss the classification of biologic wound agents used to reconstruct defects of the skin and soft tissue along with the advantages and disadvantages associated with their use.