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Patients undergoing trigger release surgery are known to be at increased risk of amyloidosis and heart failure, and therefore, amyloidosis screening during trigger release surgery may facilitate early diagnosis and treatment of cardiac amyloidosis. However, the reported prevalence of amyloid on biopsies taken during trigger release surgery has varied widely, and no biopsy-positive patients in prior studies have been diagnosed with occult cardiac amyloidosis or started on disease-modifying therapy. We review the existing literature on this topic and present a case of a patient with cardiac amyloidosis diagnosed from a biopsy taken during trigger release surgery and subsequently started on disease-modifying therapy. This case supports the potential role of amyloidosis screening during trigger release and highlights the benefits of collaboration between hand surgeons and amyloidosis specialists in multidisciplinary amyloidosis programs., Competing Interests: No benefits in any form have been received or will be received related directly to this article.

Importance: Carpal tunnel release (CTR) technique may influence the likelihood of revision surgery. Prior studies of revision CTR following endoscopic CTR (ECTR) compared with open CTR (OCTR) have been limited by sample size and duration of follow-up., Objective: To estimate the incidence of revision CTR following ECTR compared with OCTR in a national cohort., Design, Setting, and Participants: This retrospective cohort study used data from the US Veterans Health Administration. Participants included all adults (age ≥18 years) undergoing at least 1 outpatient CTR from October 1, 1999, to May 20, 2021. Data were analyzed from May 21, 2021, to November 27, 2023., Exposure: Index CTR technique., Main Outcomes and Measures: The primary outcome was time to revision CTR, defined as repeat ipsilateral CTR during the study period. Secondary outcomes were indications for revision, findings during revision, and additional procedures performed during revision., Results: Among 134 851 wrists from 103 455 patients (92 510 [89.4%] male; median [IQR] age, 62 [53-70] years) undergoing at least 1 CTR, 1809 wrists underwent at least 1 revision at a median (IQR) of 2.5 (1.0-3.8) years. In competing-risks analysis, the cumulative incidence of revision was 1.06% (95% CI, 0.99%-1.12%) at 5 years and 1.59% (95% CI, 1.51%-1.67%) at 10 years. ECTR was associated with increased hazard of revision CTR compared with OCTR (adjusted hazard ratio [aHR], 1.56; 95% CI, 1.34-1.81; P < .001). The risk difference for revision CTR associated with ECTR compared with OCTR was 0.57% (95% CI, 0.31%-0.84%) at 5 years (number needed to harm, 176) and 0.72% (95% CI, 0.36%-1.07%) at 10 years (number needed to harm, 139). Regardless of index CTR technique, the most common indication for revision was symptom recurrence (1062 wrists [58.7%]). A reconstituted transverse carpal ligament (TCL) was more common after ECTR compared with OCTR, whereas scarring of the overlying tissues and of the median nerve itself were more common following OCTR. Incomplete transverse-carpal-ligament release was observed in 251 of the wrists undergoing revision CTR (13.94%) and was more common among revisions following ECTR (odds ratio, 1.62; 95% CI, 1.11-2.37; P = .01)., Conclusions and Relevance: In this cohort study of revision CTR in the Veterans Health Administration, ECTR was associated with increased risk of revision compared with OCTR, but the absolute risk was low regardless of technique. Intraoperative findings at revision varied significantly according to index CTR technique.

Purpose: Tenosynovial biopsy during carpal tunnel release (CTR) leads to an earlier diagnosis of amyloidosis. Surgery for trigger digit-trigger release (TR)-may provide a similar opportunity. We sought to characterize the risk of amyloidosis diagnosis after TR and/or CTR., Methods: We conducted a retrospective cohort study of adults without diagnosed amyloidosis undergoing TR and/or CTR in the Veterans Health Administration from 1999 to 2019, including matched controls. We used competing-risks methodology to estimate the cumulative incidence and adjusted subdistribution hazard ratios (sHRs) of amyloidosis, heart failure, and death after TR and/or CTR., Results: Among the 126,788 patients undergoing TR and/or CTR, amyloidosis was diagnosed in 52 of 26,757 patients undergoing TR alone at a median of 4.7 years after surgery (10-year cumulative incidence: 0.26%, 95% CI: 0.18% to 0.34%), 396 of 91,384 patients undergoing CTR alone at a median of 5.1 years after surgery (10-year cumulative incidence: 0.60%, 95% CI: 0.53% to 0.67%), 50 of 8,647 patients undergoing both TR and CTR at a median of 3.1 years after surgery (10-year cumulative incidence: 0.80%, 95% CI: 0.54% to 1.1%), and 54 of 113,452 controls at a median of 5.0 years after the index date (10-year cumulative incidence 0.053%, 95% CI: 0.037% to 0.070%). In the adjusted analysis, patients who underwent TR and/or CTR had a higher risk of amyloidosis (TR: sHR adj 4.80, 95% CI: 3.33-6.92; CTR: sHR adj 10.2, 95% CI: 7.74-13.6; TR and CTR: sHR adj 14.9, 95% CI: 9.87-22.5) and heart failure (TR: sHR adj 1.91, 95% CI: 1.83-1.99; CTR: sHR adj 2.02, 95% CI: 1.97-2.07; TR and CTR: sHR adj 2.18, 95% CI: 2.04-2.33) but not death compared with the controls. Among the patients who underwent TR, age, Black race, prior CTR, heart failure, and the number of digits released were independent risk factors for amyloidosis., Conclusions: Patients undergoing TR and/or CTR are at increased risk of incident amyloidosis and heart failure compared to controls., Type of Study/level of Evidence: Prognostic II., (Copyright © 2022 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Summary: Syndactyly is one of the most common congenital differences treated by hand surgeons. Although dozens of techniques for syndactyly release have been described, a reliable method is based on a dorsal rectangular flap for commissure construction and a combination of interdigitating zigzag flaps and skin grafts for digital coverage. In this article, the authors present a detailed description of syndactyly release emphasizing principles integral to successful outcomes., (Copyright © 2021 by the American Society of Plastic Surgeons.)

Background: As carpal tunnel syndrome often precedes other signs of systemic amyloidosis, tenosynovial biopsy at the time of carpal tunnel release may facilitate early diagnosis and treatment. However, evidence-based guidelines for amyloidosis screening during carpal tunnel release have not been established. We sought to develop a predictive model for amyloidosis after carpal tunnel release to inform screening efforts., Methods: We performed a retrospective cohort study of adults without known amyloidosis undergoing at least 1 carpal tunnel release from 2000 to 2019 with use of the national Veterans Health Administration database. After estimating the cumulative incidence of amyloidosis after carpal tunnel release, we identified risk factors, constructed a predictive nomogram based on a multivariable subdistribution-hazard competing-risks model, and performed cross-validation., Results: Among 89,981 patients undergoing at least 1 carpal tunnel release, 310 were subsequently diagnosed with amyloidosis at a median interval of 4.5 years, corresponding to a cumulative incidence of 0.55% (95% confidence interval [CI]: 0.47% to 0.63%) at 10 years. Amyloidosis diagnosis following carpal tunnel release was associated with an increased hazard of heart failure (hazard ratio [HR], 4.68; 95% CI: 4.26 to 5.55) and death (HR, 1.27; 95% CI: 1.07 to 1.51) after adjustment for potential confounders. Age, male sex, Black race, monoclonal gammopathy of undetermined significance or multiple myeloma, rheumatoid arthritis, atrial fibrillation, spinal stenosis, and bilateral carpal tunnel syndrome were independently associated with increased risk of amyloidosis diagnosis and were included in the risk nomogram., Conclusions: Amyloidosis diagnosis after carpal tunnel release is rare but is associated with poor outcomes. We present an amyloidosis-risk nomogram to help guide tenosynovial biopsy at time of carpal tunnel release., Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The authors indicated that no external funding was received for any aspect of this work. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G530)., (Copyright © 2021 Written work prepared by employees of the Federal Government as part of their official duties is, under the United States Copyright Act, a ‘work of the United States Government’ for which copyright protection under that Act is not available. As such, copyright protection does not extend to the contributions of employees of the Federal Government prepared as part of their employment.)

Summary: Pollicization can be performed for secondary thumb reconstruction after traumatic injury or for primary thumb construction in cases of congenital thumb hypoplasia. Given the complexity of this operation, intimate familiarity with the involved anatomy and surgical principles is key to successful surgical outcomes. In this Video Plus article, the authors present a step-by-step approach to pollicization in case of Blauth type IIIB thumb hypoplasia., (Copyright © 2020 by the American Society of Plastic Surgeons.)

Background: Burn injuries commonly affect the hand, and the development of adduction contractures of the first web space is frequent and deleterious, both functionally and aesthetically. Many corrective techniques and algorithmic approaches have been described to treat this problem, but there is no consensus on the optimal management., Methods: A retrospective review at a single high-volume pediatric burn center was undertaken to evaluate the clinical course of these patients. All pediatric patients undergoing initial release of burn scar contracture of the first web space from 2005 through 2015 were included in a retrospective cohort study., Results: The authors identified 40 patients with 57 burned hands. The initial approach to management was variable. Z-plasty or other local flap was the first technique used in 28 hands (49 percent), split-thickness skin graft in 19 hands (33 percent), full-thickness skin graft in seven hands (12 percent), groin flaps in two hands (4 percent), and a reverse radial forearm flap in one hand (2 percent). The mean numbers of total reconstructive procedures per hand including the initial procedure were as follows: groin flap, 4.0; full-thickness skin graft, 3.1; split-thickness skin graft, 2.1; Z-plasty, 1.4; and reverse radial forearm flap, 1.0., Conclusions: Successful reconstruction of the first web space must be addressed in the context of the entire hand. It is the authors' preference to use split-thickness skin grafting whenever a skin deficiency is present-only then should leading edge contractures be addressed with Z-plasty. Based on their experience, the authors recommend five principles that are essential to successfully treat postburn contractures of the first web space., Clinical Question/level of Evidence: Therapeutic, III.

Introduction: Traumatic neuroma caused by injuries or surgery can result in neuropathic pain, functional impairment, and psychological distress, which has an impact on quality of life. The aim of this study was to identify the factors related to successful treatment of symptomatic lower extremity symptomatic neuromas using patient-reported outcome measures (PROMs)., Methods: Thirty-two patients with 48 symptomatic neuromas completed the PROMIS mobility, PROMIS pain interference (PI), Numeric Rating Scale (NRS) for pain (0-10) for both pre- and post-operative pain, and the PROMIS depression at a mean of 8.9±4.5 years following neuroma surgery. Neuromas were located around the foot and ankle (n=18, 38%), leg (n=14, 29%), around the knee (n=13, 27%), and in the thigh (n=3, 6.3%). Surgical treatment included neuroma excision and implantation (n=29, 60%) followed by neuroma excision alone or excision with placement in the subcutaneous tissue (n=12, 25%). We performed multivariable analysis to identify the factors influencing the PROMs., Results: Patients reported significant reduction in mean NRS pain after surgery (7.3 vs 4.9, p=0.0013). Higher PROMIS depression scores were independently associated with inferior PROMIS mobility scores (β=-0.38, p=0.001), higher PROMIS PI scores (β=0.68, p<0.001), and higher NRS pain scores (β=0.1, p=0.001). Additionally, smoking was independently associated with higher NRS pain scores (β=1.59, p=0.049) CONCLUSION: Surgical treatment of symptomatic neuromas of the lower extremity provides a long-term improvement in 59% of patients, but 19% of patients still reported severe persistent pain despite surgical treatment. Smoking and negative mood have negative effects on patient-reported outcomes after neuroma surgery., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Trigger finger, or stenosing tenosynovitis, is one of the most common conditions affecting the hand, yet its pathophysiology remains poorly understood, and genetic association studies of trigger finger are lacking. The purpose of this study was to identify single-nucleotide polymorphisms associated with trigger finger through a genomewide approach., Methods: The authors performed a case-control genomewide association study in the Partners HealthCare Biobank. Single-nucleotide polymorphism- and gene-based association analyses were carried out after quality control, imputation, and filtering., Results: Among 942 trigger finger cases and 24,472 controls, the authors tested 7,846,471 single-nucleotide polymorphisms for association with trigger finger. In the single-nucleotide polymorphism-based analysis, a single locus on chromosome 13 corresponding to KLHL1 met the genomewide significance threshold (lead single-nucleotide polymorphism rs59988404; OR, 1.74; 95 percent CI, 1.47 to 2.07; p = 1.99 × 10). After mapping, gene-based analysis demonstrated a significant association with POLE2 (p = 7.53 × 10) on chromosome 14. Among trigger finger cases, rs59988404 genotype was significantly associated with the total number of trigger finger procedures performed (p = 0.026)., Conclusions: In the first reported genomewide association study of trigger finger, the authors report significant associations of KLHL1 and POLE2 with risk of trigger finger. The authors' results may help to elucidate the pathophysiology of trigger finger and facilitate an individualized, precision-medicine treatment approach., Clinical Question/level of Evidence: Risk, III.

Background: Local health care facilities are often unequipped to treat complex upper extremity injuries, and patients are therefore transferred to designated trauma centers. This study describes the characteristics of patients transferred to a Level I trauma center for hand and upper extremity injuries and to investigate the accuracy of the provided diagnosis at the time of referral., Methods: Adult patients transferred from outside facilities to the authors' Level I trauma center by means of direct contract with the on-call fellow for the care of hand and upper extremity injuries were identified. Patient- and injury-related information was prospectively collected at the time of referral before patient transfer, and again following diagnostic evaluation by a hand surgeon at the authors' institution., Results: Sixty-three patients were transferred to the authors' hand surgery service from outside facilities after direct contact with the on-call fellow. Most patients were referred by emergency medicine physicians [n = 47 (76 percent)], followed by midlevel emergency department providers (physician assistant or nurse practitioner) [n = 12 (19 percent)] or hand surgeons [n = 3 (5 percent)]. Six patients were transferred directly from a Level I trauma center. Twenty-one transferred patients (33 percent) had an inaccurate diagnosis at the time of referral. Factors associated with an inaccurate diagnosis included trauma level of the referring hospital and diagnoses of infection or dysvascularity., Conclusions: The diagnostic accuracy for hand injuries transferred from outside facilities by means of provider-to-provider communication is imperfect, and some injuries are misdiagnosed. Hand surgeons should continue to improve the triage and transfer process for patients with acute hand surgery injuries., Clinical Question/level of Evidence: Diagnostic, IV.

Background: Many surgical techniques are used to treat symptomatic neuroma, but options are limited for digital neuromas because of a paucity of soft-tissue coverage and/or the absence of the terminal nerve end. The authors assessed factors that influence patient-reported outcomes after surgery for symptomatic digital neuroma., Methods: The authors retrospectively identified 29 patients with 33 symptomatic digital neuromas that were treated surgically. Patients completed the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity and Pain Interference scales, a numeric rating scale for pain, and the PROMIS Depression scale at a median follow-up of 7.6 years postoperatively (range, 3.2 to 16.8 years). Surgical treatment for neuroma included excision with nerve repair/reconstruction (n =13; 39 percent), neuroma excision alone (n =10; 30 percent), and excision and implantation (n =10; 30 percent). Multivariable linear regression was performed to identify the factors that independently influenced patient-reported outcomes., Results: The mean postoperative PROMIS Upper Extremity score was 45.2 ± 11.2, the mean Pain Interference score was 54.3 ± 10.7, and the mean numeric rating scale pain score was 3 (interquartile range, 1 to 5). Compared with other treatment techniques, neuroma excision with nerve repair/reconstruction was associated with lower numeric rating scale pain scores; lower Pain Interference scores, corresponding to less daily impact of pain; and higher Upper Extremity scores, reflecting better upper extremity function. Older age and higher Depression scores were associated with lower Upper Extremity scores and higher Pain Interference scores. Smoking was associated with higher Pain Interference and numeric rating scale pain scores., Conclusions: Neuroma excision followed by nerve repair/reconstruction resulted in better outcomes compared with neuroma excision alone with or without implantation. Patient age and psychosocial factors influenced patient-reported outcomes., Clinical Question/level of Evidence: Risk, III.

Purpose: Fibroadipose vascular anomaly (FAVA) is an intramuscular vascular malformation that has been recently described as a distinct clinical entity. The clinical, radiological, and histopathological characteristics of FAVA in the upper extremity are reviewed., Methods: This was a retrospective case series of upper-extremity FAVA lesions., Results: We reviewed 19 patients with FAVA of the upper limb. Pain, stiffness, swelling, and flexion contractures were the most common presentations. Except for one lesion confined to the hand, all lesions either presented with or developed a contracture within 10 years. Ten patients underwent surgical debulking. Six required tendon transfer reconstruction and 3 necessitated a free functional muscle transfer., Conclusions: Fibroadipose vascular anomaly in the upper extremity requires an accurate diagnosis and may benefit from early referral to a multidisciplinary vascular anomaly center with experienced hand surgeons. Compression garments, propranolol, and sclerotherapy seem to be ineffective. Surgical resection focused on symptomatic regions with appropriate reconstruction may have benefit in salvage of limbs with compromised function., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2020 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background:  Laboratory training courses have traditionally offered an attractive method to learn microsurgery in a low-risk environment. However, courses are often limited by cost, accessibility, and their one-time, nonlongitudinal nature. Our aims were to (1) describe our institution's microsurgical training course for hand surgery fellows, which is longitudinal and integrated within our fellowship curriculum and (2) investigate how this course affects the microsurgical confidence and competence of trainees throughout their fellowship year., Methods:  All hand fellows who trained in our 1-year combined hand surgery fellowship from 2016 through 2018 participated in this study. Baseline data on the type and duration of residency training, previous microsurgery experience and self-reported confidence, knowledge, and interest in microsurgery were recorded. Self-reported scores were documented using a continuous scale ranging from 0 to 10. An initial 3-day laboratory course combining the use of didactic teaching, a nonliving synthetic model, and a live rat model was conducted. Repeat laboratory training occurred thereafter at 6 and 12 months. At the end of each session, fellows repeated the baseline questionnaire and faculty assessed their microsurgical competence using a standardized global rating scale (GRS)., Results:  A total of six fellows (2 years) were enrolled. At the end of the initial course, there was a statistically significant increase in mean self-reported confidence in microsurgery from 4.3 to 6.2 and knowledge from 4.7 to 6.5. Mean scores in interest were unchanged, from 9.2 to 9.3. There was also an increase in mean GRS score from day 3 to months 6 and 12., Conclusion:  A longitudinal microsurgical training course integrated within a hand surgery fellowship is associated with increased confidence and microsurgical skill. This study describes our approach and its feasibility., Competing Interests: Dr. Eberlin is a consultant for Axogen and Integra. Dr. Chen is a consultant for Miami Device Solutions., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Patients undergoing abdominal wall reconstruction are at increased risk of postoperative respiratory failure. Understanding the epidemiology of this complication may guide preventive efforts., Methods: The authors performed a population-based retrospective cohort study of adults undergoing elective abdominal wall reconstruction (ventral hernia repair with component separation) in the United States from 2004 through 2011 using the Nationwide Inpatient Sample., Results: Of 2283 patients undergoing elective abdominal wall reconstruction, 57 percent were women, with a median age of 57 years, median hospital stay of 5 days, and mean total cost of $23,730. Postoperative respiratory failure occurred in 212 patients (9.3 percent), 164 patients (7.2 percent) were discharged to a skilled nursing facility, and 18 patients (0.8 percent) died. On multivariate analysis, age, male sex, congestive heart failure, lung disease, obesity, and obstructive sleep apnea were independently associated with increased risk of respiratory failure. Respiratory failure was associated with significantly increased risk of death and discharge to a skilled nursing facility as well as significantly increased total cost and hospital length of stay., Conclusions: Respiratory failure is an uncommon but devastating complication of abdominal wall reconstruction. The authors report clinical risk factors that may facilitate perioperative risk-reduction strategies to improve outcomes of elective abdominal wall reconstruction., Clinical Question/level of Evidence: Risk, III.

Background: Systemic inflammatory response syndrome (SIRS) is associated with organ failure and infectious complications after major burn injury. Recent evidence has linked melanocortin signaling to anti-inflammatory and wound-repair functions, with mutations in the melanocortin 1 receptor (MC1R) gene leading to increased inflammatory responses. Our group has previously demonstrated that MC1R gene polymorphisms are associated with postburn hypertrophic scarring. Thus, we hypothesized that MC1R single nucleotide polymorphisms (SNPs) would be associated with increased burn-induced SIRS and increased infectious complications., Methods: We performed a retrospective cohort study of adults (>18 y of age) admitted to our burn center with >20% total body surface area (TBSA) partial/full thickness burns between 2006 and 2013. We screened for five MC1R SNPs (V60L, V92M, R151C, R163Q, T314T) by polymerase chain reaction from genomic DNA isolated from blood samples. We performed a detailed review of each patient chart to identify age, sex, race, ethnicity, %TBSA burned, burn wound infections (BWIs), and 72-hr intravenous fluid volume, the latter a surrogate for a dysfunctional inflammatory response to injury. Association testing was based on multivariable regression., Results: Of 106 subjects enrolled, 82 had complete data for analysis. Of these, 64 (78%) were male, with a median age of 39 and median burn size of 30% TBSA. A total of 36 (44%) subjects developed BWIs. The median total administered IV crystalloid in first 72h was 24.6 L. In multivariate analysis, the R151C variant allele was a significant independent risk factor for BWI (adjusted prevalence ratio 2.03; 95% CI: 1.21-3.39; P = 0.007), and the V60L variant allele was independently associated with increased resuscitation fluid volume (P = 0.021)., Conclusions: This is the first study to demonstrate a significant association between genetic polymorphisms and a nonfatal burn-induced SIRS complication. Our findings suggest that MC1R polymorphisms contribute to dysfunctional responses to burn injury that may predict infectious and inflammatory complications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to determine if melanocortin-1 receptor (MC1R) single nucleotide polymorphisms (SNPs) are associated with complicated sepsis after trauma., Background: Nosocomial infections are an important cause of morbidity and mortality after trauma. Several SNPs in inflammation-related genes have been associated with sepsis. MC1R is an anti-inflammatory mediator that may be involved in the immune response after trauma., Patients and Methods: We genotyped eight common MC1R SNPs in genomic DNA from subjects enrolled in a previously reported prospective cohort study. Subjects were adult trauma patients admitted to the intensive care unit at a Level 1 trauma center (2003-2005)., Results: A total of 1,246 subjects were included in the analysis. The majority were male (70%), severely injured (81%), and injured by a blunt mechanism (89%). Forty percent developed sepsis, and 23% developed complicated sepsis, which was defined as sepsis with organ dysfunction. In logistic regression analysis, with adjustments for age, sex, body mass index, injury severity score, red blood cell transfusion requirement, and mechanism of injury, the MC1RR163Q variant (rs885479) was associated with a lower risk of developing complicated sepsis (adjusted odds ratio [ORadj] = 0.48, 95% confidence interval [CI]: 0.28-0.81, P = 0.006). In a subgroup of 511 subjects with genome-wide SNP data, the association between the MC1RR163Q variant and complicated sepsis remained significant after adjusting for genetic substructure (by principal components) and the above clinical factors (ORadj = 0.30, 95% CI: 0.13-0.70, P = 0.005)., Conclusions: MC1RR163Q is associated with a lower risk of complicated sepsis after trauma. Therapeutic targeting of MC1R may be beneficial for trauma patients at risk for complicated sepsis., Competing Interests: The authors have no conflicts of interest.

Importance: Metabolomics is the broad and parallel study of metabolites within an organism and provides a contemporaneous snapshot of physiologic state. Use of metabolomics in the clinical setting may help achieve precision medicine for those who have experienced trauma, where diagnosis and treatment are tailored to the individual patient., Objective: To examine whether metabolomics can (1) distinguish healthy volunteers from trauma patients and (2) quantify changes in catabolic metabolites over time after injury., Design, Setting, and Participants: Prospective cohort study with enrollment from September 2014 to May 2015 at an urban, level 1 trauma center. Included in the study were 10 patients with severe blunt trauma admitted within 12 hours of injury with systolic blood pressure less than 90 mm Hg or base deficit greater than 6 mEq/L and 5 healthy volunteers. Plasma samples (n = 35) were obtained on days 1, 3, and 7, and they were analyzed using mass spectrometry., Main Outcomes and Measures: Principal component analyses, multiple linear regression, and paired t tests were used to select biomarkers of interest. A broad-based metabolite profile comparison between trauma patients and healthy volunteers was performed. Specific biomarkers of interest were oxidative catabolites., Results: Trauma patients had a median age of 45 years and a median injury severity score of 43 (interquartile range, 34-50). Healthy fasting volunteers had a median age of 33 years. Compared with healthy volunteers, trauma patients showed oxidative stress on day 1: niacinamide concentrations were a mean (interquartile range) of 0.95 (0.30-1.45) relative units for trauma patients vs 1.06 (0.96-1.09) relative units for healthy volunteers (P = .02), biotin concentrations, 0.43 (0.27-0.58) relative units for trauma patients vs 1.21 (0.93-1.56) relative units for healthy volunteers (P = .049); and choline concentrations, 0.17 (0.09-0.22) relative units for trauma patients vs 0.21 (0.18-0.22) relative units for healthy volunteers (P = .004). Trauma patients showed lower nucleotide synthesis on day 1: adenylosuccinate concentrations were 0.08 (0.04-0.12) relative units for trauma patients vs 0.15 (0.14-0.17) relative units for healthy volunteers (P = .02) and cytidine concentrations were 1.44 (0.95-1.73) relative units for trauma patients vs 1.74 (1.62-1.98) relative units for healthy volunteers (P = .05). From trauma day 1 to day 7, trauma patients showed increasing muscle catabolism: serine levels increased from 42.03 (31.20-54.95) µM to 79.37 (50.29-106.37) µM (P = .002), leucine levels increased from 69.21 (48.36-99.89) µM to 114.16 (92.89-143.52) µM (P = .004), isoleucine levels increased from 20.43 (10.92-27.41) µM to 48.72 (36.28-64.84) µM (P < .001), and valine levels increased from 122.56 (95.63-140.61) µM to 190.52 (136.68-226.07) µM (P = .004). There was an incomplete reversal of oxidative stress., Conclusions and Relevance: Metabolomics can function as a serial, comprehensive, and potentially personalized tool to characterize metabolism after injury. A targeted metabolomics approach was associated with ongoing oxidative stress, impaired nucleotide synthesis, and initial suppression of protein metabolism followed by increased nitrogen turnover. This technique may provide new therapeutic and nutrition targets in critically injured patients.

Background: Hypertrophic scarring (HTS) is hypothesized to have a genetic mechanism, yet its genetic determinants are largely unknown. The mitogen-activated protein kinase (MAPK) pathways are important mediators of inflammatory signaling, and experimental evidence implicates MAPKs in HTS formation. We hypothesized that single-nucleotide polymorphisms (SNPs) in MAPK-pathway genes would be associated with severity of post-burn HTS., Methods: We analyzed data from a prospective-cohort genome-wide association study of post-burn HTS. We included subjects with deep-partial-thickness burns admitted to our center who provided blood for genotyping and had at least one Vancouver Scar Scale (VSS) assessment. After adjusting for HTS risk factors and population stratification, we tested MAPK-pathway gene SNPs for association with the four VSS variables in a joint regression model. In addition to individual-SNP analysis, we performed gene-based association testing., Results: Our study population consisted of 538 adults (median age 40 years) who were predominantly White (76%) males (71%) admitted to our center from 2007-2014 with small-to-moderate-sized burns (median burn size 6% total body surface area). Of 2,146 SNPs tested, a rare missense variant in the PTPN5 gene (rs56234898; minor allele frequency 1.5%) was significantly associated with decreased severity of post-burn HTS (P = 1.3×10-6). In gene-based analysis, PTPN5 (P = 1.2×10-5) showed a significant association and BDNF (P = 9.5×10-4) a borderline-significant association with HTS severity., Conclusions: We report PTPN5 as a novel genetic locus associated with HTS severity. PTPN5 is a MAPK inhibitor expressed in neurons, suggesting a potential role for neurotrophic factors and neuroinflammatory signaling in HTS pathophysiology.

Background: In the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors., Methods: We performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20% or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05., Results: After adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95% confidence interval [CI], 2.93-6.99), burn size greater than 40% TBS (RR, 4.24; 95% CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95% CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40% TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines., Conclusion: Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the "genomic storm" induced by a 20% or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40% TBS., Level of Evidence: Epidemiologic study, level III.

Introduction: Reliable characterization of a hypertrophic scar (HTS) is integral to epidemiologic studies designed to identify clinical and genetic risk factors for HTS. The Vancouver Scar Scale (VSS) has been widely used for this purpose; however, no publication has defined what score on this scale corresponds to a clinical diagnosis of HTS., Methods: In a survey of 1000 burn care providers, we asked respondents what VSS score indicates a HTS and asked them to score scar photos using the VSS. We used receiver-operating-characteristic (ROC) curves to evaluate VSS sub-scores and their combinations in diagnosis of HTS., Results: Of 130 responses (13.5%), most were physicians (43.9%) who had worked in burn care for over 10 years (63.1%) and did not use the VSS in clinical practice (58.5%). There was no consensus as to what VSS score indicates a diagnosis of HTS. VSS height score (0-3) performed best for diagnosis of HTS; using a cut-off of ≥1, height score was 99.5% sensitive and 85.9% specific for HTS., Conclusions: Burn clinicians do not routinely use the VSS and perceptions vary widely regarding what constitutes a HTS. When a dichotomous variable is needed, the VSS height score with a cut-off of ≥1 may be optimal. Our findings underscore the need for an objective tool to reproducibly characterize HTS across burn centers., (Published by Elsevier Ltd.)

Background: The pathophysiology of hypertrophic scarring is unknown in part because of the lack of a robust animal model. Although the red Duroc pig has emerged as a promising in vivo model, the cellular mechanisms underlying Duroc scarring are unknown, and the size and cost of Duroc pigs are obstacles to their use. Given the central role of the dermal fibroblast in scarring, the authors hypothesized that dermal fibroblasts from the Duroc pig exhibit intrinsic differences in key aspects of the fibroblast response to injury compared with those from the Yorkshire pig, a same-species control that heals normally., Methods: Duroc and Yorkshire dermal fibroblasts were isolated from uninjured dorsal skin. Actin stress fibers and focal adhesions were visualized by immunocytochemistry and transmission electron microscopy. Cell migration was measured using a scratch wound-closure assay. Contractile function was assessed by collagen gel contraction. Expression of scarring-related genes was determined by quantitative real-time reverse-transcriptase polymerase chain reaction, and transforming growth factor (TGF)-β1 protein expression was determined by Western blotting., Results: Duroc dermal fibroblasts display increased adhesion-complex formation, impaired migration, enhanced collagen contraction, and profibrotic gene and protein expression profiles compared with Yorkshire fibroblasts at baseline. In addition, Duroc fibroblasts overexpressed TGF-β1 and were less responsive to exogenous TGF-β1., Conclusions: Duroc dermal fibroblasts have inherent myofibroblastic differentiation that may account for the pathologic scarring in these animals. The authors' data further validate the Duroc model and support Duroc fibroblast cell culture as a simple, inexpensive, reproducible, and biologically tractable in vitro model for the study of fibroproliferative scarring.

The genetic determinants of post-burn hypertrophic scarring (HTS) are unknown, and melanocortin 1 receptor (MC1R) loss-of-function leads to fibrogenesis in experimental models. To examine the associations between self-identified race and MC1R single-nucleotide polymorphisms (SNPs) with severity of post-burn HTS, we conducted a prospective cohort study of burned adults admitted to our institution over 7 years. Subjects were evaluated using the Vancouver Scar Scale (VSS), asked to rate their itching, and genotyped for 8 MC1R SNPs. Testing for association with severe HTS (VSS>7) and itch severity (0-10) was based on multivariate regression with adjustment for known risk factors. Of 425 subjects analyzed, 77% identified as White. The prevalence of severe HTS (VSS>7) was 49%, and the mean itch score was 3.9. In multivariate analysis, Asian (prevalence ratio (PR) 1.54; 95% CI: 1.13-2.10), Black/African American (PR 1.86; 95% CI: 1.42-2.45), and Native American (PR 1.87; 95% CI: 1.48-2.35) race were independently associated with severe HTS. MC1R SNP R163Q was also significantly (P<0.001) associated with severe HTS. Asian race (linear regression coefficient 1.32; 95% CI: 0.23-2.40) but not MC1R SNP genotype was associated with increased itch score. We conclude that MC1R genotype may influence post-burn scarring.

Objective: To identify genetic variants associated with the severity of postburn hypertrophic scarring (HTS) using a genome-wide approach., Background: Risk of severe postburn HTS is known to depend on race, but the genetic determinants of HTS are unknown., Methods: We conducted a genome-wide association study (GWAS) in a prospective cohort of adults admitted with deep-partial-thickness burns from 2007 through 2014. Scar severity was assessed over time using the Vancouver Scar Scale (VSS), and DNA was genotyped with a >500,000-marker array. We performed association testing of single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) >0.01 using linear regression of VSS height score on genotype adjusted for patient and injury characteristics as well as population genetic structure. Array-wide significance was based on Bonferroni correction for multiple testing., Results: Of 538 patients (median age 40 years, median burn size 6.0% of body surface area), 71% were men and 76% were White. The mean VSS height score was 1.2 (range: 0-3). Of 289,639 SNPs tested, a variant in the CUB and Sushi multiple domains 1 (CSMD1) gene (rs11136645; MAF = 0.49), was significantly associated with decreased scar height (regression coefficient = -0.23, P = 7.9 × 10)., Conclusions: In the first published GWAS of HTS, we report that a common intronic variant in the CSMD1 gene is associated with reduced severity of postburn HTS. If this association is confirmed in an independent cohort, investigating the potential role of CSMD1 in wound healing may elucidate HTS pathophysiology.

Introduction: Abnormal pigmentation following cutaneous injury causes significant patient distress and represents a barrier to recovery. Wound depth and patient characteristics influence scar pigmentation. However, we know little about the pathophysiology leading to hyperpigmentation in healed shallow wounds and hypopigmentation in deep dermal wound scars. We sought to determine whether dermal fibroblast signaling influences melanocyte responses., Methods and Materials: Epidermal melanocytes from three Caucasians and three African-Americans were genotyped for single nucleotide polymorphisms (SNPs) across the entire genome. Melanocyte genetic profiles were determined using principal component analysis. We assessed melanocyte phenotype and gene expression in response to dermal fibroblast-conditioned medium and determined potential mesenchymal mediators by proteome profiling the fibroblast-conditioned medium., Results: Six melanocyte samples demonstrated significant variability in phenotype and gene expression at baseline and in response to fibroblast-conditioned medium. Genetic profiling for SNPs in receptors for 13 identified soluble fibroblast-secreted mediators demonstrated considerable heterogeneity, potentially explaining the variable melanocyte responses to fibroblast-conditioned medium., Discussion: Our data suggest that melanocytes respond to dermal fibroblast-derived mediators independent of keratinocytes and raise the possibility that mesenchymal-epidermal interactions influence skin pigmentation during cutaneous scarring.

Purpose: The American College of Surgeons Surgical Quality Improvement Program database collects detailed and validated data on demographics, comorbidities, and 30-day postoperative outcomes of patients undergoing operations in most subspecialties. This dataset has been previously used to quantify complications and identify risk factors in other surgical subspecialties. We sought to determine the incidence of postoperative complications following hand surgery and to identify factors associated with increased risk of complications in order to focus preventive strategies., Methods: National Surgical Quality Improvement Program data from 2006 to 2011 were queried using 302 hand-specific Current Procedural Technology codes. Descriptive statistics were calculated for the population, and potential risk factors and patient characteristics were analyzed for their association with complications in the 30-day postoperative period using both univariate and multivariate analyses., Results: There were 208 hand-specific Current Procedural Technology codes represented in the data, and of these, 84 were associated with at least 1 complication. The overall incidence of complications within 30 days of hand surgery was 2.5% (95% confidence interval, 2.2%-2.8%). In univariate analysis, older age, diabetes, chronic obstructive pulmonary disease, congestive heart failure, atherosclerosis, steroids, bleeding disorder, increasing American Society of Anesthesiologists class, increasing wound class, emergency procedure, longer operative time, and preoperative transfusion were associated with significantly higher risk of complications, and local anesthesia and outpatient surgery were associated with lower risk. In the multivariate model, male sex, increasing American Society of Anesthesiologists class, wound class 4, and preoperative transfusion were associated with significantly higher risk, and outpatient surgery was associated with significantly lower risk. The most common complication was surgical-site infection (1.2%)., Conclusions: The incidence of complications was low, with overall health status being more important than specific comorbidities in predicting complication risk. This information may be valuable in counseling patients before surgery and in identifying patients at higher risk for complications following hand surgery., Type of Study/level of Evidence: Therapeutic III., (Copyright © 2015 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

While cellular metabolism is known to regulate a number of key biological processes such as cell growth and proliferation, its role in wound healing is unknown. We hypothesized that cutaneous injury would induce significant metabolic changes and that the impaired wound healing seen in diabetes would be associated with a dysfunctional metabolic response to injury. We used a targeted metabolomics approach to characterize the metabolic profile of uninjured skin and full-thickness wounds at day 7 postinjury in nondiabetic (db/-) and diabetic (db/db) mice. By liquid chromatography mass spectrometry, we identified 129 metabolites among all tissue samples. Principal component analysis demonstrated that uninjured skin and wounds have distinct metabolic profiles and that diabetes alters the metabolic profile of both uninjured skin and wounds. Examining individual metabolites, we identified 62 with a significantly altered response to injury in the diabetic mice, with many of these, including glycine, kynurenate, and OH-phenylpyruvate, implicated in wound healing for the first time. Thus, we report the first comprehensive analysis of wound metabolic profiles, and our results highlight the potential for metabolomics to identify novel biomarkers and therapeutic targets for improved wound healing outcomes., (© 2015 by the Wound Healing Society.)

An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ., Competing Interests: The authors declare no conflict of interest.

Oncolytic viruses have been combined with standard cancer therapies to increase therapeutic efficacy. Given the sequential activation of herpes viral genes (herpes simplex virus-1, HSV-1) and the temporal cellular changes induced by ionizing radiation, we hypothesized an optimal temporal sequence existed in combining oncolytic HSV-1 with ionizing radiation. Murine U-87 glioma xenografts were injected with luciferase encoding HSV-1, and ionizing radiation (IR) was given at times before or after viral injection. HSV-1 replication and tumor-volume response were followed. Radiation given 6-9 h after HSV-1 injection resulted in maximal viral luciferase expression and infectious viral production in tumor xenografts. The greatest xenograft regression was also seen with radiation given 6 h after viral injection. We then tested if HSV-1 replication had a dose response to ionizing radiation. HSV-1 luciferase expression exhibited a dose response as xenografts were irradiated from 0 to 5 Gy. There was no difference in viral luciferase expression as IR dose increased from 5 Gy up to 20 Gy. These results suggest that the interaction of IR with the HSV-1 lytic cycle can be manipulated for therapeutic gain by delivering IR at a specific time within viral replicative cycle.

Background: The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. Recent data have identified new functions of STAT1 associated with tumourigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumourigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism with potential implication in the Warburg effect., Methods: We generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumour xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumours. Transcriptional profiling was based on Affymetrix Human GeneChip(R) Gene 1.0 ST microarrays. Proteomes were determined from the tandem mass spectrometry (MS/MS) data by searching against the human subset of the UniProt database. Data were analysed using Significance Analysis of Microarrays for ribonucleic acid and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis with statistical significance measured by Fisher's exact test., Results: Knockdown of STAT1 led to significant growth suppression in untreated tumours and radio sensitization of irradiated tumours. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumour-specific glycolysis. In addition, IR drastically suppressed the GG pathway in STAT1 KD tumours without significant change in STAT1 WT tumours., Conclusion: Our results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes. STAT1-dependent expressional regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.

Background: Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress., Methodology/principal Findings: Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1(H) genotype) are selected by the lung microenvironment. STAT1(H) tumor cells also demonstrate resistance to IFN-gamma (IFNgamma), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1(L) genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress., Conclusions: Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization.