Patient-level indirect treatment comparison of lanadelumab versus pdC1-INH i.v. in hereditary angioedema patients: PATCH study.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. METHODS: Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. RESULTS: Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). CONCLUSION: This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.

Ultimate Limits for Quickest Quantum Change-Point Detection.

Detecting abrupt changes in data streams is crucial because they are often triggered by events that have important consequences if left unattended. Quickest change-point detection has become a vital sequential analysis primitive that aims at designing procedures that minimize the expected detection delay of a change subject to a bounded expected false alarm time. We put forward the quantum counterpart of this fundamental primitive on streams of quantum data. We give a lower bound on the mean minimum delay when the expected time of a false alarm is asymptotically large, under the most general quantum detection strategy, which is given by a sequence of adaptive collective (potentially weak) measurements on the growing string of quantum data. In addition, we give particular strategies based on repeated measurements on independent blocks of samples that asymptotically attain the lower bound and thereby establish the ultimate quantum limit for quickest change-point detection. Finally, we discuss online change-point detection in quantum channels.

Intraoperative Heparin Bolus and Postoperative Anticoagulation with Low Molecular Weight Heparin Increase Reliability of Microsurgical Free Flaps for Upper Extremity Reconstruction.

BACKGROUND: Microsurgery is an indispensable tool of upper extremity reconstruction addressing defect coverage and the restoration of function. Perioperative anticoagulation and antiplatelet therapy are controversially discussed with impact on microsurgical outcome, but without clear evidence. This study aims to evaluate the impact of perioperative anticoagulation and antiplatelet therapy in microsurgical upper extremity reconstruction. METHODS: All eligible patients treated with microsurgical upper extremity reconstruction between January 2000 and July 2014 were included in a comparative analysis to define a superior anticoagulation and antiplatelet regime in a retrospective study. Endpoints were all major complications (e.g., total flap loss, arterial and venous thrombosis) as well as minor complication. RESULTS: A total of 183 eligible free flaps to the upper extremity were transferred in 169 patients. Altogether, 11 arterial (6.0%) and 9 venous (4.9%) thromboses, 11 total flap losses (6.0%), and 16 cases with hematoma (8.7%) were detected. In the subgroup analysis, patients who did not receive any heparin intraoperatively (n = 21; 11.5%) had a higher rate of major complications (p = 0.001), with total flap loss being the most frequent event (p = 0.004). A trend was shown for intraoperative bolus administration of 501 to 1,000 units unfractionated heparin (UFH) intravenously to have the lowest rate of major complications (p = 0.058). Intraoperative administration of acetylsalicylic acid (n = 13; 8.1%) did not have any influence on the rate of major complications. Postoperative anticoagulation with continuous UFH intravenously (n = 68; 37.2%) resulted in more frequent complications (p = 0.012), for example, an increased rate of total flap loss (p = 0.02) and arterial thrombosis (p = 0.02). CONCLUSION: The results of the present study favor administration of 501 to 1,000 units UFH intravenously as an intraoperative bolus (e.g., 750 units UFH intravenously). Postoperative low molecular weight heparin subcutaneous application in a prophylactic dose given once or twice a day was associated with less complications compared with continuous infusion of UFH, although continuously applied UFH may reflect an increased risk profile.

A Retrospective Matched-Pair Analysis of Long-term Outcomes after Successful Lower Extremity Free Flap Salvage.

BACKGROUND: Pedicle occlusion with total free flap loss after microvascular lower extremity reconstruction is a considerably rare yet devastating complication. Fortunately, in the majority of cases, emergency salvage takebacks of compromised free flaps are initiated in a timely manner. In this report, we present our analysis of long-term outcomes following transient vascular compromise mitigated through successful free flap salvage in the lower extremity. METHODS: We performed a single-center retrospective matched-pair analysis of 46 patients with lower extremity free flap reconstructions. Cases underwent successful revisions of microvascular compromise (n = 23), whereas controls had uneventful postoperative courses (n = 23). Patient-reported outcome questionnaires and physical evaluations were used to assess general quality of life, functional outcomes, and cosmesis (Lower Extremity Functional Scale [LEFS], Lower Limb Outcomes Questionnaire [LLOQ], Short Form 36 (SF-36), Vancouver Scar Scale [VSS]). The mean follow-up time was 4.4 years. RESULTS: The health-related quality of life assessed by the SF-36 did not differ significantly between both groups in any of the subscales (p ≥ 0.15 for all subscales). Functional outcomes did not show significant differences between both groups according to the LEFS (p = 0.78) and LLOQ (p = 0.45). The overall scar appearance assessed by the VSS showed significantly poorer cosmesis in the re-exploration group (p = 0.014). CONCLUSION: Salvage of compromised free flaps in the lower extremity yields similar long-term outcomes compared to noncompromised free flaps with regard to function and quality of life. However, free flap revisions may lead to impaired scar formation. This study provides further evidence that the opportunity for urgent re-exploration is indispensable.

From Esthetic Medicine to Optimizing Reconstructive Outcome: A Feasibility Trial on Secondary Refinement of Fasciocutaneous Anterolateral Thigh Flaps with Cryolipolysis.

BACKGROUND: Free adipocutaneous anterolateral thigh (ALT) flaps have evolved as workhorse flaps to reconstruct complex, multicompound defects. While coverage is safely achieved, flaps may remain bulky. As a standard of care, flaps are refined with liposuction, partial excision, or combination of both. Cryolipolysis is widely used for fat reduction in esthetic medicine. This pilot comparative study analyses whether cryolipolysis may serve as a safe alternative method to effectively reduce volume in fasciocutaneous flaps. Moreover, patients' satisfaction with the procedure is evaluated. METHODS: In this single-center, retrospective, interventional comparative cohort study, 10 patients with free subfascial ALT flaps for distal extremity reconstruction underwent cryolipolysis (60 minutes, -9°C). Circumference of the extremities and subcutaneous fat thickness were determined before (T1) and 12 weeks (T2) after cryolipolysis. Patient satisfaction was evaluated with a questionnaire of Likert's scale questions. Duration of hospital stay, intervention time, costs, and possible complications were analyzed and compared with surgical flap contouring (n = 12). RESULTS: All patients undergoing cryolipolysis were male, with a median age of 52 years without arterial disease-like state or deep vein thrombosis (DVT). At T2, a significant reduction of circumference of 1.8 ± 0.9 cm (p < 0.001) and subcutaneous fat layer of 7.7 ± 3.0 mm (p < 0.0001) was recorded. Overall, 90% of the patients were satisfied with the result. Cryolipolysis was well tolerated. One patient developed a second-degree frostbite which healed without further intervention. Cryolipolysis proofed to be as safe as surgical flap contouring. Hospital stay was significantly shorter (p < 0.01) and personal resources were spared when flap contouring was performed with cryolipolysis. CONCLUSION: This is a novel application of evolving body-contouring cryolipolysis from esthetic medicine into optimizing outcomes in reconstructive surgery. Cryolipolysis has been shown to be relatively safe and effective to reduce ALT's volume with high patients' satisfaction. This successful pilot study encourages further investigation with a prospective randomized control trial.

Selective reconstitution of IFN­Î³ gene function in Ncr1+ NK cells is sufficient to control systemic vaccinia virus infection.

IFN-γ is an enigmatic cytokine that shows direct anti-viral effects, confers upregulation of MHC-II and other components relevant for antigen presentation, and that adjusts the composition and balance of complex cytokine responses. It is produced during immune responses by innate as well as adaptive immune cells and can critically affect the course and outcome of infectious diseases, autoimmunity, and cancer. To selectively analyze the function of innate immune cell-derived IFN-γ, we generated conditional IFN-γOFF mice, in which endogenous IFN-γ expression is disrupted by a loxP flanked gene trap cassette inserted into the first intron of the IFN-γ gene. IFN-γOFF mice were intercrossed with Ncr1-Cre or CD4-Cre mice that express Cre mainly in NK cells (IFN-γNcr1-ON mice) or T cells (IFN-γCD4-ON mice), respectively. Rosa26RFP reporter mice intercrossed with Ncr1-Cre mice showed selective RFP expression in more than 80% of the NK cells, while upon intercrossing with CD4-Cre mice abundant RFP expression was detected in T cells, but also to a minor extent in other immune cell subsets. Previous studies showed that IFN-γ expression is needed to promote survival of vaccinia virus (VACV) infection. Interestingly, during VACV infection of wild type and IFN-γCD4-ON mice two waves of serum IFN-γ were induced that peaked on day 1 and day 3/4 after infection. Similarly, VACV infected IFN-γNcr1-ON mice mounted two waves of IFN-γ responses, of which the first one was moderately and the second one profoundly reduced when compared with WT mice. Furthermore, IFN-γNcr1-ON as well as IFN-γCD4-ON mice survived VACV infection, whereas IFN-γOFF mice did not. As expected, ex vivo analysis of splenocytes derived from VACV infected IFN-γNcr1-ON mice showed IFN-γ expression in NK cells, but not T cells, whereas IFN-γOFF mice showed IFN-γ expression neither in NK cells nor T cells. VACV infected IFN-γNcr1-ON mice mounted normal cytokine responses, restored neutrophil accumulation, and showed normal myeloid cell distribution in blood and spleen. Additionally, in these mice normal MHC-II expression was detected on peripheral macrophages, whereas IFN-γOFF mice did not show MHC-II expression on such cells. In conclusion, upon VACV infection Ncr1 positive cells including NK cells mount two waves of early IFN-γ responses that are sufficient to promote the induction of protective anti-viral immunity.

Quantum Sequential Hypothesis Testing.

We introduce sequential analysis in quantum information processing, by focusing on the fundamental task of quantum hypothesis testing. In particular, our goal is to discriminate between two arbitrary quantum states with a prescribed error threshold ε when copies of the states can be required on demand. We obtain ultimate lower bounds on the average number of copies needed to accomplish the task. We give a block-sampling strategy that allows us to achieve the lower bound for some classes of states. The bound is optimal in both the symmetric as well as the asymmetric setting in the sense that it requires the least mean number of copies out of all other procedures, including the ones that fix the number of copies ahead of time. For qubit states we derive explicit expressions for the minimum average number of copies and show that a sequential strategy based on fixed local measurements outperforms the best collective measurement on a predetermined number of copies. Whereas for general states the number of copies increases as log1/ε, for pure states sequential strategies require a finite average number of samples even in the case of perfect discrimination, i.e., ε=0.

Multidisciplinary team meetings for patients with complex extremity defects: a retrospective analysis of treatment recommendations and prognostic factors for non-implementation.

BACKGROUND: This study aimed to assess a multidisciplinary team (MDT) meeting approach for the management of patients with complex extremity defects, analyze treatment recommendations, and evaluate factors influencing non-implementation. METHODS: All patients introduced to an MDT meeting for complex extremity defects from 2015 to 2017 were included in a retrospective cohort study. Patients' characteristics and defect causes were evaluated. Treatment recommendations (TR) of MDT meetings and subsequent implementation were reviewed (cohort with implementation of TR versus cohort with non-implementation of TR), and factors associated with non-adherence to recommendations were statistically analyzed using logistic regression. RESULTS: Fifty-one patients (41 male) with a mean age of 54 years were presented in 27 MDT meetings. Most of the patients (70%) suffered from reconstructive challenging or combined bone- and soft tissue defects, primarily located at the lower extremity (88%). Large skeletal defects, chronic osteomyelitis, and multi-fragmented fractures were present in 65% of cases. Forty-five percent of the patients suffered from peripheral vascular disease, necessitating surgical optimization. Of the 51 MDT decisions, 40 were implemented (78%; (32/40) limb salvage versus 22%; (8/40) limb amputation). Limb salvage was successfully achieved in 91% (29/32) of the cases. Failed limb salvages were due to flap failure (33%; 1/3), recurring periprosthetic joint infections (66%; 2/3) and concomitant reconstructive failure. Patients who underwent limb amputation, as recommended, showed proper stump healing and regained mobility with a prosthesis. Overall the MDT treatment plan was effective in 92.5% (37/40) of the patients, who adhered to the MDT treatment recommendation. In eleven patients (22%; 11/51), the MDT treatment was not implemented. MDT decisions were less likely to be implemented, if amputation was recommended (p = 0.029). CONCLUSIONS: MDT meetings represent a valid tool to formulate individualized treatment plans, avoiding limb amputation in most patients with severe extremity defects. Recommendation for limb amputation is less likely to be implemented than plans for limb salvage. TRIAL REGISTRATION: Retrospectively registered.

A meta-analysis evaluating risk factors for compound free flaps for upper extremity defect reconstruction comparing complications and functional outcomes of compound free flaps with and without bone components.

BACKGROUND: Compound flaps offer the advantage of one stage defect reconstruction respecting all relevant tissues and early functional recovery by optimal vascularity of all components. Due to its specific vascular anatomy and the three-dimensional donor site, compound flaps with bone components may result in higher complication rates compared to soft tissue compound flaps. The meta-analysis summarizes the available evidence and evaluates whether bone components are a risk factor for periprocedural complications in upper extremity multidimensional defect reconstruction. METHOD: PubMed and Embase were searched for all publications addressing compound free flaps for upper extremity defect reconstruction with bone or soft tissue components published between January 1988 and May 2018. The methodological quality was assessed with the American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies. Flap loss, thrombosis rate, early infection, hematoma, seroma, as well as donor site complications were extracted and analyzed. RESULTS: Twelve out of 1157 potentially eligible studies (evidence-III) comprising 159 patients were finally included with publication bias for all summarized complication rates. Complication rates for flaps with/ without bone components were: total flap loss 5%, 95% CI = 3%-10% (6%/5%); partial flap loss 8%, 95% CI = 5%-15%, (9%/8%); arterial/venous thrombosis 7%, 95% CI = 4%-12%, (8%/5%)/14%, 95% CI = 9%-21% (16%/6%, P < .05) with higher risk for flaps with bone components; infection 6%, 95% CI = 3%-12% (6%/6%); hematoma 6%, 95% CI = 3%-11% (6%/5%); seroma 5%, 95% CI = 3%-10% (5%/5%); dehiscence 10%, 95% CI = 6%-17% (11%/9%). CONCLUSION: Compound flaps for upper extremity defect reconstruction including bone components have a higher venous thrombosis rate compared to compound soft-tissue flaps.

Use of venous couplers in microsurgical lower extremity reconstruction: A systematic review and meta-analysis.

BACKGROUND: Free tissue transfer for lower limb reconstruction has become a workhorse procedure for limb-salvage. Compared with other recipient sites, the lower extremity has a higher risk of microvascular complications, in particular with venous anastomosis. The study's objective is to evaluate the evidence, safety, and efficacy of venous coupler use in microsurgical anastomosis in lower limb reconstruction to provide objective appraisal of the surgical techniques. METHODS: A systematic review (SR) and meta-analysis (MA) were performed analyzing articles from PubMed, Cochrane, Embase, and Web of Science from January 1990, to August 2018. Abstracts and titles were screened and assessed for eligibility by independent reviewers. Following full-text review, articles were included in the SR and MA. Case reports were excluded. Cochrane Collaboration and the Quality of Reporting of Meta-analyses (QUOROM) guidelines were followed. RESULTS: Out of 15 included studies that met the inclusion criteria for the SR, 9 were included in MA. Patients treated with venous couplers did not experience more surgical complications (risk ratio (RR) 0.79; 95% confidence interval (CI) 0.48-1.33; p = .38), total failure (RR 0.61; 95% CI 0.22-1.70; p = .34), venous compromise (RR 0.72; 95% CI 0.23-2.27; p = .57), arterial compromise (RR 0.85; 95% CI 0.25-2.88; p = .80), partial failure (RR 0.77; 95% CI 0.33-1.77; p = .54), or reoperation (RR 11.79; 95% CI 0.49-286.55; p = .13) in comparison with hand-sewn anastomosis. CONCLUSIONS: Outcomes of venous couplers in lower limb reconstruction are comparable to those of hand-sewn anastomosis. However, this study was limited by the quality of the available literature. Additional prospective studies should aim to directly compare both techniques and potential further benefits in clinical trials.

What We Really can Learn From Aviation: Checklist-based Team Time-Out in Conjunction With Interpersonal Competence Training for the Daily Management of a Surgical Department.

Objective. Aviation and affiliated training concepts have gained a pioneering role in the establishment of interpersonal competence training for physicians and in particular for surgical disciplines. Strengthening interpersonal competence in conjunction with standardized processes and tools aims at implementing safety and error culture in the clinical surroundings while improving patient safety. In a surgical center, safety culture starts with decisive day-to-day management, continues with WHO team time-out and optimal surroundings for the operation, and goes beyond mortality and morbidity conferences and reevaluation of the daily work. Nevertheless, operational day-to-day management has been only little in the focus of security and error culture in surgical literature yet. Method. Interpersonal competence training has been introduced in the hospital group. In 2017, a checklist-based team time-out was implemented to optimize day-to-day management so that conflicts and collisions can be identified timely. Results. The daily completed checklist addresses changes in staff and resource availability, patient-relevant, and other organizational factors. The introduction has provided a significant level of stability and proven itself as part of the safety culture and exemplary leadership beyond the "classical" fields in surgery. Conclusion. This "simple" instrument from the aviation toolbox in conjunction with interpersonal competence training can be recommended to improve the management and safety culture in a surgical clinic to streamline operations and positively affect patient safety and staff development as well as employee satisfaction. Nevertheless, it is not sufficient to implement standard operation procedures templates and checklists, and they have to be lived daily and by everyone.

Safety of a Modified Lipoabdominoplasty Technique for Donor-Site Closure in Abdominal-Based Free Flap Breast Reconstruction.

BACKGROUND: The aesthetic and functional outcomes of the donor site following abdominal-based free flap breast reconstruction have been suboptimal. The objective of this study is to evaluate a modified liposuction-assisted abdominoplasty technique combined with rectus plication (LPARSP) adopted from cosmetic abdominoplasty practice. PATIENTS AND METHODS: All abdominal-based free flap breast reconstructions from 01/2017 to 03/2019 were reviewed. Patients with central fullness and sufficient tissue surplus on the abdomen, thighs and flanks who received LPARSP and rectus plication were identified (LPARSP group) and matched for age and body mass index with patients who underwent conventional abdominoplasty (CA group). Abdominal skin sensation, objective functional and aesthetic measures of the abdomen, as well as patient-reported outcomes (Breast-Q), were analyzed. RESULTS: A total of 28 patients were included. Groups were similar in demographics. The mean amount of lipoaspirate in the LPARSP group was 1054±613.5 ml. The postoperative course was similar in both groups. The LPARSP technique resulted in a lower positioned horizontal scar (p = 0.03). The aesthetic outcome was superior in the LPARSP group (p < 0.0001). Furthermore, the LPARSP group presented with a decreased bulging rate (p = 0.05), and secondary refinement procedures were less frequently demanded (p = 0.02). In addition, the abdominal wall sensation of the flanks was improved in the LPARSP group (p = 0.05), whereby patient-reported outcome measures did not differ between groups. CONCLUSIONS: Lipoabdominoplasty with rectus plication represents a safe approach for donor-site closure in selected patients undergoing abdominal-based free flap breast reconstruction. Superior functional and aesthetic results paired with improved abdominal wall sensation are achieved compared to CA. LEVEL OF EVIDENCE IV: 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 .

Vein Grafting in Microsurgical Lower Extremity Reconstruction: Outcome Analysis of Primary versus Secondary Salvage Procedures.

BACKGROUND: Many microsurgeons fear high complication rates and free flap loss when vein grafting is necessary to restore blood flow at the recipient site. The aims of this study were to comparatively analyze surgical outcomes of interposition vein grafts (VG) in microsurgical primary lower extremity reconstruction and secondary salvage procedures. METHODS: A retrospective study was conducted on 58 patients undergoing free flap transfers with vein grafting for primary lower extremity reconstruction (cohort 1) and secondary salvage procedures (cohort 2) between 2002 and 2016. A matched-pair analysis of both cohorts and 58 non-VG flaps was performed. Patient data, preoperative conditions, flap and vein graft characteristics, postoperative outcomes such as flap failure, thrombosis, and wound complications were analyzed. RESULTS: A total of 726 free flap transfers were performed. In total, 36 primary reconstructions (5%) utilized 41 interposition VG (cohort 1). Postoperative vascular compromise was observed in 65 free flaps (9%). In total, 22 out of 65 secondary salvage procedures (33.8%) utilized 26 interposition VG (cohort 2). Two total flap losses occurred in each cohort (5.6 vs. 9.1%; p = 0.63). Postoperative complications were observed in 38.9% of free flaps in cohort 1 and 72.7% in cohort 2 (p = 0.01). Takeback for microvascular compromise was comparable in both cohorts (19.4 vs. 22.7%; p = 0.75). Microvascular complications occurred more often in cohort 2 (22.7%) than in cohort 1 (8.3%; p = 0.28). Lower extremity salvage rates were high among both cohorts (94.4 vs. 90.9%; p = 0.63). Matched-pair analysis did not show any relevant differences on takebacks and flap loss (p = 0.32 and p = 1.0). CONCLUSION: In complex lower extremity reconstructions, VG can be performed with acceptable complication rates and outcomes in primary and especially in salvage cases. With careful planning and a consistent surgical protocol, VG can provide reliable success rates in limb salvage.

Lymphatic Tissue Engineering: A Further Step for Successful Lymphedema Treatment.

BACKGROUND: Secondary lymphedema, caused by oncologic surgery, radiation, and chemotherapy, is one of the most relevant, nononcological complications affecting cancer survivors. Severe functional deficits can result in impairing quality of life and a societal burden related to increased treatment costs. Often, conservative treatments are not sufficient to alleviate lymphedema or to prevent stage progression of the disease, as they do not address the underlying etiology that is the disruption of lymphatic pathways. In recent years, lymphatic surgery approaches were revolutionized by advances in microsurgical technique. Currently, lymphedema can effectively be treated by procedures such as lymphovenous anastomosis (LVA) and lymph node transfer (LNT). However, not all patients have suitable lymphatic vessels, and lymph node harvesting is associated with risks. In addition, some data have revealed nonresponders to the microsurgical techniques. METHODS: A literature review was performed to evaluate the value of lymphatic tissue engineering for plastic surgeons and to give an overview of the achievements, challenges, and goals of the field. RESULTS: While certain challenges exist, including cell harvesting, nutrient supply, biocompatibility, and hydrostatic properties, it is possible and desirable to engineer lymph nodes and lymphatic vessels. The path toward clinical translation is considered more complex for LNTs secondary to the complex microarchitecture and pending final mechanistic clarification, while LVA is more straight forward. CONCLUSION: Lymphatic tissue engineering has the potential to be the next step for microsurgical treatment of secondary lymphedema. Current and future researches are necessary to optimize this clinical paradigm shift for improved surgical treatment of lymphedema.

A Structured, Microsurgical Training Curriculum Improves the Outcome in Lower Extremity Reconstruction Free Flap Residency Training: The Ludwigshafen Concept.

BACKGROUND: Risk stratification, economic pressure, and a flat learning curve make the realization and development of proper microsurgical skills and competences a challenging task in the daily clinical practice. In previous studies, we were able to show that microsurgical procedures, e.g., free flaps and replantations, are safe training procedures and teachable in daily clinical practice in view of certain issues of risk stratification. The present study aims to evaluate further improvements in terms of safety and complication rates for free flaps as a training procedure after introduction and continuous implementation of a structured in-house training curriculum for microsurgical skills and competences and a 24-hour free accessible microsurgical training facility for the plastic surgery resident. METHODS: This retrospective comparative cohort study was conducted to review whether microsurgical skills for free flaps to the lower extremity can further be improved after implementation of the curriculum and a 24-hour accessible training facility. Therefore, we compared cohort A before (2009-2012) and B after (2014-2017) implementation. Patient demographics, procedural characteristics, and outcome parameters for free tissue transfer of the lower extremity were evaluated. RESULTS: The comparison of both cohorts showed a significantly reduced postoperative complication rate for cohort B (p <0.05). Furthermore, operation time was shorter, and the hospital stay could be significantly decreased (p <0.01). Workhorse flaps for plastic surgical training were the anterior lateral thigh (ALT) flap or the musculus latissimus dorsi (LD) flap. However, even more complex procedures with arteriovenous loops could be safely performed by plastic surgery residents under the supervision of the senior surgeon in exceptional cases. CONCLUSION: The implementation of a regularly held, microsurgical in-house training curriculum with 24-hour accessible training facility improves procedural and outcome parameters for free flaps to the lower extremity for surgical residents and is an elementary part of skills and competency training. However, risk stratification, repeated surgical exposure, expertise, and institutional infrastructures are essential and must be taken into consideration.

Implementation and Validation of Free Flaps in Acute and Reconstructive Burn Care.

Microsurgical free flap reconstruction in acute burn care offers the option of reconstructing even challenging defects in a single stage procedure. Due to altered rheological and hemodynamic conditions in severely burned patients, it bears the risk of a higher complication rate compared to microsurgical reconstruction in other patients. To avoid failure, appropriate indications for free flap reconstruction should be reviewed thoroughly. Several aspects concerning timing of the procedure, individual flap choice, selection and preparation of the recipient vessels, and perioperative measures must be considered. Respecting these specific conditions, a low complication rate, comparable to those seen in microsurgical reconstruction of other traumatic limb defects, can be observed. Hence, the free flap procedure in acute burn care is a relatively safe and reliable tool in the armamentarium of acute burn surgery. In reconstructive burn care, microsurgical tissue transfer is routinely used to treat scar contractures. Due to the more robust perioperative condition of patients, even lower rates of complication are seen in microsurgical reconstruction.

A Systematic Review of Learning Curves in Plastic and Reconstructive Surgery Procedures.

BACKGROUND: Surgical learning curves reflect the trainee's rate of progress in gaining skills and competence for new procedures. Complex interventions such as free tissue transfers, with various linked skills and competences, transferred to one procedure are likely to have steep learning curves. This work aimed to report influence of learning curves on outcomes such as success rate, operative time, and complication rates in plastic surgery procedures. METHODS: The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic database literature search (PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trails) was performed. Articles were included when reporting effects of learning curves on outcomes in plastic surgery procedures. RESULTS: Twenty-nine articles focusing on learning curves in plastic surgery procedures were included. Studies reported on non-free flap breast reconstruction, mastectomy, and free flap reconstruction in general and for breast reconstruction and did not allow for pooling of the data because of heterogeneity. Most common outcomes for measuring improvements were success rate, operation time, and complication rate, which demonstrated improvements in almost all studies. Plateaus were reached in 45 to 100 cases for breast reconstructions and were not reported for other procedures. Only 2 studies did not find associations between surgical experience and clinical outcomes. CONCLUSIONS: There are sparse data on learning curves in plastic surgery. Existing studies draw a heterogeneous picture, but especially free flap breast reconstructions seem to undergo learning curves with improvements in operative time, complication rates, and success rates. However, well-designed studies with clearly defined outcomes and comparison between surgeons of different levels over time should be performed.Systematic review registration: PROSPERO: CRD42018108634.

Pharmaceutical Preconditioning With Nitric Oxide Synthase and L-Arginine in Ischemic Tissues.

BACKGROUND: Nitric oxide (NO) is a multifunctional signaling molecule involved in regulating vascular tone and tissue oxygenation. It is also an important cytoprotective agent against ischemia-reperfusion injury (IRI). Enhancing NO bioavailability via exogenous NO synthases (NOSs) and L-arginine promotes conversation to NO, circumventing the problem of nonfunctioning NOSs under hypoxic and acidic conditions. In this study, the authors evaluated the therapeutic efficacy of neuronal, inducible, and endothelial NOS and L-arginine on reperfusion-induced skin flap alterations. METHODS: The vascular pedicle isolated rat skin flap model was used and underwent 3 hours of ischemia. At 30 minutes before ischemia, normal saline, endothelial-, inducible-, and neuronal NOSs (1/2 IU) and L-arginine (100 mg/kg body weight) were administered by means of intravenous infusion. The IRI-induced alterations were measured 5 days after the operation. RESULTS: The 3 isoforms of NOS increased the flap vitality rate (VR) from 10% to 23% compared with the control group. L-Arginine treatment also increased the VR by approximately 15%. The combination of L-arginine with NOS resulted in even higher flap VRs. The best results could be achieved with the combination of endothelial NOS (2 IU) and L-arginine. CONCLUSIONS: Modulation of NO bioavailability via exogenous application of NOSs and L-arginine significantly improved VRs in a skin flap rat model. This pharmacologic preconditioning has the potential to attenuate IRI-induced alterations in skin flaps.

Role, Management, and Outcome of Free Flap Reconstruction for Acute Full-Thickness Burns in Hands.

INTRODUCTION: Severe thermal trauma to the hand can result in major impairment and reduced function due to defective healing or even extremity loss. Full-thickness injuries frequently incur exposure of tendons or bone and require an early and stable coverage with soft tissue transplants to allow for rapid induction of exercise and to preserve structures and hand function. Free tissue transfer to the hand after thermal trauma is a rare indication, and safety, management, and outcome of free flap surgery for severe acute burn injuries to the hand remains underreported. METHODS: Patients with primary reconstructions of full-thickness burn injuries to the hand undergoing microsurgical free tissue transfer surgery were retrospectively assessed in a period from 2013 to 2016. Salvage strategy of the extremity, postoperative complications, length of hospital stay, and primary reconstructive result were quantified and analyzed. Functional outcome measures (range of motion and grip strength) were assessed during clinical follow-up examinations. RESULTS: During the investigated period, 13 patients were identified undergoing reconstruction of 14 hands via free flap transplantation after severe burn injury in the acute phase. Nine anteriolateral thigh flaps (64%), 3 latissimus dorsi flaps (18%), 1 serratus anterior flap, and 1 tensor fasciae lata flap (7%) were performed. In all cases, salvage of the affected extremity was achieved, although 1 flap (7%) was lost during the early postoperative period requiring secondary reconstruction via pedicled groin flap. Further complications were venous thrombosis (n = 2; 14%) and hematoma (n = 2; 14%). Mean length of hospital stay was 51 days. Functional outcome during follow-up examination after an average of 9.3 months was inhomogeneous depending on the pattern of injury and ranged from complete recovery to nearly entire loss of hand function. CONCLUSIONS: Free flap transfer can be a mandatory and valuable tool to cover full-thickness burn injuries of the hand early in the clinical course of thermal trauma and may provide extremity salvage by favorable means of reconstruction to achieve acceptable functional outcomes, in the most severe cases. Although microsurgical failure rates in burn patients are slightly higher than in free flap transfer to the upper extremity in general, it can be performed with reasonable risk-to-benefit ratio.

Inducible Nitric Oxide Synthase and L-Arginine Optimizes Nitric Oxide Bioavailability in Ischemic Tissues Under Diabetes Mellitus Type 1.

BACKGROUND: The mechanisms influencing the balance of nitric oxide (NO) bioavailability in tissues are negatively affected under diabetic and also under ischemic conditions. Free tissue transplantation for diabetic patients has to deal with both ischemic and diabetic circumstances, which lead to a significantly decrease in providing NO, thus increasing ischemia-reperfusion injury. In previous studies, we could prove that enhancing NO bioavailability leads to attenuated ischemia-reperfusion injury macrocirculatory and microcirculatory alterations in healthy and also in diabetes type 2 rats. This study is evaluating the role of inducible nitric oxide synthase in different dosages and L-arginine under diabetes type 1 conditions. METHODS: Diabetic type 1 conditions were established via streptozotocin over a period of 4 weeks and verified via blood sugar, insulin, and C-peptide levels. Vascular pedicle isolated rat skin flap model that underwent 3 hours of ischemia was used. At 30 minutes before ischemia, normal saline, inducible nitric oxide synthase (NOS) (1/2 IE), and L-arginine (50 mg/kg body weight) were administered systemically. Ischemia/reperfusion (I/R)-induced alterations were measured 5 days after the operation. RESULTS: The inducible NOS (iNOS) attenuated I/R-induced alterations under diabetic type 1 conditions significantly with vitality rates of 16.1% compared with control group (5.5%). Best results could be achieved with the combination of iNOS (1 IE) and L-arginine displaying vitality rates of 43%. Increased dosage of inducible nitric oxide (2 IE) led to decreased vitality rates (22.2%/27.4% without/with L-arginine). CONCLUSIONS: Supporting the mechanisms of NO bioavailability via exogenous application of iNOS and L-arginine significantly attenuated I/R-induced alterations in a skin flap rat model. This pharmacologic preconditioning could be an easy and effective interventional strategy to uphold conversation of L-arginine to NO even on ischemic and type 1 diabetic conditions.