Occipital site deactivation for the treatment of chronic migraine: a minimally invasive approach.

In this paper, we describe our experience in treating migraine headache localized in the occipital area. Using our minimally-invasive approach, from June 2011 till January 2022, we have performed MH decompression surgery over 232 patients with occipital migraine trigger site. After a mean follow-up of 20 months (range, 3-62 months), patients complaining for occipital MH had 94% positive surgical outcome (86% complete MH elimination). Only rare minor complications were reported (e.g., oedema, paresthesia, ecchymosis, and numbness). Presented, in part, at the XXIV Annual Meeting European Society of Surgery (Genoa, Italy, May 28-29, 2022), at the Celtic Meeting of the British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS), (Dunblane, Scotland, September 8-9, 2022), at the Fourteenth Quadrennial European Society of Plastic, Reconstructive and Aesthetic Surgery Conference, (Porto, Portugal, October 5-7, 2022), at the 91st Annual Meeting of the American Society of Plastic Surgery, (Boston, USA, October 27-30, 2022), and at the 76 BAPRAS (British Association of Plastic, Reconstructive and Aesthetic Surgery) Scientific Meeting, (London, UK, November 30 - December 2, 2022).

The predictive and prognostic role of single nucleotide gene variants of PD-1 and PD-L1 in patients with advanced melanoma treated with PD-1 inhibitors.

Background: Despite having revolutionized the treatment paradigm for advanced melanoma, not all patients benefit from immune checkpoint inhibitor therapy. To date, there are no predictive biomarkers for response or the occurrence of immune-related adverse events (irAEs) to programmed cell death protein 1 (PD-1) inhibitors. Our aim was to investigate the predictive and prognostic role of single nucleotide variants (SNVs) of genes involved in the PD-1 axis. Methods: We analysed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3 G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three programmed death-ligand 1 (PD-L1) SNVs: +8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815). Association of SNV genotypic frequencies with best overall response to PD-1 inhibitors and development of irAEs were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS. Results: A total of 125 patients with advanced melanoma were included in the analysis. A reduction in irAEs risk was observed in patients carrying the PD-L1 +8293 C/A genotype compared with those carrying the C/C genotype (risk ratio = 0.45; 95% CL 0.22-0.93; P = 0.031). A trend for a reduction in irAEs was also observed with the PD1.5 T allele (risk ratio = 0.70, 95% confidence limits 0.48-1.01 versus C allele). None of the SNVs was associated with response to therapy. Finally, a survival benefit was observed in patients harbouring the PD1.7 C/C genotype (hazard ratio = 0.37; 95% confidence limits 0.14-0.96; P = 0.028) in the homozygous model. Conclusions: Our study showed that PD-1.5 and PD-L1 +8293 SNVs may play a role as a predictive biomarker of development of irAEs to PD-1 inhibitors. PD1.7 SNV may also be associated with a reduction of the risk of death, although further translational research is needed to confirm these results.

Principles and techniques of migraine surgery.

OBJECTIVE: The idea to treat migraine patients with a surgical procedure is relatively recent. The aim of this paper was to describe the surgical techniques and our 11-year experience in migraine surgery. PATIENTS AND METHODS: From June 2011 till December 2021, we have performed MH decompression surgery over 527 patients with either frontal (90 pts), occipital (232 pts) or temporal (205 pts) migraine trigger sites. RESULTS: The surgical procedure elicited a positive response in: (a) occipital trigger site, 95% of patients (86% complete recovery); (b) frontal trigger site, 87% of patients (32% complete recovery); (c) temporal trigger site, 88% of patients (50% complete recovery). CONCLUSIONS: The described techniques allowed us to obtain a high rate of positive results with a low percentage of minor complications.

Simulation and optimization of reconstructive surgery procedures on human skin.

The complex procedures involved in the reconstructive surgery of human skin to minimize post-operative scarring are here modeled by means of an automated computational tool. A finite strain no-compression membrane model accounting for the tendency to develop wrinkling regions in the skin is presented. The constitutive behavior of the material is then described by a suitable hyperelastic incompressible potential. Transpositions of skin flaps during surgery procedures are here computationally described by a general mapping technique of the internal boundary corresponding to surgery cut. The archetypal reconstructive surgery of a Z-plasty, where a rotational transposition of the resulting triangular flaps is involved, is considered in details, along with multiple Z-plasty and rhombic flap transposition. The results are discussed in terms of optimal deformation parameters, related to stress/strain localization, displacement discontinuities and wrinkling.

The Art of Rhinoplasty: Researching Technical and Cultural Foundations of Western World Rhinosurgery, from the Middle Ages to the Renaissance.

The analysis of the written sources allowed to follow the gradual development of every new technique in the field of rhinoplasty but also to understand the value of this surgery in those ancient times, highlighting a deep connection between traumatologic surgery of the nose and the development of modern "aesthetic and reconstructive" Rhinosurgery. Specifically, we analyzed the techniques described by less known surgeons to emphasize their cultural and surgical value. As a matter of fact, the descriptions offered by these authors clearly show the importance of rhinoplasty as a cardinal and autonomous practice since Antiquity, also clarifying the persistence and development of specific techniques for this surgical practice in the History of medicine. In the manuscript, the contributions of the Italian surgeons, such as Brancas and Vianeos families, are highlighted, demonstrating their influence on the progress of this surgical specialty in the Early Modern Age. Finally, we deepen the description of Gaspare Tagliacozzi's work, pointing out the topics and controversial debates arising from his techniques and innovations in "rhinosurgery" and also in the field of tissue transplantation, laying the foundations of modern Plastic Surgery.Level of Evidence V 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 Table of Contents or online Instructions to Authors www.springer.com/00266 .

Breast surgeons updating on the thresholds of COVID-19 era: results of a multicenter collaborative study evaluating the role of online videos and multimedia sources on breast surgeons education and training.

OBJECTIVE: Current trends show a rise of attention given to breast cancer patients' quality of life and the surgical reconstructive result. Along with this trend, surgical training quality and efficacy are gaining importance and innovative training methods such as online videos shared on social media portals, are becoming main updating tools. In hazardous times like COVID-19 pandemic nowadays, online communication becomes of vital importance and adaptation and innovation are fundamental to keep research and education alive. The authors aimed to investigate the role of video and multimedia sources on the daily activity and surgical training of a representative group of surgeons specifically dedicated to oncologic, oncoplastic and reconstructive breast surgeries. MATERIALS AND METHODS: A survey was produced and administered to 20 major Italian Breast Centers. Collected data were analyzed with Fisher's Exact Test. RESULTS: From October 2019 to March 2020, a total of 320 surveys were collected. Among the responders, there were 188 trainees (intern medical doctors and residents) and 110 faculty, 72% of them belonged to a plastic surgery environment, while 28% to general surgery environment. Almost all respondents have ever watched videos concerning breast surgery. CONCLUSIONS: The results of the study show how breast surgeons rely on videos and web platforms, mostly YouTube, when searching for training info about surgical procedures. Social media offer great opportunities for sharing knowledge and diffusion of new ideas but greater attention to their reliability is mandatory.

Vitiligo management: combination of surgical treatment and phototherapy under reflectance confocal microscopy monitoring.

OBJECTIVE: Vitiligo is a chronic acquired pigmentary skin disorder characterized by well-defined asymptomatic white macule as a result of loss of functional melanocytes in the epidermis. The psychological burden experienced by patients is of great interest and consequently research of the best medical approach is constantly developing. This review focuses on surgical approach and the combination of surgery and phototherapy. In addition, reflectance confocal microscopy (RCM) could be useful to discriminate between stable or active vitiligo and to evaluate efficacy of therapy. MATERIALS AND METHODS: We searched PubMed with the following keywords: (vitiligo[Title/Abstract]) AND therapy[Title/Abstract]) AND surgery[Title/Abstract]) AND phototherapy[Title/Abstract]) AND reflectance confocal microscopy[Title/Abstract]). RESULTS: To date, surgery is an effective therapeutic approach in stable vitiligo. Phototherapy, which is the most effective medical option, can improve the results obtained with surgery if performed in combination. Preliminary data show that RCM help physician in evaluating stability of vitiligo and is also useful to monitor clinical response. CONCLUSIONS: Vitiligo is a psychosocially debilitating disease requiring a multidisciplinary approach. Even if a standard management could not be stated, combination of surgery and phototherapy in stable vitiligo could lead to great improvement than monotherapy. RCM is a modern tool which should be used in order to perform surgery and phototherapy properly and to subsequently evaluate efficacy on a microscopic level.

Autologous fat transplantation for secondary breast reconstruction: our experience.

BACKGROUND: Autologous fat transplantation is used after breast reconstruction to improve the breast profile. There are a variety of different methods used for fat harvesting, preparation, and reinjection. This study describes the specific techniques we used in this series of autologous fat transplantations in breast reconstruction patients and reports their outcomes compared with other studies in the literature. PATIENTS AND METHODS: At the University Hospital of Parma between May 2012 and December 2016, we performed 53 autologous fat transplantations for secondary breast reconstruction patients with an average age of 49 years (range: 34-65 y). A tumescent fluid (NaCl, epinephrine, and a local anaesthetic) was injected, and the lipoaspirate was harvested using a closed aspiration-injection system connected to a 50 ml syringe, a 4 mm infiltration cannula, and a -650 mmHg vacuum. The average amount of lipoaspirate obtained was 100 ml (range: 50-200 ml). Centrifugation of the lipoaspirate (3000 rpm for 3 min) was performed to isolate the adipose tissue (average amount obtained, 80 ml; range: 30-180 ml). Under local anaesthesia, the retrograde injection of thin layers of fat graft in multiple tunnels was performed in the subcutaneous and/or subglandular planes. RESULTS: Average follow-up was six months. Comparable to other studies, our complication rate was 7.4% (n = 4/53) and included cyst formation at the injection site (n = 1/53) and hematoma at the donor site (n = 3/53). Repeat fat grafting was performed in 28.3% of patients (n = 15/53) due to fat graft resorption. CONCLUSIONS: Autologous fat transplantation is a useful procedure for correcting irregularities in the breast contour in secondary breast reconstruction.

How to isolate a ready-to-use adipose-derived stem cells pellet for clinical application.

Adipose-derived stem cells (ASCs) are multipotent mesenchymal stem cells (MSCs) that show definitive stem cell characteristics such as plastic adherence in culture, ability to maintain multipotency upon in vitro expansion, and self-renewal capacity. ASCs are particularly promising for use in regenerative medicine because they can be harvested easily from adipose tissue by standard liposuction, with minimal donor site morbidity. Since ASCs do not necessitate ex vivo expansion to obtain clinically significant cell numbers, it is critical to identify a standardized method that maximizes the number of ASCs collected. Based on current literature, there is no standardized method to isolate ASCs for clinical application. Furthermore, clinical studies involving ASCs often show inconsistencies in the reported results. Such studies often use research-derived isolation protocols, which are complex, time-consuming, and involve the use of chemical and animal-derived reagents. In this paper, we present an in-depth review of the available data on ASC isolation protocols. Moreover, we describe our isolation protocol that allows the collection of a ready-to-use ASC pellet for clinical application.

Oncoplastic breast surgery: comprehensive review.

Breast cancer is the most common female cancer in Western populations, affecting 12.5% of women, with 1.38 million patients per year. Breast-conserving surgery followed by postoperative radiotherapy replaced the radical and modified-radical procedures of Halsted and Patey as the standard of care for early-stage breast cancer once the overall and disease-free survival rates of breast-conserving surgery were demonstrated to be equivalent to those of mastectomy. However, excision of >20% of breast tissue, low or centrally located cancer, and large-sized breasts with various grades of breast ptosis, result a in unacceptable cosmetic outcomes. Oncoplastic breast surgery evolved from the breast-conserving surgery by broadening its general indication to achieve wider excision margins without compromising on the cosmetic outcomes. Thus, oncoplastic breast surgery can be defined as a tumor-specific immediate breast reconstruction method that applies aesthetically derived breast reduction techniques to the field of breast cancer surgery and allows for higher volume excision with no aesthetic compromise. However, contralateral breast symmetrization should be regarded as an intrinsic component of the oncoplastic surgery. The main procedures involved are volume-displacement or volume-replacement techniques, which depend on breast size and cancer size/location. Volume-displacement or reshaping procedures apply the plastic surgery principles to transpose a dermo-glandular flap of breast tissue into the defect site, while volume-replacement techniques use autologous tissues to replace the volume loss that follows tumor resection. Furthermore, these procedures are more complex and time-consuming than those involved in breast-conserving surgery. Based on current literature, the authors analyze the different techniques and indications of the oncoplastic breast surgery, determining its complication rate, in order to help both surgeons and their patients in the decision-making stage of breast reconstruction.

Quantitative difference of acute intraoperative expansion in various body regions.

OBJECTIVE: To investigate the efficacy of intraoperative sustained limited expansion (ISLE) by examining the ex vivo biomechanical properties of acutely expanded skin flaps. MATERIALS AND METHODS: Fourteen fresh male cadavers were tested. On both sides of each cadaver, a 4 × 10 cm, the laterally based flap was raised at the external auditory canal of the scalp and a 15 × 8 cm, the proximately based flap was raised at the lateral arm, anterior thorax, and lateral thigh. For each body region, a flap on one side was subject to acute intermittent expansion, while the corresponding contralateral flap served as the control. Both control and acutely expanded flaps underwent stepwise loading to assess their biomechanical properties. RESULTS: No dimensional changes were observed in the acutely expanded flaps when compared to the controls. Mean stiffness and strain values were not significantly different from control values for flaps raised on the scalp, but statistically significant changes were found for those on the lateral arm, anterior thorax and lateral thigh (p < 0.05). CONCLUSIONS: ISLE produced statistically significant biomechanical improvements when applied to the flaps raised on the arm, thorax and thigh, leading to a significant gain in compliance. We suggest that the ineffectiveness of ISLE, when applied to scalp flaps, was due to the inelasticity of the galea aponeurotica. Our findings confirm the general effectiveness of acute skin expansion as means of reducing wound-closure tension after large skin excisions; at least in regions other than the scalp.

Isolation of autologous adipose tissue-derived mesenchymal stem cells for bone repair.

INTRODUCTION: Adipose tissue represents an abundant and accessible source of adult stem cells that can differentiate into cells and tissues of mesodermal origin, including osteogenic cells. METHODS: This paper describes the procedure to obtain a 5-cm3 saline sample, containing the adipose-derived stem cells (ASCs) pellet, starting from lipoaspirate obtained from a conventional abdominal liposuction. RESULTS: A mean of 2.5×106 cells is isolated for each procedure; 35% (875000) of these are CD34+/CD45- cells, which express a subset of both positive (CD10, CD13, CD44, CD59, CD73, CD90, HLAABC) and negative (CD33, CD39, CD102, CD106, CD146, HLADR) cell-associated surface antigens, characterizing them as ASCs. CONCLUSIONS: This procedure is easy, effective, economic and safe. It allows the harvesting of a significant number of ASCs that are ready for one-step bony regenerative surgical procedures.

A comparative study of proliferation and hepatic differentiation of human adipose-derived stem cells.

Human adipose-derived stem cells possess a lot of stem cell characteristics, so they may be considered a source of stem cell population. On the basis of that, we have investigated the hepatic potential of adipose-derived stem cells, obtained from liposuction, following two differentiation protocols. In the first procedure, medium was supplemented with epidermal growth factor (EGF), basic fibroblast growth factor, hepatocyte growth factor (HGF) and nicotinamide; the second involved the addition of factors such as dexametasone, EGF, insulin-transferrin-sodium selenite, HGF, dimethyl sulfoxide and oncostatin. In parallel, we carried out our study in the Hep G2 cell line, as human hepatic differentiated in vitro model. Immunocytochemical analysis and RT-PCR were performed using hepatic markers to evaluate cell differentiation. DNA content, MTT test and carboxyl fluorescein succinimidyl ester staining were carried out to evaluate cell proliferation. We reported the evidence of basal hepatic marker in undifferentiated adipose-derived stem cells, which confirmed their multipotency. A strong expression of albumin and alpha-fetoprotein was observed in hepatic-induced adipose-derived stem cells following both differentiation procedures. Morphological aspects of the two types of hepatic adipose-derived stem cells were alike. Proliferation index suggested that the first differentiation procedure promoted better growth than the second. These preliminary findings suggest adipose-derived stem cells may be induced into hepatic lineage, and the most significant difference between the two standard differentiation procedures concerns proliferation rate. This aspect is to be considered when adipose-derived stem cells are employed in research and clinical studies.

In vitro polydeoxyribonucleotide effects on human pre-adipocytes.

OBJECTIVES: Adipose tissue is the most abundant and accessible source of adult stem cells. Human processed lipoaspirate contains pre-adipocytes that possess one of the a characteristic pathways of multipotent adult stem cells and are able to differentiate in vitro into mesenchymal and also neurogenic lineages. Because stem cells have great potential for use in tissue repair and regeneration, it would be significant to be able to obtain large amounts of these cells in vitro. As demonstrated previously, purine nucleosides and nucleotides mixtures can act as mitogens for several cell types. The aim of this study was to evaluate the effects of polydeoxyribonucleotides (PDRN), at appropriate concentrations, on human pre-adipocytes grown in a controlled medium, also using different passages, so as to investigate the relationship between the effect of this compound and cellular senescence, which is the phenomenon when normal diploid cells lose the ability to divide further. MATERIALS AND METHODS: Human pre-adipocytes were obtained by liposuction. Cells from different culture passages (P6 and P16) were treated with PDRN at different experimental times. Cell number was evaluated for each sample by direct counting after trypan blue treatment. DNA assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test were also carried out in all cases. RESULTS AND CONCLUSIONS: PDRN seemed to promote proliferation of human pre-adipocytes at both passages, but cell population growth increased in pre-adipocyte at P16, after 9 days as compared to control. Our data suggest that PDRN could act as a pre-adipocyte growth stimulator.

Characterization and induction of human pre-adipocytes.

Human processed lipoaspirate is a source of multipotent adult stem cells that are able to differentiate between mesenchymal and neurogenic lineage. We characterized PLA cells by cytometry and then they were cultured to induce differentiation into myogenic and neurogenic lineage. Lipoaspirates were digested with collagenase to obtain the pellet, which was labelled with anti-CD44, anti-CD45, and anti-CD90. We used BD FACS Calibur flow cytometer to acquire cellular events. Some cells were cultured at 37 degrees C and 5% CO(2) in neurogenic or myogenic medium and analysed by immunocytochemistry, using Neuron specific enolase, Vimentin, Glial fibrillary acidic protein, Tau, MAP2 to confirm neurogenic differentiation, MyoD1, Myosin heavy chain, Actin smooth muscle, vimentin to confirm myogenic differentiation. The cytometry results suggest that a part of the cells are of a mesenchymal origin, among which there are progenitor endothelial cells and leucocytes. Microscopy observation already reveals neuronal morphology and longitudinal multinucleated cells compared to control cells. Neurogenic cells only express NSE (early neuronal progenitor marker), but not GFAP, Tau, MAP2 (mature neuron and glial markers); myogenic cells are positive for MyoD1 and Myosin heavy chain. This demonstrates that lipoaspirate cells are capable of differentiating in vitro over a short period of time, and could be employed in biological and clinical research, like mesenchymal adult stem cells.

Characterization of multipotent cells from human adult hair follicles.

Recent works demonstrated the presence of a multipotent epithelial cell population in the bulge region of adult human hair follicles. These cells can be cultured in vitro, thus leading to the preparation of dermal-epidermal substitutes which are applicable in the treatment of burns and ulcers. We evaluated the main marker expression in cells obtained from stripped human hair follicles. A pool of hair follicles were incubated at 37 degrees C and 5% CO(2) in a growth medium. The cells were then labelled with antibodies (anti-CD34, anti-CD38, anti-CD45, anti-CD90, anti-CD133, anti-CD146) and analysed by cytometry. We also used hair follicles for immunohistochemical studies, employing antibodies such as CD34, Actin Smooth Muscle, Filaggrin, Desmin, Vimentin, Glial Fibrillary Acidic Protein, Ki-67, PanCytokeratin, CK15, CK19. The cytometry results revealed that a part of bulge cells were CD34+ (1-2%). CD34+ population comprises both large, CD45-, CD133-, CD146- cells and small, CD45+, CD133+, CD146+ cells. Thus, a part of CD34+ cells present a mature endothelial marker (CD146). An expression of the proliferation marker Ki-67 and the stem cell marker CD34 is present in the follicle bulge region. In conclusion, we observed that the stripped hair follicle has the same multipotent cell population as adult and fetal scalp hair follicles.

In vivo experimental testing and model identification of human scalp skin.

A comprehensive experimental/numerical procedure is formulated and validated for the in vivo characterization of the mechanical properties of human skin and the simulation of reconstructive surgery. The procedure uses in vivo experimental tests on undermined skin flaps, which can be performed during surgery, a numerical model formulated within the framework of nonlinear finite strain elasticity and a nonlinear parameter identification technique for the calibration of the model from indirect measurements. The procedure is applied to characterize the scalp skin tested in Raposio and Nordström (Skin Res. Technol. 4 (1998) 94). The skin is treated as a time independent, isotropic and hyperelastic membrane and the problem is solved through a finite element discretization. The study highlights that the model parameters can be determined with good accuracy using displacement measurements of a few points in the domain.

[Computer-based preoperative planning for breast reconstruction in the woman with unilateral breast hypoplasia]. / Pianificazione computerizzata per la ricostruzione mammaria in donne affette da ipoplasia mammaria unilaterale.

BACKGROUND: Aim of this paper is to describe a computer program which can provide objective and quantitative data useful for the selection of the proper implant in order to obtain the symmetry with the contralateral breast in case of unilateral breast reconstruction by tissue expansion, especially for the surgeon without experience or for the occasional operator. METHODS: Our C++ program provides the final implant volume using the measurements of the semi-circumference and projection of the contralateral breast performed on the supine patient. The aim is the symmetry of the two breasts. RESULTS: According to our experience in breast reconstruction by tissue expanders, this program allows non invasive and simple measurements of the breast volume, useful to obtain the mammary symmetry. CONCLUSIONS: In case of breast reconstruction by tissue expansion, the preoperative evaluation is usually based on the surgeon's experience and on empirical observations without knowing the correct volume to reach. For this reason our program is useful to know the necessary volume for breast reconstruction, and therefore it allows the surgeon to obtain a better plastic result.

[Experimental model for the evaluation of topical application of a solution to help myocutaneous flap transposition]. / Modèle expérimental pour l'évaluation d'une solution topique améliorant la survie des lambeaux myocutanés.

The aim of this article is the evaluation of the topical application of a solution of hydrogen peroxide (H2O2) 8% and dimethyl sulphoxide (DMSO) 50% in order to reduce ischaemic failure in random skin flaps. This study was performed using a rabbit model. Two parallel, cephalad-based para-midline random cutaneous flap (10 cm x 2.5 cm) were elevated and resutured in place on the dorsum of 40 New Zealand rabbits. The 80 flaps thus obtained were then randomly divided into one control group and three experimental groups of 20 flaps each. Flaps from the control group (group A) were topically treated with saline, while flaps from experimental group B were treated with H2O2 8%, flaps from experimental group C with DMSO 50%, and flaps from experimental group D with a solution of 50% DMSO + 8% H2O2. Each solution was topically applied, 20 cc per three times a day, on the flaps for seven days, starting on the immediate postoperative period. Transcutaneous oxygen tension (Ptc O2) measurements were carried out in all flaps, 72 h after flap elevation. The percentage of surviving skin area of each flap was determined by planimetry 7 days after flap elevation. The mean surviving area of the group A (control) flaps was 71%. The mean surviving area of the group B (H2O2-treated) flaps was 72%. The mean surviving area of the group C (DMSO-treated) flaps was 76%, and that of the group D (DMSO + H2O2-treated) flaps was 92%. While no statistically significant differences were found between the survival rates of both the flaps treated with H2O2 or DMSO alone and that of the control group, the mean surviving rate of the DMSO + H2O2 treated flaps (+20%) was statistically higher than that of the control flaps. Similarly, a statistically significant difference has been found between the mean Ptc O2 values of the DMSO + H2O2 flaps and those of the other three groups of flaps.