Positional obstructive sleep apnea and periodic limb movement during sleep: A large multi-center study.

Objectives: The relationships among positional obstructive sleep apnea (POSA), obstructive sleep apnea (OSA), and periodic limb movement during sleep (PLMS) are unclear. We analyzed these relationships according to OSA severity and explored the underlying mechanisms. Methods: We retrospectively reviewed 6,140 eligible participants who underwent full-night diagnostic polysomnography in four clinical centers over a period of 5 years with eventsynchronized analysis. The PLMS index (PLMI) and periodic limb movements with arousal index (PLMAI) were evaluated. The effects of POSA on the PLMI, PLMAI, and PLMS were analyzed according to OSA severity. Results: The mean PLMI and PLMAI, as well as PLMS prevalence, were significantly lower in those with severe OSA than in those with mild and moderate OSA. The mean PLMI was higher in mild OSA group than in control group. The mean PLMI (4.80 ± 12.71 vs. 2.59 ± 9.82 events/h, p < 0.001) and PLMAI (0.89 ± 3.66 vs. 0.53 ± 3.33 events/h, p < 0.001), and the prevalence of PLMS (11% vs. 5.3%, p < 0.001) were higher in patients with POSA than patients with non-POSA. This trend was particularly marked in severe OSA group (OR 1.55, 95%CI [1.07-2.27]) and less so in mild (OR 0.56, 95%CI [0.30-1.03]) and moderate (OR 1.82, 95%CI [0.99-3.34]) OSA groups. Conclusion: The POSA group tended to have a higher prevalence of PLMS, particularly in those with severe OSA. If PLMS is prominent, diagnosis and treatment of POSA and OSA may be considered.

Neutrophil extracellular traps promote ΔNp63+ basal cell hyperplasia in chronic rhinosinusitis.

BACKGROUND: Neutrophil extracellular traps (NETs) are observed in chronic rhinosinusitis (CRS), although their role remains unclear. OBJECTIVES: This study aimed to investigate the influence of NETs on the CRS epithelium. METHODS: Forty-five sinonasal biopsy specimens were immunofluorescence-stained to identify NETs and p63+ basal stem cells. Investigators treated human nasal epithelial cells with NETs and studied them with immunofluorescence staining, Western blotting, and quantitative real-time PCR. NET inhibitors were administered to a murine neutrophilic nasal polyp model. RESULTS: NETs existed in tissues in patients with CRS with nasal polyps, especially in noneosinophilic nasal polyp tissues. p63+ basal cell expression had a positive correlation with the release of NETs. NETs induced the expansion of Ki-67+p63+ cells. We found that ΔNp63, an isoform of p63, was mainly expressed in the nasal epithelium and controlled by NETs. Treatment with deoxyribonuclease (DNase) I or Sivelestat (NET inhibitors) prevented the overexpression of ΔNp63+ epithelial stem cells and reduced polyp formation. CONCLUSIONS: These results reveal that NETs are implicated in CRS pathogenesis via basal cell hyperplasia. This study suggests a novel possibility of treating CRS by targeting NETs.

Analysing the impact of body position shift on sleep architecture and stage transition: A comprehensive multidimensional study using event-synchronised polysomnography data.

Although understanding the physiological mechanisms of obstructive sleep apnea (OSA) is important for treating OSA, limited studies have examined OSA patients' sleep architecture at the epoch-by-epoch level and analysed the impact of sleep position and stage on OSA pathogenesis. The epoch-labelled polysomnogram was analysed multidimensionally to investigate the effect of sleep position on the sleep architecture and risk factors of apnea in patients with OSA. This retrospective multicentric case-control study reviewed full-night diagnostic polysomnography of 6983 participants. The difference in the proportion of time spent supine during non-rapid eye movement (NREM) and REM stages, and the mean duration of respiratory events per body position were evaluated. The frequency of sleep stage transition per body position shift type was computed. Further subgroup analysis was performed based on OSA severity and positional dependency. Supine time in patients with OSA varied across sleep stages, with lower proportions in N3 and REM, and shorter durations with severity. Patients with OSA spent less time in supine positions during N3 and REM, and experienced longer apnea events in both positions compared to the control group. The frequency of all sleep stage transitions increased with OSA severity and was higher among non-positional OSA than positional OSA and the control group, regardless of body position shift type. The sleep stage transition from N3 and REM to wakefulness was notably heightened during position shift. Understanding the sleep architecture of patients with OSA requires analysing various sleep characteristics including sleep position simultaneously, with future studies focusing on position detection to predict sleep stages and respiratory events.

Standardized image-based polysomnography database and deep learning algorithm for sleep-stage classification.

STUDY OBJECTIVES: Polysomnography (PSG) scoring is labor-intensive, subjective, and often ambiguous. Recently several deep learning (DL) models for automated sleep scoring have been developed, they are tied to a fixed amount of input channels and resolution. In this study, we constructed a standardized image-based PSG dataset in order to overcome the heterogeneity of raw signal data obtained from various PSG devices and various sleep laboratory environments. METHODS: All individually exported European data format files containing raw signals were converted into images with an annotation file, which contained the demographics, diagnoses, and sleep statistics. An image-based DL model for automatic sleep staging was developed, compared with a signal-based model, and validated in an external dataset. RESULTS: We constructed 10253 image-based PSG datasets using a standardized format. Among these, 7745 diagnostic PSG data were used to develop our DL model. The DL model using the image dataset showed similar performance to the signal-based dataset for the same subject. The overall DL accuracy was greater than 80%, even with severe obstructive sleep apnea. Moreover, for the first time, we showed explainable DL in the field of sleep medicine as visualized key inference regions using Eigen-class activation maps. Furthermore, when a DL model for sleep scoring performs external validation, we achieved a relatively good performance. CONCLUSIONS: Our main contribution demonstrates the availability of a standardized image-based dataset, and highlights that changing the data sampling rate or number of sensors may not require retraining, although performance decreases slightly as the number of sensors decreases.

Protein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development.

Chronic colonic inflammation is a feature of cancer and is strongly associated with tumorigenesis, but its underlying molecular mechanisms remain poorly understood. Inflammatory conditions increased ITF2 and p65 expression both ex vivo and in vivo, and ITF2 and p65 showed positive correlations. p65 overexpression stabilized ITF2 protein levels by interfering with the binding of Parkin to ITF2. More specifically, the C-terminus of p65 binds to the N-terminus of ITF2 and inhibits ubiquitination, thereby promoting ITF2 stabilization. Parkin acts as a E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 facilitated nuclear translocation of p65 and thus increased colitis-associated cancer tumorigenesis, which was mediated by Azoxymethane/Dextran sulfate sodium or dextran sulfate sodium. Upregulated ITF2 expression was lost in carcinoma tissues of colitis-associated cancer patients, whereas p65 expression much more increased in both dysplastic and carcinoma regions. Therefore, these findings indicate a critical role for ITF2 in the repression of colitis-associated cancer progression and ITF2 would be an attractive target against inflammatory diseases including colitis-associated cancer.

Surface Active Salivary Metabolites Indicate Oxidative Stress and Inflammation in Obstructive Sleep Apnea.

PURPOSE: Obstructive sleep apnea (OSA), a highly prevalent and potentially serious sleep disorder, requires effective screening tools. Saliva is a useful biological fluid with various metabolites that might also influence upper airway patency by affecting surface tension in the upper airway. However, little is known about the composition and role of salivary metabolites in OSA. Therefore, we investigated the metabolomics signature in saliva from the OSA patients and evaluated the associations between identified metabolites and salivary surface tension. METHODS: We studied 68 subjects who visited sleep clinic due to the symptoms of OSA. All underwent full-night in-lab polysomnography. Patients with apnea-hypopnea index (AHI) < 10 were classified to the control, and those with AHI ≥ 10 were the OSA groups. Saliva samples were collected before and after sleep. The centrifuged saliva samples were analyzed by liquid chromatography with high-resolution mass spectrometry (ultra-performance liquid chromatography-tandem mass spectrometry; UPLC-MS/MS). Differentially expressed salivary metabolites were identified using open source software (XCMS) and Compound Discoverer 2.1. Metabolite set enrichment analysis (MSEA) was performed using MetaboAnalyst 5.0. The surface tension of the saliva samples was determined by the pendant drop method. RESULTS: Three human-derived metabolites (1-palmitoyl-2-[5-hydroxyl-8-oxo-6-octenoyl]-sn-glycerol-3-phosphatidylcholine [PHOOA-PC], 1-palmitoyl-2-[5-keto-8-oxo-6-octenoyl]-sn-glycerol-3-phosphatidylcholine [KPOO-PC], and 9-nitrooleate) were significantly upregulated in the after-sleep salivary samples from the OSA patients compared to the control group samples. Among the candidate metabolites, only PHOOA-PC was correlated with the AHI. In OSA samples, salivary surface tension decreased after sleep. The differences in surface tension were negatively correlated with PHOOA-PC and 9-nitrooleate concentrations. Furthermore, MSEA revealed that arachidonic acid-related metabolism pathways were upregulated in the after-sleep samples from the OSA group. CONCLUSIONS: This study revealed that salivary PHOOA-PC was correlated positively with the AHI and negatively with salivary surface tension in the OSA group. Salivary metabolomic analysis may improve our understanding of upper airway dynamics and provide new insights into novel biomarkers and therapeutic targets in OSA.

Modified Keystone Perforator Island Flap Techniques for Small- to Moderate-Sized Scalp and Forehead Defect Coverage: A Retrospective Observational Study.

We aimed to demonstrate the effective application of keystone perforator island flap (KPIF) in scalp and forehead reconstruction by demonstrating the authors' experience with modified KPIF reconstruction for small- to moderate-sized scalp and forehead defects. Twelve patients who underwent modified KPIF reconstruction of the scalp and forehead from September 2020 to July 2022 were enrolled in this study. In addition, we retrospectively reviewed and evaluated the patient's medical records and clinical photographs. All defects (size range, 2 cm × 2 cm to 3 cm × 7 cm) were successfully covered using four modified KPIF techniques (hemi-KPIF, Sydney Melanoma Unit Modification KPIF, omega variation closure KPIF, and modified type II KPIF) with ancillary procedures (additional skin grafts and local flaps). All flaps (size range, 3.5 cm × 4 cm to 7 cm × 16 cm) fully survived, and only one patient developed marginal maceration that healed with conservative management. Furthermore, through the final scar evaluation with the patient satisfaction survey and Harris 4-stage scale, all patients were satisfied with their favorable outcomes at the average final follow-up period of 7.66 ± 2.14 months. The study showed that the KPIF technique with appropriate modifications is an excellent reconstructive modality for covering scalp and forehead defects.

Effects of Neutrophil and Eosinophil Extracellular Trap Formation on Refractoriness in Chronic Rhinosinusitis With Nasal Polyps.

PURPOSE: This study investigated the clinical implications of neutrophil extracellular trap (NET) formation (NETosis) and eosinophil extracellular trap (EET) formation (EETosis) regarding refractoriness in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). METHODS: Nasal polyp specimens were obtained from 117 patients with CRSwNP who received endoscopic sinus surgery. Disease control status at postoperative 1 year was assessed. Refractory cases were defined as partly controlled or uncontrolled cases according to the EPOS 2020 guidelines. NETosis and EETosis were evaluated through immunofluorescence staining (citrullinated histone H3-human neutrophil elastase and citrullinated histone-galectin-10, respectively) followed by manual counting. The z-score of NET and EET counts was used to define the following four groups: low extracellular trap formation (ETosis), NETosis-predominant, EETosis-predominant, and high-ETosis. RESULTS: The refractory and non-refractory groups showed significant differences in the tissue eosinophil count (P = 0.005) and EET count (P = 0.029). The tissue neutrophil count and the NET/neutrophil ratio were significantly different between the refractory and non-refractory groups of patients with neutrophilic CRS (P = 0.045, 0.031, respectively). Refractoriness significantly differed among the low-ETosis (30.77%), NETosis-predominant (47.83%), EETosis-predominant (56.67%), and high-ETosis (83.33%) groups (P = 0.005). CONCLUSIONS: The results of this study suggest that tissue Eosinophilia and EETosis may play a prognostic role, primarily in CRSwNP and thattissue neutrophilia and NETosis can play as prognostic biomarkers in neutrophilic CRSwNP.

Modified Keystone Perforator Island Flap for Tension-Reducing Coverage of Axillary Defects Secondary to Radical Excision of Chronic Inflammatory Skin Lesions: A Retrospective Case Series.

Axillary defect coverage is often challenging after radical excision of chronic inflammatory skin lesions, such as complicated epidermoid cysts and hidradenitis suppurativa. This retrospective case series aims to demonstrate our experience with axillary reconstruction using the modified keystone perforator island flap (KPIF) technique, emphasizing its tension-reducing effects. All patients who presented for axillary reconstruction after radical excision of chronic inflammatory skin lesions between May 2019 and December 2020 were identified using the medical record database. Eleven patients ranging in age from 17 to 71 years underwent modified KPIF axillary reconstruction. Four types of modifications (modified type II KPIF, omega variation closure, Sydney melanoma unit modification, and hemi-KPIF) were used. All defects (size range, 2.5 × 3 cm2 to 8 × 13 cm2) were successfully covered using these modified KPIF techniques. All flaps (size range, 3.5 × 3.5 cm2 to 11 × 30 cm2) fully survived without complications. All patients exhibited favorable functional outcomes, and no cases of recurrence or limitations in joint range of motion were observed during the follow-up period (range, 4-5 months). Modified KPIF techniques may represent a reliable, effective alternative reconstructive modality for managing axillary defects.

Modified Mini-Keystone Flaps for Coverage of Tiny Volar Pulp Defects of the Fingertips in Cases with Missing Amputation Skin Stumps: A Retrospective Study.

This study aimed to demonstrate the expanding versatility of keystone flap reconstruction in fingertips. Fifteen patients who underwent the modified mini-keystone flap reconstruction for tiny volar pulp defects of the fingertip between September 2020 and February 2021 were included in this study (average age: 43.4 ± 13.52 years, range: 19-61 years). Patient data were retrospectively collected from their medical records. The two-point discrimination test was used to evaluate the degree of sensory recovery. All defects were successfully covered with the modified mini-keystone flap. The defect sizes ranged from 0.5 cm × 1 cm to 1.2 cm × 2.0 cm, and the flap sizes ranged from 0.7 cm × 1.5 cm to 1.5 cm × 3.0 cm. Although one patient showed a small distal margin maceration, all flaps survived fully. The overall outcomes were favorable at the mean follow-up period of 5.73 ± 0.79 months. We suggest that the modified mini-keystone flap technique is a promising alternative modality for covering tiny volar pulp defects of the fingertip, with few complications and favorable outcomes.

Loop and Bridge Conformations of ABA Triblock Comb Copolymers: A Conformational Assessment for Molecular Composites.

We computationally investigate the conformational behavior, "bridging" chain, between different the phase-separated domains vs "looping" chain on the same domain, for two chain architectures of ABA triblock copolymers, one with a linear architecture (L-TBC) and the other with comb architecture (C-TBC) at various segregation regimes using dissipative particle dynamics (DPD) simulations. The power-law relation between the bridge fraction (Φ) and the interaction parameter (χ) for C-TBC is found to be Φ∼χ-1.6 in the vicinity of the order-disorder transition (χODT), indicating a drastic conversion from the bridge to the loop conformation. When χ further increases, the bridge-loop conversions slow down to have the power law, Φ∼χ-0.18, approaching the theoretical power law Φ∼χ-1/9 predicted in the strong segregation limit. The conformational assessment conducted in the present study can provide a strategy of designing optimal material and processing conditions for triblock copolymer either with linear or comb architecture to be used for thermoplastic elastomer or molecular nanocomposites.

Optimizing Chain Topology of Bottle Brush Copolymer for Promoting the Disorder-to-Order Transition.

The order-disorder transitions (ODT) of core-shell bottle brush copolymer and its structural isomers were investigated by dissipative particle dynamics simulations and theoretically by random phase approximation. Introducing a chain topology parameter λ which parametrizes linking points between M diblock chains each with N monomers, the degree of incompatibility at ODT ((χN)ODT; χ being the Flory-Huggins interaction parameter between constituent monomers) was predicted as a function of chain topology parameter (λ) and the number of linked diblock chains per bottle brush copolymer (M). It was found that there exists an optimal chain topology about λ at which (χN)ODT gets a minimum while the domain spacing remains nearly unchanged. The prediction provides a theoretical guideline for designing an optimal copolymer architecture capable of forming sub-10 nm periodic structures even with non-high χ components.

DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition.

BACKGROUND: Diesel exhaust particles (DEPs) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear. OBJECTIVE: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model. METHODS: Gene set enrichment and weighted gene coexpression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal people or patients with chronic rhinosinusitis with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite, followed by zinc finger E-box-binding homeobox (ZEB)2 small hairpin RNA delivery. RESULTS: Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells. Similarly, DEP-exposed human nasal epithelial cells exhibited EMT characteristics, which were dependent on ZEB2 expression. Human nasal epithelial cells derived from patients with chronic rhinosinusitis presented more prominent EMT features after DEP treatment, when compared with those from control subjects and patients with NPs. Coexposure to DEP and house dust mite synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice. CONCLUSIONS: Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.

Matrix Stiffening Enhances DNCB-Induced IL-6 Secretion in Keratinocytes Through Activation of ERK and PI3K/Akt Pathway.

Matrix stiffness, a critical physical property of the cellular environment, is implicated in epidermal homeostasis. In particular, matrix stiffening during the pathological progression of skin diseases appears to contribute to cellular responses of keratinocytes. However, it has not yet elucidated the molecular mechanism underlying matrix-stiffness-mediated signaling in coordination with chemical stimuli during inflammation and its effect on proinflammatory cytokine production. In this study, we demonstrated that keratinocytes adapt to matrix stiffening by increasing cell-matrix adhesion via actin cytoskeleton remodeling. Specifically, mechanosensing and signal transduction are coupled with chemical stimuli to regulate cytokine production, and interleukin-6 (IL-6) production is elevated in keratinocytes on stiffer substrates in response to 2,4-dinitrochlorobenzene. We demonstrated that ß1 integrin and focal adhesion kinase (FAK) expression were enhanced with increasing stiffness and activation of ERK and the PI3K/Akt pathway was involved in stiffening-mediated IL-6 production. Collectively, our results reveal the critical role of matrix stiffening in modulating the proinflammatory response of keratinocytes, with important clinical implications for skin diseases accompanied by pathological matrix stiffening.

Enhanced eosinophil-mediated inflammation associated with antibody and complement-dependent pneumonic insults in critical COVID-19.

Despite the worldwide effect of the coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased T helper (Th)2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation are associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of Fcγ receptor (FcγR) signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.

Early postoperative treatment of mastectomy scars using a fractional carbon dioxide laser: a randomized, controlled, split-scar, blinded study.

BACKGROUND: Mastectomy leaves unsightly scarring, which can be distressing to patients. Laser therapy for scar prevention has been consistently emphasized in recent studies showing that several types of lasers, including fractional ablation lasers, are effective for reducing scar formation. Nonetheless, there are few studies evaluating the therapeutic efficacy of ablative CO2 fractional lasers (ACFLs). METHODS: This study had a randomized, comparative, prospective, split-scar design with blinded evaluation of mastectomy scars. Fifteen patients with mastectomy scars were treated using an ACFL. Half of each scar was randomized to "A," while the other side was allocated to group "B." Laser treatment was conducted randomly. Scars were assessed using digital photographs of the scar and Vancouver scar scale (VSS) scores. Histological assessments were also done. RESULTS: The mean VSS scores were 2.20±1.28 for the treatment side and 2.96±1.40 for the control side. There was a significant difference in the VSS score between the treatment side and the control side (P=0.002). The mean visual analog scale (VAS) scores were 4.13±1.36 for the treatment side and 4.67±1.53 for the control side. There was a significant difference in VAS score between the treatment side and the control side (P=0.02). CONCLUSIONS: This study demonstrated that early scar treatment using an ACFL significantly improved the clinical results of the treatment compared to the untreated scar, and this difference was associated with patient satisfaction.

Urine 5-Eicosatetraenoic Acids as Diagnostic Markers for Obstructive Sleep Apnea.

Early detection of obstructive sleep apnea (OSA) is needed to reduce cardiovascular sequelae and mortality. Full-night polysomnography has been used for diagnosing OSA, but it is too expensive and inconvenient for patients to handle. Metabolome-wide analyses were performed to find and validate surrogate markers for OSA. We further investigated the mechanism underlying hypoxic induction of the markers in human cells and mice. Arachidonic acid derivatives 5-HETE and 5-oxoETE were detected in urine samples. The levels (mean ± SD, ng per mg creatinine) of 5-HETE and 5-oxoETE were 56.4 ± 26.2 and 46.9 ± 18.4 in OSA patients, respectively, which were significantly higher than those in controls (22.5 ± 4.6 and 18.7 ± 3.6). Both levels correlated with the apnea-hypopnea index and the lowest oxygen saturation on polysomnography. After the treatment with the continuous positive airway pressure, the metabolite levels were significantly reduced compared with those before the treatment. In human mononuclear cells subjected to intermittent hypoxia, 5-HETE and 5-oxoETE productions were induced by hypoxia-inducible factor 1 and glutathione peroxidase. When mice were exposed to intermittent hypoxia, 5-HETE and 5-oxoETE were excreted more in urine. They were identified and verified as new OSA markers reflecting hypoxic stress. The OSA markers could be used for OSA diagnosis and therapeutic evaluation.

A comparative study for tension-reducing effect of Type I and Type II keystone perforator island flap in the human back.

The keystone perforator island flap (KPIF) is popular in reconstructive surgery. However, despite its versatility, its biomechanical effectiveness is unclear. We present our experience of KPIF reconstruction in the human back and evaluate the tension-reducing effect of the KPIF. Between September 2019 and August 2020, 17 patients (51.82 ± 14.72 years) underwent KPIF reconstruction for back defects. In all cases, we measured wound tension at the defect and donor sites before and after KPIF reconstruction using a tensiometer. All defects occurred after complete excision of complicated epidermoid cysts and debridement of surrounding tissues. The defects were successfully covered with Type IIA KPIFs. All flaps survived, and there were no significant postoperative complications. The mean "tension change at the defect after Type I KPIF" and "tension change at the defect after Type II KPIF" were - 2.97 ± 0.22 N and - 5.59 ± 0.41 N, respectively, (P < 0.001). The mean "rate of tension change at the defect after Type I KPIF" and "rate of tension change at the defect after Type II KPIF" were - 36.54 ± 1.89% and - 67.98 ± 1.63%, respectively, (P < 0.001). Our findings confirm the stepwise tension-reducing effect of KPIF and clarify the biomechanics of this flap.