ABSTRACT
Background and Objectives@#The purpose of this study was to analyze the survival data of salivary gland cancer (SGCs) patients to construct machine learning and deep learning models that can predict survival and use them to stratify SGC patients according to risk estimate.Subjects and Method We retrospectively analyzed the clinicopathologic data from 460 patients with SGCs from 2006 to 2018. @*Results@#In Cox proportional hazard (CPH) model, pM, stage, lymphovascular invasion, lymph node ratio, and age exhibited significant correlation with patient’s survival. In the CPH model, the c-index value for the training set was 0.85, and that for the test set was 0.81. In the Random Survival Forest model, the c-index value for the training set was 0.86, and that for the test set was 0.82. Stage and age exhibited high importance in both the Random Survival Forest and CPH models. In the deep learning-based model, the c-index value was 0.72 for the training set and 0.72 for the test set. Among the three models mentioned above, the Random Survival Forest model exhibited the highest performance in predicting the survival of SGC patients. @*Conclusion@#A survival prediction model using machine learning techniques showed acceptable performance in predicting the survival of SGC patients. Although large-scale clinical and multicenter studies should be conducted to establish more powerful predictive model, we expect that individualized treatment can be realized according to risk stratification made by the machine learning model.
ABSTRACT
Background/Objectives@#This study analyzed the prognostic significance of clinico-pathologic factors including comprehensive nodal factors in parotid gland cancers (PGCs) patients and constructed a survival prediction model for PGCs patients using machine learning techniques.Materials & Methods: A total of 131 PGCs patients were enrolled in the study. @*Results@#There were 19 cases (14.5%) of lymph nodes (LNs) at the lower neck level and 43 cases (32.8%) involved multiple level LNs metastases. There were 2 cases (1.5%) of metastases to the contralateral LNs. Intraparotid LNs metastasis was observed in 6 cases (4.6%) and extranodal extension (ENE) findings were observed in 35 cases (26.7%). Lymphovascular invasion (LVI) and perineural invasion findings were observed in 42 cases (32.1%) and 49 cases (37.4%), respectively. Machine learning prediction models were constructed using clinico-pathologic factors including comprehensive nodal factors and Decision Tree and Stacking model showed the highest accuracy at 74% and 70% for predicting patient’s survival. @*Conclusion@#Lower level LNs metastasis and LNR have important prognostic significance for predicting disease recurrence and survival in PGCs patients. These two factors were used as important features for constructing machine learning prediction model. Our machine learning model could predict PGCs patient’s survival with a considerable level of accuracy.
ABSTRACT
Background and Objectives@#With the introduction of sialendoscopy, minimal invasive surgery has become possible for the removal of sialoliths, although sialendoscopic removal of parotid stones remains a surgical challenge. Sialendoscopic stone removal can be differently applied according to the location and size of stones. This study was conducted to evaluate the surgical outcomes of sialaendoscopic stone removal and to provide a strategy for choosing an adequate surgical approach according to the characteristics of parotid stones.Subjects and Method A retrospective study was conducted of 43 patients with parotid sialolithiasis who were treated by sialendoscopic stone removal between March 2017 and January 2021. Surgical techniques were classified into sialendoscopy alone (SA), sialendoscopy-assisted transoral approach (STO), and sialendoscopy-combined retroauricular approach (SRA). The parotid gland stones were categorized by size, location, and multiplicity. @*Results@#Of the 43 patients, 13 patients underwent SA, 10 received STO, and 20 were treated with different SRA approaches. The SRA approaches included three distal, seven proximal, and ten intraglandular stone removal cases. The success rate of stone removal was 92% (12 cases) by SA, 90% (9 cases) by STO, and 100% (20 cases) by SRA. In cases of SA and STO, all patients had distant stones except for one who had proximal stones. Postoperative complications including pain, swelling, wound dehiscence, sialocele, duct stricture, and facial palsy mainly occurred in cases treated with SRAs. @*Conclusion@#Appropriate use of various sialendoscopy-assisted approaches is mandatory to preserve the gland and minimize surgical complications in patients with different features of parotid gland stones.
ABSTRACT
There are several lasers available for office-based or suspension microlaryngoscopy laser procedures in the treatment of laryngeal diseases. Each has advantages and disadvantages given the depth of penetration per unit of power, absorption in water, spectral absorption characteristics, mode of delivery, safety, and cost. It is important to note that while the proper selection of indication of treatment based on a laser wavelength is critical, of equal importance is selecting the appropriate power setting, focal length (or spot size), and time of exposure. The photoangiolytic lasers precisely target hemoglobin within the microcirculation of the highly vascularized tissue and may have better hemostatic effects and preservation of surrounding normal tissue than the CO2 laser. Although the choice of laser is purely theoretical and cannot be accurately concluded which parameters of laser (wattage and pulse width) were best to use, photoangiolytic laser surgery is safe and effective for specific laryngeal lesions. In this review, indications for photoangiolytic laser procedures for various laryngeal diseases, laser settings and surgical techniques for specific laryngeal lesions including sulcus vocalis, laryngeal dysplasia, and recurrent respiratory papillomatosis will be introduced. Pros and cons of in-office laser surgery using photoangiolytic laser and flexible CO2 laser will also be addressed.
ABSTRACT
There are several lasers available for office-based or suspension microlaryngoscopy laser procedures in the treatment of laryngeal diseases. Each has advantages and disadvantages given the depth of penetration per unit of power, absorption in water, spectral absorption characteristics, mode of delivery, safety, and cost. It is important to note that while the proper selection of indication of treatment based on a laser wavelength is critical, of equal importance is selecting the appropriate power setting, focal length (or spot size), and time of exposure. The photoangiolytic lasers precisely target hemoglobin within the microcirculation of the highly vascularized tissue and may have better hemostatic effects and preservation of surrounding normal tissue than the CO2 laser. Although the choice of laser is purely theoretical and cannot be accurately concluded which parameters of laser (wattage and pulse width) were best to use, photoangiolytic laser surgery is safe and effective for specific laryngeal lesions. In this review, indications for photoangiolytic laser procedures for various laryngeal diseases, laser settings and surgical techniques for specific laryngeal lesions including sulcus vocalis, laryngeal dysplasia, and recurrent respiratory papillomatosis will be introduced. Pros and cons of in-office laser surgery using photoangiolytic laser and flexible CO2 laser will also be addressed.
ABSTRACT
Objectives@#. In subset of patients, acinic cell carcinoma (AcCC) exhibits aggressive features such as recurrence, distant metastasis, and mortality. This study aimed to investigate clinicopathologic factors influencing patients’ prognosis and to identify adverse features predictive of an unfavorable prognosis. @*Methods@#. Between January 2000 and December 2016, 59 patients with AcCC were enrolled in this study. @*Results@#. The patients’ 5-year overall survival rate was 93.3%, and their 5-year recurrence-free survival rate was 80.5%. During the study period, recurrence occurred in 10 patients. The mean time to recurrence after surgery was 26 months (range, 5–60 months). During the study period, three patients died from the disease. Univariate analysis showed that sex, surgical extent, extranodal extension, T classification, and TNM stage were significantly associated with disease recurrence. Multivariate analysis showed that, among the clinicopathologic factors included in the analysis, only TNM stage displayed a statistically significant correlation with disease recurrence. @*Conclusion@#. Surgical treatment alone yielded good results for AcCC, and additional treatment did not affect the recurrence-free survival rate or the overall survival rate, even when the resection margin was less than 1 mm. Other pathologic factors did not show prognostic significance for disease recurrence or death.
ABSTRACT
BACKGROUND@#Hepatocyte growth factor (HGF) has been shown to facilitate vocal fold (VF) wound healing. This study was undertaken to determine whether the therapeutic efficacy of HGF could be enhanced by applying it in hyaluronic acid and alginate (HA/ALG) composite hydrogels into VFs after injury in a rabbit model. @*METHODS@#HGF was loaded into HA/ALG composite hydrogel (HGF–HA/ALG) and its in vitro release profile was evaluated. In addition, HGF–HA/ALG was injected into the VFs of rabbits immediately after direct injury and HGF or PBS was injected in the same manner into control groups. Macroscopic features were observed by endoscopy at 3 months postinjury. Functional analyses including mucosal waves of VFs and viscoelastic properties were performed by kymography following high-speed digital imaging and rheometer. Histopathological and immunohistochemical evaluations were also conducted on VFs. @*RESULTS@#HGF release from HGF–HA/ALG was sustained for up to 3 weeks. Rabbits treated with HGF–HA/ALG showed improved mucosal vibrations and VF viscoelastic properties as compared with the PBS and HGF controls.Histopathological staining revealed HGF–HA/ALG treated VFs showed less fibrosis than PBS and HGF controls, and immunohistochemical analysis demonstrated amounts of type I collagen and fibronectin were lower in HGF–HA/ALG treated animals than in PBS and HGF controls at 3 months post-injury. @*CONCLUSION@#HGF containing HA/ALG hydrogel enhanced healing in our rabbit model of VF injury.
ABSTRACT
Background@#Before publication of the new classification system named the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) in 2018, there was no standard classification for salivary gland lesions obtained by fine-needle aspiration (FNA). We therefore aimed to evaluate the diagnostic utility of this system by retrospectively reviewing FNA samples using the MSRSGC and to determine their risk of developing into neoplasms and becoming malignant. @*Methods@#Retrospective slide review and classification of salivary gland FNAs obtained over a 6-year period (2013–2018) at a single center were performed by two pathologists. The risks of neoplasm and malignancy for each category also were calculated. @*Results@#This study surveyed 374 FNAs (371 patients) performed over a six-year period and selected 148 cases that included documented surgical follow-up (39.6%). Among the surgically treated cases, the distributions of FNA categories were as follows: non-diagnostic (ND; 16.9%), non-neoplastic (NN; 2.7%), atypia of undetermined significance (AUS; 3.4%), benign (BN; 54.7%), salivary gland neoplasm of uncertain malignant potential (SUMP; 10.1%), suspicious for malignancy (SM; 6.8%), and malignant (M; 5.4%). The risk of malignancy (ROM) was 24.0% for ND, 0% for NN, 40.0% for AUS, 2.5% for BN, 46.7% for SUMP, 100% for SM, and 87.5% for M. The overall diagnostic accuracy was 95.9% (142/148 cases). @*Conclusions@#The newly proposed MSRSGC appears to be a reliable system for classification of salivary gland lesions according to the associated ROM.
ABSTRACT
The Korean Society of Laryngology, Phoniatrics and Logopedics appointed a task force to establish clinical practice guidelines for the management of unilateral vocal fold paralysis (UVFP). These guidelines cover a comprehensive range of management-related factors, including the diagnosis and treatment of UVFP, and provide in-depth information based on current, up-to-date knowledge. Detailed evidence profiles are provided for each recommendation. The CORE databases, including OVID Medline, Embase, the Cochrane Library, and KoreaMed, were searched to identify all relevant papers, using a predefined search strategy. When insufficient evidence existed, expert opinions and Delphi questionnaires were used to fill the evidence gap. The committee developed 16 evidence-based recommendations in six categories: initial evaluation (R1–4), spontaneous recovery (R5), medical treatment (R6), surgical treatment (R7–14), voice therapy (R15), and aspiration prevention (R16). The goal of these guidelines is to assist general otolaryngologists and speech-language pathologists who are primarily responsible for treating patients with UVFP. These guidelines are also intended to facilitate understanding of the condition among other health-care providers, including primary care physicians, nurses, and policy-makers.
ABSTRACT
BACKGROUND@#Hepatocyte growth factor (HGF) has been shown to facilitate vocal fold (VF) wound healing. This study was undertaken to determine whether the therapeutic efficacy of HGF could be enhanced by applying it in hyaluronic acid and alginate (HA/ALG) composite hydrogels into VFs after injury in a rabbit model. @*METHODS@#HGF was loaded into HA/ALG composite hydrogel (HGF–HA/ALG) and its in vitro release profile was evaluated. In addition, HGF–HA/ALG was injected into the VFs of rabbits immediately after direct injury and HGF or PBS was injected in the same manner into control groups. Macroscopic features were observed by endoscopy at 3 months postinjury. Functional analyses including mucosal waves of VFs and viscoelastic properties were performed by kymography following high-speed digital imaging and rheometer. Histopathological and immunohistochemical evaluations were also conducted on VFs. @*RESULTS@#HGF release from HGF–HA/ALG was sustained for up to 3 weeks. Rabbits treated with HGF–HA/ALG showed improved mucosal vibrations and VF viscoelastic properties as compared with the PBS and HGF controls.Histopathological staining revealed HGF–HA/ALG treated VFs showed less fibrosis than PBS and HGF controls, and immunohistochemical analysis demonstrated amounts of type I collagen and fibronectin were lower in HGF–HA/ALG treated animals than in PBS and HGF controls at 3 months post-injury. @*CONCLUSION@#HGF containing HA/ALG hydrogel enhanced healing in our rabbit model of VF injury.
ABSTRACT
Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm first described and often encountered in the pleura. It has also been documented in a variety of extrapleural sites including the abdominal cavity, respiratory tract, lung, breast, and rarely in the head and neck region. SFT in the hard palate is an extremely unusual location. We present a rare case of SFT that presented as a palate mass, which was suggested as a mesenchymal cell neoplasm by preoperative punch biopsy, and finally diagnosed as STF after successful surgical excision. SFTs should be considered as a differential diagnosis of palate benign tumor when preoperative pathologic findings show mesenchymal neoplasms of fibroblastic or myofibroblastic origin. Possible malignant variants should be distinguished by evaluating the histological parameters, including high cellularity, frequent mitotic activity, nuclear pleomorphism, and presence of necrosis.
ABSTRACT
Korean Society of Thyroid-Head and Neck Surgery appointed a Task Force to provide guidance on the implementation of a surgical treatment of oral cancer. MEDLINE databases were searched for articles on subjects related to “surgical management of oral cancer” published in English. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. The quality of evidence was rated with use RoBANS (Risk of Bias Assessment Tool for Nonrandomized Studies) and AMSTAR (A Measurement Tool to Assess the Methodological Quality of Systematic Reviews). Evidence-based recommendations for practice were ranked according to the American College of Physicians grading system. Additional directives are provided as expert opinions and Delphi questionnaire when insufficient evidence existed. The Committee developed 68 evidence-based recommendations in 34 categories intended to assist clinicians and patients and counselors, and health policy-makers. Proper surgical treatment selection for oral cancer, which is directed by patient- and subsite-specific factors, remains the greatest predictor of successful treatment outcomes. These guidelines are intended for use in conjunction with the individual patient's treatment goals.
Subject(s)
Humans , Advisory Committees , Bias , Carcinoma, Squamous Cell , Counseling , Expert Testimony , Mouth Neoplasms , Neck , Republic of KoreaABSTRACT
Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm first described and often encountered in the pleura. It has also been documented in a variety of extrapleural sites including the abdominal cavity, respiratory tract, lung, breast, and rarely in the head and neck region. SFT in the hard palate is an extremely unusual location. We present a rare case of SFT that presented as a palate mass, which was suggested as a mesenchymal cell neoplasm by preoperative punch biopsy, and finally diagnosed as STF after successful surgical excision. SFTs should be considered as a differential diagnosis of palate benign tumor when preoperative pathologic findings show mesenchymal neoplasms of fibroblastic or myofibroblastic origin. Possible malignant variants should be distinguished by evaluating the histological parameters, including high cellularity, frequent mitotic activity, nuclear pleomorphism, and presence of necrosis.
Subject(s)
Abdominal Cavity , Biopsy , Breast , Diagnosis, Differential , Fibroblasts , Head , Lung , Myofibroblasts , Neck , Necrosis , Palate , Palate, Hard , Pleura , Respiratory System , Solitary Fibrous TumorsABSTRACT
Mucosal bridges of vocal fold have been described as a parallel band to vocal folds with the presence of sulcus vocalis. However, the type of mucosal bridge crossing each vocal fold has not been well documented in the literature. Herein, we present two cases of mucosal bridge found in the vocal fold connecting the mid-portions of true vocal folds. Two patients who had no history of laryngeal trauma, surgery or oro-tracheal intubation visited our clinic due to voice change. Laryngoscopic examination revealed that they had a mid-portion mucosal band without any other mucosal lesions. Two patients underwent laryngomicrosurgery with pulsed dye laser. After the surgery, they showed significant improvement of voice quality.
Subject(s)
Humans , Intubation , Laryngoscopy , Lasers, Dye , Membranes , Vocal Cords , Voice , Voice Disorders , Voice QualityABSTRACT
BACKGROUND AND OBJECTIVES: Laryngopharyngeal reflux disease (LPRD) is relatively common disease. N-acetyl cysteine (NAC) has both mucolytic and antioxidant effect, also may be beneficial in inflammatory airway diseases. The purpose of this study was to evaluate the efficacy and safety of inhaled NAC therapy in LPRD. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 525 LPRD patients at 12 medical centers. Finally 401 patients subjected to inhaled NAC therapy for 2 months were enrolled in the study. We analyzed the change of Reflux Symptom Index (RSI) and Reflux Finding Score (RFS) after use of NAC for 4 weeks and 8 weeks in addition to the patient's compliance of the treatment. RESULTS: The RSI score significantly decreased from 19.87±6.34 to 12.78±6.93 after 4 weeks and to 10.65±7.47 after 8 weeks. The RFS score also significantly decreased from 9.29±3.4 to 7.17±3.41 after 4 weeks and to 6.1±3.73 after 8 weeks (p<0.05). During the treatment periods, 42 patients (10.4%) reported to have 80 episodes of discomfort. Throat discomfort (33%) and nausea (28%) were most common complaints, but the duration of discomfort was usually less than 4 weeks. CONCLUSION: Inhaled NAC treatment is highly effective for the reduction of both subjective and objective findings in LPRD patients. This study will provide the evidence of new treatment option for patients with LPRD. However, further studies will be needs to assess the real effect of inhaled NAC therapy as a standard treatment regimen of LPRD.
Subject(s)
Humans , Antioxidants , Compliance , Cysteine , Cystine , Inhalation , Laryngopharyngeal Reflux , Medical Records , Nausea , Pharynx , Retrospective StudiesABSTRACT
Sulcus vocalis remains a surgical challenge despite many recent advances in laryngomicrosurgeries. We previously reported that 585-nm Pulsed dye laser (PDL) exerts favorable outcome in treatment of sulcus vocalis due to its therapeutic effects of collagen rearrangement and improved wound remodeling. In spite of the usefulness of PDL glottoplasty for treating sulcus vocalis, the device is no more available in the country. It prompted us to focus another angiolytic laser ; 532-nm KTP laser which has similar mechanisms of action and has been used for treatment of other laryngeal lesions elsewhere. Herein, we present a case of sulcus vocalis successfully treated with KTP laser. A patient underwent laryngomicrosurgery with angiolytic KTP laser (KTP glottoplasty) by the same surgical procedure with PDL glottoplasty. After the surgery, the patient presented improved voice outcome in time without complications.
Subject(s)
Humans , Collagen , Laryngoscopy , Lasers, Dye , Lasers, Solid-State , Therapeutic Uses , Voice , Voice Disorders , Wounds and InjuriesABSTRACT
Xerostomia is a subjective sensation of a dry mouth which is frequently encountered in otorhinolaryngologic practice. There are a variety of salivary and nonsalivary causes of xerostomia such as side effects of medication, systemic disorders, radiation and Sjögren's syndrome. The patients with xerostomia have difficulties in chewing, swallowing, speaking, tasting and mataining oral hygiene. Because of the ageing population, and the concomitant increase in medicated individuals, otorhinolaryngologists can expect to be presented with xerostomia in an increasing number of patients in the coming years and therefore should be familiar with its diagnosis and treatment. A systematic approach should be needed to determine the etiology of xerostomia and the management of xerostomia should be multidisciplinary and multimodal. This review summarizes the current literature on the diagnosis, and complications of xerostomia, and on the management of patients with xerostomia.
Subject(s)
Humans , Deglutition , Diagnosis , Mastication , Mouth , Oral Hygiene , Saliva , Sensation , XerostomiaABSTRACT
BACKGROUND AND OBJECTIVES: The symptoms of salivary diseasess are often nonspecific, and a variety of investigative methods can be employed. Conventional sialography, which is still widely used for diagnosis of salivary ductal pathologies, has the withdrawback of invasiveness and radiation exposure, and thus ultrasound and magnetic resonance (MR) sialography can replace the conventional tools. This study was performed to evaluate the usefulness of MR sialography for the diagnosis of idiopathic chronic sialadenitis. SUBJECTS AND METHOD: From November 2013 to June 2014, we have retrospectively analyzed 26 patients who have had swelling and pain of salivary glands and undergone MR sialography for further diagnosis of the idiopathic salivary obstructive symptom. We analyzed the symptom scores, salivary flow rate (SFR) and parameters of salivary gland scintigraphy. Then we evaluated correlation among MR sialography findings (duct visualization, grade of stenosis at main duct, degree of sialectasis and glandular volume size). RESULTS: Among the 26 patients, stenosis of salivary duct was observed in 14 patients (53.8%), chronic sialadenitis without stenosis in 6 patients (23.1%), Sjogren's syndrome in 3 patients (11.5%), Juvenile reccutent parotitis in 1 patient (3.8%), and 2 patients were norma (7.7%). The degree of sialectasis was significantly correlated with Tmin (time interval, in minutes, from stimulation to minimum count), maximum secretion (p<0.05), and glandular volume size was also significantly correlated with unstimulated SFR (p<0.05). But others did not show any significant correlations. From these findings, we report three cases that were useful to diagnose the gland disease using MR sialography. CONCLUSION: Resutls show that MR sialogarphy indirectly reflects the salivary gland function. Therefore MR sialography can be helpful when the differential diagnosis of idiopathic chronic sialadenitis is difficult with conventional tools.
Subject(s)
Humans , Constriction, Pathologic , Diagnosis , Diagnosis, Differential , Parotitis , Pathology , Radionuclide Imaging , Retrospective Studies , Salivary Ducts , Salivary Glands , Sialadenitis , Sialography , Sjogren's Syndrome , UltrasonographyABSTRACT
Foreign bodies in the laryngopharynx and esophagus are common diagnoses in the clinic of otolaryngology department. There are various types of foreign bodies in the laryngopharynx and esophagus depending on environmental and individual features. Fish bones are the most common type of foreign body in the laryngopharynx and esophagus in Korea. Most of them can be found on inspection or by using a laryngoscope and removed easily. Although foreign bodies are rarely known to migrate from the laryngopharynx and esophagus to the thyroid gland for abscess formation, physicians must be cautious as sometimes they can migrate to other tissues. We describe a case of 53-year-old women with thyroid gland abscess formation due to migrated foreign bodies she had swallowed.
Subject(s)
Female , Humans , Middle Aged , Abscess , Diagnosis , Esophagus , Foreign Bodies , Hypopharynx , Korea , Laryngoscopes , Otolaryngology , Thyroid GlandABSTRACT
OBJECTIVES: Radioiodine (RI) therapy is known to subject cellular components of salivary glands (SG) to oxidative stress leading to SG dysfunction. However, the protective effects of antioxidants on RI-induced SG damage have not been well investigated. The authors investigated the morphometric and functional effects of epigallocatechin-3-gallate (EGCG) administered prior to RI therapy and compared this with the effects of amifostine (a well-known antioxidant) in a murine model of RI sialadenitis. METHODS: Four-week-old female C57BL/6 mice (n=48) were divided into four groups; a normal control group, a RI-treated group (0.01 mCi/g mouse, orally), an EGCG and RI-treated group, and an amifostine and RI-treated group. Animals in these groups were divided into 3 subgroups and euthanized at 15, 30, and 90 days post-RI treatment. Salivary flow rates and lag times were measured, and morphologic and histologic examinations and TUNEL (terminal deoxynucleotidyl transferase biotin-dUDP nick end labeling) assays were performed. Changes in salivary (99m)Tc pertechnetate uptake and excretion were followed by single-photon emission computed tomography. RESULTS: Salivary flow rates and lag times to salivation in the EGCG or amifostine groups were better than in the RI-treated group. Histologic examinations of SGs in the EGCG or amifostine group showed more mucin-rich parenchyma and less periductal fibrosis than in the RI-treated group. Fewer apoptotic cells were observed in acini, ducts, and among endothelial cells in the EGCG or amifostine group than in the RI group. In addition, patterns of (99m)Tc pertechnetate excretion were quite different in the EGCG or amifostine group than in the RI group. CONCLUSION: EGCG supplementation before RI therapy could protect from RI-induced SG damage in a manner comparable to amifostine, and thus, offers a possible means of preventing SG damage by RI.