Stromal lenticule addition keratoplasty with corneal crosslinking for corneal ectasia secondary to FS-LASIK:a case series

●AIM:To explore the clinical efficacy and safety of stromal lenticule addition keratoplasty(SLAK)with corneal crosslinking(CXL)on patients with corneal ectasia secondary to femtosecond laser-assisted in situ keratomileusis(FS-LASIK).●METHODS:A series of 5 patients undertaking SLAK with CXL for the treatment of corneal ectasia secondary to FS-LASIK were followed for 4-9mo.The lenticules were collected from patients undertaking small incision lenticule extraction(SMILE)for the correction of myopia.Adding a stromal lenticule was aimed at improving the corneal thickness for the safe application of crosslinking and compensating for the thin cornea to improve its mechanical strength.●RESULTS:All surgeries were conducted successfully with no significant complications.Their best corrected visual acuity(BCVA)ranged from 0.05 to 0.8-2 before surgery.The pre-operational total corneal thickness ranged from 345-404μm and maximum keratometry(Kmax)ranged from 50.8 to 86.3.After the combination surgery,both the corneal keratometry(range 55.9 to 92.8)and total corneal thickness(range 413-482μm)significantly increased.Four out of 5 patients had improvement of corneal biomechanical parameters(reflected by stiffness parameter A1 in Corvis ST).However,3 patients showed decreased BCVA after surgery due to the development of irregular astigmatism and transient haze.Despite the onset of corneal edema right after SLAK,the corneal topography and thickness generally stabilized after 3mo.●CONCLUSION:SLAK with CXL is a potentially beneficial and safe therapy for advanced corneal ectasia.Future work needs to address the poor predictability of corneal refractometry and compare the outcomes of different surgical modes.

Surgical Correction of Coronary Artery Ectasia Combining Congenital Coronary Artery Fistula

Background:Coronary artery ectasia(CAE)complicated with concomitant congenital coronary artery fistula(CCAF)is rare.This study characterizes the clinical characteristics of CAE combining CCAF,and reports a single-institution experience with surgical correction of CAE combining CCAF.Methods:A total of 24 symptomatic patients(8 males,median 52.5 years old)who underwent surgical correction of CAE combining CCAF in this center were reviewed.Based on the size of ectatic segment,the CAE were classified as a giant CAE(>20 mm,n=14)and a non-giant CAE(≤20 mm,n=10).Individualized surgical approaches were chosen.The patients were followed up for a median of 3.8 years.Results:The overwhelming majority of CAEs were solitary,and only 4.2%of CAEs were associated with multiple lesions.CAEs were predominantly located in the right coronary artery with predilection to women more than to men(2:1).95.8%of patients with the CCAF had single fistula defect.The right atrium was the most frequent drainage site(33.3%)followed by the left ventricle(25.0%).Surgical mortality was 4.2%.All 22 follow-up patients survived with recovery from symptoms and New York Heart Association(NYHA)functional class I-II.In 10 patients with non-giant CAEs undergoing closure of fistula alone,favorable in-hospital outcomes were recorded,but residual fistula(one patient)and acute inferior wall myocardial infarction related to intracoronary thrombosis(one patient)were observed at follow-up.In 11 patients with giant CAEs undergoing aneurysm resection plus distal bypass grafting at the time of closure of fistula,favorable in-hospital outcomes and encouraging midterm results were recorded.Additionally,in 3 patients with giant CAEs undergoing closure of fistula plus aneurysmal plication,adverse events occurred,including surgical death related to rupture of the ectatic segment(one patient),perioperative myocardial infarction caused by acute thromboembolism(one patient),nonfatal inferior wall myocardial infarction related to intracoronary thrombosis(one patient)at follow-up.Conclusion:Individualized surgical approaches based on the size and the location of ectatic coronary artery as well as fistula should be offered to symptomatic patients with CAE combining CCAF.

Diagnosis and management of gastric antral vascular ectasia

Gastric antral vascular ectasia (GAVE) is an uncommon but often severe cause of upper gastrointestinal (GI) bleeding, responsible of about 4% of non-variceal upper GI haemorrhage. The diagnosis is mainly based on endoscopic pattern and, for uncertain cases, on histology. GAVE is characterized by a pathognomonic endoscopic pattern, mainly represented by red spots either organized in stripes radially departing from pylorus, defined as watermelon stomach, or arranged in a diffused-way, the so called honeycomb stomach. The histological pattern, although not pathognomonic, is characterized by four alterations:vascular ectasia of mucosal capillaries, focal thrombosis, spindle cell proliferation and fibrohyalinosis, which consist of homogeneous substance around the ectatic capillaries of the lamina propria. The main differential diagnosis is with Portal Hypertensive Gastropathy, that can frequently co-exists, since about 30% of patients with GAVE co-present a liver cirrhosis. Autoimmune disorders, mainly represented by Reynaud's phenomenon and sclerodactyly, are co-present in about 60% of patients with GAVE; other autoimmune and connective tissue disorders are occasionally reported such as Sjogren's syndrome, systemic lupus erythematosus, primary biliary cirrhosis and systemic sclerosis. In the remaining cases, GAVE syndrome has been described in patients with chronic renal failure, bone marrow transplantation and cardiac diseases. The pathogenesis of GAVE is still obscure and many hypotheses have been proposed such as mechanical stress, humoural and autoimmune factors and hemodynamic alterations. In the last two decades, many therapeutic options have been proposed including surgical, endoscopic and medical choices. Medical therapy has not clearly shown satisfactory results and surgery should only be considered for refractory severe cases, since this approach has significant mortality and morbidity risks, especially in the setting of portal hypertension and liver cirrhosis. Endoscopic therapy, particularly treatment with Argon Plasma Coagulation, has shown to be as effective and also safer than surgery, and should be considered the first-line treatment for patients with GAVE-related bleeding.

Corneal collagen crosslinking for corneal ectasia of post-LASIK: one-year results

AIM: To evaluate the efficacy and safety of corneal collagen crosslinking (01) to prevent the progression of post-laser in situ keratomileusis (LASIK) corneal ectasia. METHODS: In a prospective, nonrandomized, single-centre study, CXL was performed in 20 eyes of 11 patients who had LASIK for myopic astigmatism and subsequently developed keratectasia. The procedure included instillation of 0.1% riboflavin-20% dextrane solution 30 minutes before UVA irradiation and every 5 minutes for an additional 30 minutes during irradiation. The eyes were evaluated preoperatively and at 1-, 3-, 6-, and 12-month intervals. The complete ophthalmologic examination comprised uncorrected visual acuity, best spectacle-corrected visual acuity, endothelial cell count, ultrasound pachymetry, corneal topography, and in vivo confocal microscopy. RESULTS: CXL appeared to stabilise or partially reverse the progression of post-LASIK corneal ectasia without apparent complication in our cohort. UCVA and BCVA improvements were statistically significant (P<0.05)beyond 12 months after surgery (improvement of 0.07 and 0.13 logMAR at 1 year, respectively). Mean baseline flattest meridian keratometry and mean steepest meridian keratometry reduction (improvement of 2.00 and 1.50 diopters (D), respectively) were statistically significant (P < 0.05) at 12 months postoperatively. At 1 year after 01, mean endothelial cell count did not deteriorate. Mean thinnest cornea pachymetry increased significantly. CONCLUSION: The results of the study showed a long-term stability of post-LASIK corneal ectasia after crosslinking without relevant side effects. It seems to be a safe and promising procedure to stop the progression of post-LASIK keratectasia, thereby avoiding or delaying keratoplasty.

Massive gastric antral vascular ectasia successfully treated by endoscopic band ligation as the initial therapy

Gastric antral vascular ectasia(GAVE) accounted for 4% of non-variceal gastrointestinal hemorrhage.Even though unclear pathogenesis,GAVE often associated with chronic renal failure,autoimmune diseases and cirrhosis.Asymptomatic lesions were reasonably not to treated.The treatment options for GAVE are nonendoscopic and endoscopic treatments.For the pharmacological treatment,some success were reported for the use of octreotide,thalidomide and tranexamic acid.While the endoscopic treatment is the mainstay for treatment of symptomatic lesions.The endoscopic ablative therapies such as argon plasma coagulation was reported with good clinical outcomes.However,these treatment options had some limitation due to the need of special equipment and multiple sessions needed to control the bleeding.We reported another treatment option using the routine-achievable instrument such as endoscopic band ligation as an initial treatment which also provided a good treatment outcome and less sessions.

Transjugular intrahepatic portosystemic shunt as bridge-to-surgery in refractory gastric antral vascular ectasia

Gastric antral vascular ectasia(GAVE) may cause gastrointestinal bleeding(GIB). The treatment of GAVE relies on endoscopic approaches such as electrocoagulation(argon plasma coagulation, laser therapy, heater probe therapy, radiofrequency ablation), cryotherapy, and band ligation. In refractory cases, antrectomy may be considered. In the event of an associated cirrhosis and portal hypertension, it has been suggested that antrectomy could be an option, provided the mortality risk isn't considered too great. We report the case of a 67-year-old cirrhotic patient who presented with GAVE related GIB, unresponsive to multiple endoscopic treatments. The patient had a good liver function(model for end-stage disease 10). After a multidisciplinary meeting, a transjugular intrahepatic portosystemic shunt(TIPS) procedure was performed, in order to treat the cirrhosis associated ascites. The outcome was successful. An antrectomy was then performed, with no recurrence of GIB and no transfusion need during three months of follow up. In this case, the TIPS procedure achieved a complete ascites regression, allowing a safer surgical treatment of the GAVE-related GIB.

Endoscopic resolution and recurrence of gastric antral vascular ectasia after serial treatment with argon plasma coagulation

AIM To evaluate long-term endoscopic resolution and recurrence rate of gastric antral vascular ectasia(GAVE) after argon plasma coagulation(APC) treatment.METHODS This was an IRB-approved retrospective single center study that included patients endoscopically treated for GAVE between 1/1/2008 to 12/31/2014. The primary and secondary end points of the study were rate of endoscopic resolution of GAVE after APC treatment and recurrence rate of GAVE after endoscopic resolution, respectively. Endoscopic resolution of GAVE was defined as no endoscopic evidence of GAVE after treatment with APC. Recurrence of GAVE was defined as endoscopic reappearance of GAVE after prior resolution.RESULTS Twenty patients met the study criteria. Median age(range) of the patients was 59.5 years(42-74 years). GAVE was associated with underlying cirrhosis in 16(80%) patients. Indications for initial esophagogastroduodenoscopy(EGD) included hematemesis and/or melena(9/20, 45%), iron deficiency anemia(6/20, 30%), screening or surveillance of varices(4/20, 20%), and occult gastrointestinal bleeding(1/20, 5%). The patients were treated with a total of 55 APC sessions(range 1-7 sessions). Successful endoscopic resolution of GAVE wasachieved in 8 out of 20 patients(40%). There was no correlation between number of treatment sessions and GAVE treatment success(P = NS). Recurrence of GAVE was noted on a subsequent EGD in 2 out of 8 patients(25%) with prior endoscopic resolution of GAVE. Median follow-up period for the study population was 627 d(range 63-1953 d).CONCLUSION Endoscopic resolution rate of GAVE was low(40%) with a 25% recurrence rate after treatment with APC. These rates suggest that APC treatment of GAVE may not be optimal in many circumstances.

Detection of active bleeding from gastric antral vascular ectasia by capsule endoscopy

Gastric antral vascular ectasia(GAVE) has been recognized as one of the important causes of occult and obscure gastrointestinal bleeding.The diagnosis is typically made based on the characteristic endoscopic features,including longitudinal row of flat,reddish stripes radiating from the pylorus into the antrum that resemble the stripes on a watermelon.These appearances,however,can easily be misinterpreted as moderate to severe gastritis.Although it is believed that capsule endoscopy(CE) is not helpful for the study of the stomach with its large lumen,GAVE can be more likely to be detected at CE rather than conventional endoscopy.CE can be regarded as "physiologic" endoscopy,without the need for gastric inflation and subsequent compression of the vasculature.The blood flow of the ecstatic vessels may be diminished in an inflated stomach.Therefore,GAVE may be prominent in CE.We herein describe a case of active bleeding from GAVE detected by CE and would like to emphasize a possibility that CE can improve diagnostic yields for GAVE.

Clinical outcomes after implantation of a new intrastromal corneal ring with 140-degree of arc in patients with corneal ectasia

AIM：To evaluate the clinical and tomographic outcomes after implantation of a new intrastromal corneal ring segment（ICRS） with 140-degrees of arc in eyes with corneal ectasia.METHODS：We evaluated patients with corneal ectasia implanted with Ferrara 140° ICRS from April 2010 to February 2015.Outcome measures included preoperative and postoperative corrected distance visual acuity（CDVA）,keratometry simulated（K） reading,tomographic astigmatism and asphericity.All patients were evaluated using the Pentacam Scheimpflug system.RESULTS：The study evaluated 58 eyes.The mean followup was 16.81±10.8 mo.The CDVA（logM AR） improved from 0.5±0.20（20/60） to 0.3±0.21（20/40）（P〈0.01）.The average K reduced from 49.87±7.01 to 47.34±4.90 D（P〈0.01）.The asphericity changed from-0.60±0.86 to-0.23±0.67 D（P〈0.01）.The mean preoperative tomographic astigmatism decreased from-8.0±3.45 to-4.53±2.52 D（P〈0.01）.CONCLUSION：The new ICRS model with 140-degrees of arc effectively improve the visual acuity and reduce the high astigmatism usually found in patients with corneal ectasia.

Successful treatment of refractory gastric antral vascular ectasia by distal gastrectomy:A case report

Gastric antral vascular ectasia(GAVE) is an uncommon and often neglected cause of gastric hemorrhage. The treatments for GAVE include surgery,endoscopy and medical therapies. Here,we report an unusual case of GAVE. A 72-year-old man with a three-month history of recurrent melena was diagnosed with GAVE. Endoscopy revealed the classical "watermelon stomach" appearance of GAVE and complete pyloric involvement. Melena reoccurred three days after argon plasma coagulation treatment,and the level of hemoglobin dropped to 47 g/L. The patient was then successfully treated with distal gastrectomy with Billroth Ⅱ anastomosis. We propose that surgery should be considered as an effective option for GAVE patients with extensive and severe lesions upon deterioration of general conditions and hemodynamic instability.

Long term efficacy and stability of corneal collagen cross linking for post-LASIK ectasia: an average of 80mo follow-up

This study was designed to evaluate efficacy and stability of corneal collagen crosslinking(CXL) in halting the progression of post-laser in situ keratomileusis(LASIK) ectasia and provide long-term follow-up results with an average of 80 mo. Patients with post-LASIK ectasia were treated with CXL between December 2007 and January 2012. Main outcome measures were uncorrected distance visual acuities(UDVA) and corrected distance visual acuities(CDVA), minimum and maximum keratometry(K) values, spherical and cylindrical refraction, and corneal thickness. The study evaluated 17 eyes for 13 patients(8 men, 5 women) with mean age of 31y(range 23 to 39) and mean follow-up of 80.7±15(range 57 to 102)mo. UDVA and CDVA improved from logMAR 0.53±0.36(20/63) to 0.49±0.4(20/50)(P=0.43) and from 0.18±0.17(20/28) to 0.16±0.16(20/27)(P=0.55) respectively. In 15 eyes UDVA and in 13 eyes CDVA either remained stable or improved ≥1 Snellen lines(88.2%) and(76.5%) respectively. Although statistically insignificant, spherical and cylindrical refraction decreased post-CXL from-1.26±2.87 to-0.38±2.32 diopters(D)(P=0.054) and from-3.80±2.47 to-3.04±2.18 D(P=0.13) respectively. Kmax significantly decreased from 44.23±3.76 to 42.85±3.08 D(P=0.013) and Kmin decreased from 41.07±3.61 to 40.00±2.65 D(P=0.057). Corneal thickness decreased from 470±42 to 460±41 μm, but was statistically non-significant(P=0.063). Therefore, CXL is effective in halting and partially reversing the progression of postLASIK ectasia on the long-term(mean follow-up of more than 80mo), thus highlighting the stability and maintained effect of CXL for such cases.

Post photorefractive keratectomy corneal ectasia

Dear Editor,We write to describe two cases of corneal ectasia occurred after photorefractive keratectomy.Due to the wide diffusion of refractive surgery,many ophthalmologists attempted to identify the risk factors and prevention methods to avoid such severe complication of this technique.

Antithrombotic treatment strategy for patients with coronary artery ectasia and acute myocardial infarction: A case report

BACKGROUND There is no consensus on the antithrombotic treatment strategy for patients with coronary artery ectasia(CAE).CASE SUMMARY This case reports the dynamic observation of a patient for 48 mo after a diagnosis of CAE with acute myocardial infarction(AMI).The first antithrombotic agents used were aspirin(100 mg/d)and clopidogrel(75 mg/d).During the sixth month of observation,a second AMI occurred involving the same culprit vessel;therefore,antithrombotic agents were changed to aspirin(100 mg/d)and ticagrelor(90 mg twice per day).Twelve months after the second AMI,an attempt to reduce the dosage ticagrelor failed;therefore the original dose was continued.The CAE was relatively stable during the following 4 years.CONCLUSION This case indicates that a combination of aspirin and ticagrelor may be more effective for CAE patients with AMI than aspirin and clopidogrel.

Long-term efficacy of endoscopic coagulation for different types of gastric vascular ectasia

AIM: To examine the long-term therapeutic efficacies of endoscopic cauterization for gastric vascular ectasia, according to the type of lesion. METHODS: Thirty-eight patients with hemorrhagic gastric vascular ectasia (VE) were treated by endoscopic cauterization: 13 by heater probe coagulationand 25 by argon plasma coagulation. Depending on the number of lesions, 14 and 24 patients were classified into localized VE (≤ 10; LVE) and extensive VE (> 10; EVE), respectively. The patients were followedup by repeated endoscopic examinations after the therapy, and the incidences of VE recurrence and rebleeding from the lesions were evaluated. RESULTS: Although the VE lesions disappeared initially in all the patients after the therapy, the recurrence of VE developed in 25 patients (66%) over a mid-term observation period of 32 mo, and re-bleeding occurred in 15 patients (39%). The recurrence of VE was found in all patients with EVE, with re-bleeding occurring in 14 patients (58%). In contrast, only 1 patient (7%) with LVE showed recurrence of the lesions and complicating hemorrhage. Both the cumulative recurrence-free rates and cumulative re-bleeding-free rates were significantly lower in the EVE group than in the LVE group (P < 0.001 and P < 0.001, respectively). Moreover, the cumulative re-bleeding-free rate in the EVE group was 47.6% at 1 year and 25.4% at 2 years in patients with chronic renal failure, which were significantly lower than the rates in the patients without chronic renal failure (83.3% and 74.1%, respectively) (P < 0.05). CONCLUSION: The recurrence of VE and re-bleeding from the lesions was more frequent in the patients with EVE, especially in those with complicating renal failure.

Multivessel coronary artery ectasia and severe calcification in a patient with pheochromocytoma:a case report

Multivessel coronary artery ectasia with severe calcification is rare among patients with coronary artery disease. A 74-year-old Chinese woman suffered from acute myocardial infarction on a background of 50 years of poorly controlled hypertension secondary to pheochromocytoma, which was surgically removed in June 2012 prior to the presentation. Coronary angiography revealed total occlusion of the proximal left anterior descending artery, and multiple ectasias with severe calcification in the left main, circumflex and right coronary artery. After an aspiration thrombectomy and balloon angioplasty, grade 3 coronary flow was restored in the left descending coronary artery. No cardiac events were found in the 12-month follow-up. We conclude that multivessel coronary artery ectasia and severe calcification may be present in patients with a long-standing history of hypertension secondary to pheochromocytoma.

Accelerated versus standard corneal cross linking in the treatment of ectasia post refractive surgery and penetrating keratoplasty: a medium term randomized trial

AIM: To compare the clinical outcomes of the standard corneal cross linking(CXL) and the accelerated CXL in patients with progressive corneal ectasia post refractive surgery and penetrating keratoplasty.METHODS: Totally 120 eyes of 83 patients scheduled to receive either standard CXL(3 m W/cm^2 for a period of 30 min) or accelerated CXL(18 m W/cm2 for a period of 5 min). The main outcomes for comparison were the change in: maximum-K reading(K-max), manifest refractive spherical equivalent(SE), central corneal thickness(CCT), and the best corrected distance visual acuity(CDVA).RESULTS: One hundred and eleven eyes completed the study. The main outcome measurement was the K-max reading. Both group showed significant improvement in the value postoperatively at 6 and 12 mo. The mean change in the standard group was 1.21±0.11 D and in the accelerated group was 0.90±0.05 D at the end of 12 mo postoperatively, with no statistically significant difference between the 2 groups. Similarly, CDVA improved significantly from their preoperative value in the standard group by 2.98±0.11 letters, and in the accelerated group by 2.20±0.06 letters, with no statistically significant difference between the two groups. Both of the SE, and CCT showed no statistically significant difference at the end of follow up period in each group.CONCLUSION: Both standard CXL and accelerated CXL are safe and effective treatment in halting ectasia after corneal refractive surgery. The accelerated CXL results are comparable to the standard CXL with short time exposure of the cornea to ultraviolet irradiation, leading to reduced operation time, reduced operative ocular discomfort, and corneal haze.

Relationship between coronary artery ectasia, cocaine abuse and acute coronary syndromes

Coronary artery ectasia(CAE)often represents a coronary angiography finding casually detected or following the occurrence of an acute coronary syndrome.The pathogenetic role of cocaine abuse in the genesis of CAE is still little known and very few data are available in literature.We describe a case of a 31-year-old male cocaine user admitted to our department for typical acute chest pain.Coronary angiography showed diffuse coronary ectasia with slow flows and without hemodynamically significant stenosis.An increasing of matrix metalloproteinases values and a reduction of their tissue inhibitors was showed both during hospitalization and at one month after discharge.This case report emphasizes the close relationship between cocaine abuse,CAE and acute coronary syndromes in patients without hemodynamically significant coronary stenosis.As reported by Satran et al,cocaine abuse should be considered an important risk factor for CAE and these patients appear to be at increased risk of angina and acute myocardial infarct.Further studies that can strengthen this hypothesis would be useful to deepen and better analyze this interesting association.

A novel endoscopic ablation of gastric antral vascular ectasia

An 80-year-old woman was admitted to our hospital because of tarry stool with iron deficiency anemia. Her past history included autoimmune hepatitis. Esophagogastroduodenal endoscopy was performed to investigate the bleeding source and revealed multiple linear gastric vascular malformations in the antrum and cardia, compatible with Gastric antral vascular ectasia (GAVE). Endoscopic ablation was carried out with the tip of the hot biopsy forceps without opening at soft coagulation mode of 80W. The patient tolerated the procedure well and there were no complications associated with endoscopic therapies. After two sessions of endoscopic ablation her anemia improved to around 10 g/dL, an increase of 3.6 g/dL. Various endoscopic treatments have been described to manage GAVE. The most popular is argon plasma coagulation (APC), although APC is associated with over-distension induced by the argon plasma gas. To avoid over-distension and to reduce the abdominal discomfort/pain of this patient,we have used hot biopsy forceps instead of APC. Our case suggests that this procedure is effective, easy and convenient,as no special equipment or skill is necessary.

Case series on multimodal endoscopic therapy for gastric antral vascular ectasia, a tertiary center experience

AIM To study and describe patients who underwent treatment for gastric antral vascular ectasia(GAVE) with different endoscopic treatment modalities.METHODS We reviewed patients with GAVE who underwent treatment at University of Alabama at Birmingham between March 1, 2012 and December 31, 2016. Included patients had an endoscopic diagnosis of GAVE with associated upper gastrointestinal bleeding or iron deficiency anemia.RESULTS Seven out of 15 patients had classic watermelon description for GAVE, 1/15 with diffuse/honeycomb pattern and 6/15 with nodular GAVE per EGD description. Seven out of 15 patients required multimodal treatment. Four out of six of patients with endoscopically nodular GAVE required multimodal therapy. Overall, mean pre-and post-treatment hemoglobin(Hb) values were 8.2 ± 0.8 g/dL and 9.7 ± 1.6 g/dL, respectively(P ≤ 0.05). Mean number of packed red blood cells transfusions before and after treatment was 3.8 ± 4.3 and 1.2 ± 1.7(P ≤ 0.05), respectively.CONCLUSION Patients with nodular variant GAVE required multimodal approach more frequently than non-nodular variants. Patients responded well to multimodal therapy and saw decrease in transfusion rates and increase in Hb concentrations. Our findings suggest a multimodal approach may be beneficial in nodular variant GAVE.

Recurrent ventricular tachycardia secondary to severe coronary artery ectasia

A 64-year-old male with a history of thoracic aortic ulcer s/p thoracic endovascular aortic repair presented to the hospital with typical chest pain.His initial physical exam was unremarkable.Cardiac biomarkers were negative on admission and electrolytes were within normal limits.