Surgical strategies for challenging common bile duct stones in the endoscopic era: A comprehensive review of current evidence

While endoscopic retrograde cholangiopancreatography(ERCP)remains the primary treatment modality for common bile duct stones(CBDS)or choledocho-lithiasis due to advancements in instruments,surgical intervention,known as common bile duct exploration(CBDE),is still necessary in cases of difficult CBDS,failed endoscopic treatment,or altered anatomy.Recent evidence also supports CBDE in patients requesting single-step cholecystectomy and bile duct stone removal with comparable outcomes.This review elucidates relevant clinical anatomy,selection indications,and outcomes to enhance surgical understanding.The selection between trans-cystic(TC)vs trans-choledochal(TD)approaches is described,along with stone removal techniques and ductal closure.Detailed surgical techniques and strategies for both the TC and TD approaches,including instrument selection,is also provided.Additionally,this review comprehensively addresses operation-specific complications such as bile leakage,stricture,and entrapment,and focuses on preventive measures and treatment strategies.This review aims to optimize the management of CBDS through laparoscopic CBDE,with the goal of improving patient outcomes and minimizing risks.

Various approaches of laparoscopic common bile duct exploration plus primary duct closure for choledocholithiasis:A systematic review and meta-analysis

Background： Common bile duct （CBD） stones may occur in up to 3%–14.7% of all patients with cholecystectomy.Various approaches of laparoscopic CBD exploration plus primary duct closure （PDC） are the most commonly used and the best methods to treat CBD stone. This systematic review was to comparethe effectiveness and safety of the various approaches of laparoscopic CBD exploration plus PDC forcholedocholithiasis

Role of laparoscopic common bile duct exploration in the management of choledocholithiasis

Surgical fraternity has not yet arrived at any consensus for adequate treatment of choledocholithiasis. Sequential treatment in the form of pre-operative endoscopic retrograde cholangio-pancreatography followed by laparoscopic cholecystectomy(LC) is considered as optimal treatment till date. With refinements in technique and expertise in field of minimal access surgery, many centres in the world have started offering one stage management of choledocholithiasis by LC with laparoscopic common bile duct exploration(LCBDE). Various modalities have been tried for entering into concurrent common bile duct(CBD) [transcystic(TC) vs transcholedochal(TD)], for confirming stone clearance(intraoperative cholangiogram vs choledochoscopy), and for closure of choledochotomy(T-tube vs biliary stent vs primary closure) during LCBDE. Both TC and TD approaches are safe and effective. TD stone extraction is involved with an increased risk of bile leaks and requires more expertise in intra-corporeal suturing and choledochoscopy. Choice depends on number of stones, size of stone, diameter of cystic duct and CBD. This review article was undertaken to evaluate the role of LCBDE for the management of choledocholithiasis.

Outcomes of laparoscopic bile duct exploration for choledocholithiasis with small common bile duct

BACKGROUND Laparoscopic cholecystectomy(LC)combined with laparoscopic common bile duct(CBD)exploration(LCBDE)is one of the main treatments for choledocholithiasis with CBD diameter of larger than 10 mm.However,for patients with small CBD(CBD diameter≤8 mm),endoscopic sphincterotomy remains the preferred treatment at present,but it also has some drawbacks associated with a series of complications,such as pancreatitis,hemorrhage,cholangitis,and duodenal perforation.To date,few studies have been reported that support the feasibility and safety of LCBDE for choledocholithiasis with small CBD.AIM To investigate the feasibility and safety of LCBDE for choledocholithiasis with small CBD.METHODS A total of 257 patients without acute cholangitis who underwent LC+LCBDE for cholecystolithiasis from January 2013 to December 2018 in one institution were reviewed.The clinical data were retrospectively collected and analyzed.According to whether the diameter of CBD was larger than 8 mm,257 patients were divided into large CBD group(n=146)and small CBD group(n=111).Propensity score matching(1:1)was performed to adjust for clinical differences.The demographics,intraoperative data,short-term outcomes,and long-term follow-up outcomes for the patients were recorded and compared.RESULTS In total,257 patients who underwent successful LC+LCBDE were enrolled in the study,146 had large CBD and 111 had small CBD.The median follow-up period was 39(14-86)mo.For small CBD patients,the median CBD diameter was 0.6 cm(0.2-2.0 cm),the mean operating time was 107.2±28.3 min,and the postoperative bile leak rate,rate of residual CBD stones(CBDS),CBDS recurrence rate,and CBD stenosis rate were 5.41%(6/111),3.60%(4/111),1.80%(2/111),and 0%(0/111),respectively;the mean postoperative hospital stay was 7.4±3.6 d.For large CBD patients,the median common bile duct diameter was 1.0 cm(0.3-3.0 cm),the mean operating time was 115.7±32.0 min,and the postoperative bile leak rate,rate of residual CBDS,CBDS recurrence rate,and CBD stenosis rate were 5.41%(9/146),1.37%(2/146),6.85%(10/146),and 0%(0/146),respectively;the mean postoperative hospital stay was 7.7±2.7 d.After propensity score matching,184 patients remained,and all preoperative covariates except diameter of CBD stones were balanced.Postoperative bile leak occurred in 11 patients overall(5.98%),and no difference was found between the small CBD group(4.35%,4/92)and the large CBD group(7.61%,7/92).The incidence of CBDS recurrence did not differ significantly between the small CBD group(2.17%,2/92)and the large CBD group(6.52%,6/92).CONCLUSION LC+LCBDE is safe and feasible for choledocholithiasis patients with small CBD and did not increase the postoperative bile leak rate compared with choledocholithiasis patients with large CBD.

Topical nitrate drip infusion using cystic duct tube for retained bile duct stone:A six patients case series

A retained bile duct stone after operation for cholelithiasis still occurs and causes symptoms such as biliary colic and obstructive jaundice.An endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy(EST),followed by stone extraction,are usually an effective treatment for this condition.However,these procedures are associated with severe complications including pancreatitis,bleeding,and duodenal perforation.Nitrates such as glyceryl trinitrate(GTN) and isosorbide dinitrate(ISDN) are known to relax the sphincter of Oddi.In 6 cases in which a retained stone was detected following cholecystectomy,topical nitrate drip infusion via cystic duct tube(C-tube) was carried out.Retained stones of 2-3 mm diameter and no dilated common bile duct in 3 patients were removed by drip infusion of 50 mg GTN or 10 mg ISDN,which was the regular dose of intravenous injection.Three other cases failed,and EST in 2 cases and endoscopic biliary balloon dilatation in 1 case were performed.One patient developed an adverse event of nausea.Severe complications were not observed.We consider the topical nitrate drip infusion via C-tube to be old but safe,easy,and inexpensive procedure for retained bile duct stone following cholecystectomy,inasmuch as removal rate was about 50% in our cases.

Laparoscopic hepatic left lateral lobectomy combined with fiber choledochoscopic exploration of the common bile duct and traditional open operation

AIM: To investigate the possibilities and advantages of laparoscopic hepatic left lateral lobectomy combined with fiber choledochoscopic exploration of the common bile duct compaired with traditional open operation.METHODS: Laparoscopic hepatic left lateral lobectomy combined with fiber choledochoscopic exploration of the common bile duct and traditional open operation were performed in two groups of patients who had gallstones in the left lobe of liver and in the common bile duct. The hospitalization time, hospitalization costs, operation time, operative complications and post-operative liver functions of the two groups of patients were studied.RESULTS: The operation time and post-operative liver functions of the two groups of patients had no significant differences, while the hospitalization time, hospitalization costs and operative complications of the laparoscopic hepatic left lateral lobectomy combined with fiber choledochoscopic exploration in the common bile duct group were significantly lower than those in the traditional open operation group.CONCLUSION: For patients with gallstones in the left lobe of liver and in the common bile duct, laparoscopic hepatic left lateral lobectomy combined with fiber choledochoscopic exploration of the common bile duct can significantly shorten the hospitalization time, reduce the hospitalization costs and the post-operative complications,without prolonging the operation time and bringing about more liver function damages compared with traditional open operation. This kind of operation has more advantages than traditional open operation.

Bile leakage after loop closure vs clip closure of the cystic duct during laparoscopic cholecystectomy:A retrospective analysis of a prospective cohort

BACKGROUND Laparoscopic cholecystectomy(LC)is one of the most frequently performed surgical procedures.Cystic stump leakage is an underestimated,potentially life threatening complication that occurs in 1%-6%of the patients.With a secure cystic duct occlusion technique during LC,bile leakage becomes a preventable complication.AIM To investigate the effect of polydioxanone(PDS)loop closure of the cystic duct on bile leakage rate in LC patients.METHODS In this retrospective analysis of a prospective cohort,the effect of PDS loop closure of the cystic duct on bile leakage complication was compared to patients with conventional clip closure.Logistic regression analysis was used to develop a risk score to identify bile leakage risk.Leakage rate was assessed for categories of patients with increasing levels of bile leakage risk.RESULTS Of the 4359 patients who underwent LC,136(3%)underwent cystic duct closure by a PDS loop.Preoperatively,loop closure patients had significantly more complicated biliary disease compared to the clipped closure patients.In the loop closure cohort,zero(0%)bile leakage occurred compared to 59 of 4223(1.4%)clip closure patients.For patients at increased bile leakage risk(risk score≥1)rates were 1.6%and up to 13%(4/30)for clip closure patients with a risk score≥4.This risk increase paralleled a stepwise increase of actual bile leakage complication for clip closure patients,which was not observed for loop closure patients.CONCLUSION Cystic duct closure with a PDS loop during LC may reduce bile leakage in patients at increased risk for bile leakage.

Laparoscopic common bile duct exploration to treat choledocholithiasis in situs inversus patients:A technical review

Situs inversus(SI)is a rare congenital condition characterized by a mirror-image transposition of the major visceral organs.Since the 1990s,more than one hundred SI patients have been reported to have successfully undergone laparoscopic cholecystectomy.In these cases,the major problem is to overcome is the left-right condition for right-handed surgeons.Laparoscopic common bile duct exploration(LCBDE),an alternative to treat patients with bile duct stones,has shown equivalent efficacy and is less likely to cause pancreatitis than endoscopic retrograde cholangiopancreatography.Recent updated meta-analyses revealed that a shorter postoperative hospital stay,fewer procedural interventions,cost-effectiveness,a higher stone clearance rate,and fewer perioperative complications are additional advantages of LCBDE.However,the technique is technically demanding,even for skilled laparoscopic surgeons.Conducting LCBDE in patients with difficult situations,such as SI,is more complex than usual.We herein review published SI patients with choledocholithiasis treated by LCBDE,including our own experience,and this paper focuses on the technical aspects.

Simultaneous liver mucinous cystic and intraductal papillary mucinous neoplasms of the bile duct:A case report

Cystic hepatic neoplasms are rare tumors,and are classified into two separate entities:mucinous cystic neoplasms(MCNs)and intraductal papillary mucinous neoplasms of the bile duct(IPMN-B).We report the case of a 56-year-old woman who presented with abdominal pain and jaundice due to the presence of a large hepatic multilocular cystic tumor associated with an intraductal tumor.Partial hepatectomy with resection of extrahepatic bile ducts demonstrated an intrahepatic MCN and an intraductal IPMN-B.This is the first report of the simultaneous occurrence of these two histologically distinct entities in the liver.

Clinical Application of Primary Suture Following Three-Port Laparoscopic Common Bile Duct Exploration: A Report of 176 Cases

Objective: To investigate the feasibility, safety and the clinical value of primary suture following 3-port laparoscopic common bile duct exploration (LCBDE). Methods: From January 2012 to September 2014, 176 patients suffered from choledocholithiasis were treated with primary suture following 3-port LCBDE and the clinical data were retrospectively analyzed. Results: All cases were operated successfully and none was converted to open surgery. The duration of operation was 92.2 ± 18.8 min and the length of postoperative hospital stay was 4.4 ± 3.7 d. Postoperative bile leakage occurred in 2 cases and these patients recovered by simple drainage for 3 to 7 days without re-operation. All patients recovered smoothly without any serious complications. Conclusions: Primary suture following 3-port LCBDE is safe, effective and mini-invasive, which is worthy of further clinical application.

Hem-o-lok clip migration to the common bile duct after laparoscopic common bile duct exploration:A case report

BACKGROUND Laparoscopic cholecystectomy(LC)and laparoscopic common bile duct exploration(LCBDE)has been widely used for management of gallbladder and common bile duct(CBD)stones.Post-operative clip migration is a rare complication of laparoscopic biliary surgery,which can serve as a nidus for stone formation and cause recurrent cholangitis.CASE SUMMARY A 59-year-old female was admitted to hospital because of fever and acute right upper abdominal pain.She has a history of LC and had a LCBDE surgery 2 mo ago.Physical examination revealed tenderness in the upper quadrant of right abdomen.Computed tomography scan demonstrated a high-density shadow at the distal CBD,which was considered as migrated clips.The speculation was confirmed by endoscopic retrograde cholangiopancreatography examination,and two displaced Hem-o-lok clips were removed with a stone basket.No fever or abdominal pain presented after the operation.In addition to the case report,literature regarding surgical clip migration after laparoscopic biliary surgery was reviewed and discussed.CONCLUSION Incidence of postoperative clip migration may be reduced by using clips properly and correctly;however,new methods should be explored to occlude cystic duct and vessels.If a patient with a past history of LC or LCBDE presents with features of sepsis and recurrent upper quadrant pain,clip migration must be considered as one of the differential diagnosis.

Cystic Enlargement of the Bile Duct: Case Report and Review of Literature

Congenital cystic dilatations of the bile duct are rare malformations representing 1 per 13,000 births with a female predominance. Diagnosis of this pathology is based on radiological imaging especially radiological investigations conducted on an ultrasound coupled with Computed tomography (CT) scan and especially a bili-MRI which allows the analysis of the bile duct malformations and the anomalies of the pancreaticobiliary junction. We will discuss in this clinical case the various radiological aspects of cystic dilatations of the biliary duct.

Two-stage vs single-stage management for concomitant gallstones and common bile duct stones

AIM:To evaluate the safety and effectiveness of twostage vs single-stage management for concomitant gallstones and common bile duct stones.METHODS:Four databases,including PubMed,Embase,the Cochrane Central Register of Controlled Trials and the Science Citation Index up to September 2011,were searched to identify all randomized controlled trials(RCTs).Data were extracted from the studies by two independent reviewers.The primary outcomes were stone clearance from the common bile duct,postoperative morbidity and mortality.The secondary outcomes were conversion to other procedures,number of procedures per patient,length of hospital stay,total operative time,hospitalization charges,patient acceptance and quality of life scores.RESULTS:Seven eligible RCTs [five trials(n = 621) comparing preoperative endoscopic retrograde cholangiopancreatography(ERCP)/endoscopic sphincterotomy(EST) + laparoscopic cholecystectomy(LC) with LC + laparoscopic common bile duct exploration(LCBDE);two trials(n = 166) comparing postoperative ERCP/EST + LC with LC + LCBDE],composed of 787 patients in total,were included in the final analysis.The metaanalysis detected no statistically significant difference between the two groups in stone clearance from the common bile duct [risk ratios(RR) =-0.10,95% confidence intervals(CI):-0.24 to 0.04,P = 0.17],postoperative morbidity(RR = 0.79,95% CI:0.58 to 1.10,P = 0.16),mortality(RR = 2.19,95% CI:0.33 to 14.67,P = 0.42),conversion to other procedures(RR = 1.21,95% CI:0.54 to 2.70,P = 0.39),length of hospital stay(MD = 0.99,95% CI:-1.59 to 3.57,P = 0.45),total operative time(MD = 12.14,95% CI:-1.83 to 26.10,P = 0.09).Two-stage(LC + ERCP/EST) management clearly required more procedures per patient than single-stage(LC + LCBDE) management.CONCLUSION:Single-stage management is equivalent to two-stage management but requires fewer procedures.However,patient's condition,operator's expertise and local resources should be taken into account in making treatment decisions.

Single-session minimally invasive management of common bile duct stones

Up to 18% of patients submitted to cholecystectomy had concomitant common bile duct stones.To avoid serious complications,these stones should be removed.There is no consensus about the ideal management strategy for such patients.Traditionally,open surgery was offered but with the advent of endoscopic retrograde cholangiopancreatography(ERCP) and laparoscopic cholecystectomy(LC) minimally invasive approach had nearly replaced laparotomy because of its well-known advantages.Minimally invasive approach could be done in either twosession(preoperative ERCP followed by LC or LC followed by postoperative ERCP) or single-session(laparoscopic common bile duct exploration or LC with intraoperative ERCP).Most recent studies have found that both options are equivalent regarding safety and efficacy but the singlesession approach is associated with shorter hospital stay,fewer procedures per patient,and less cost.Consequently,single-session option should be offered to patients with cholecysto-choledocholithiaisis provided that local resources and expertise do exist.However,the management strategy should be tailored according to many variables,such as available resources,experience,patient characteristics,clinical presentations,and surgical pathology.

Mirizzi syndrome in an anomalous cystic duct:A case report

Mirizzi syndrome is a rare complication of gallstone disease,and results in partial obstruction of the common bile duct or a cholecystobiliary fistula. Moreover,congenital anatomical variants of the cystic duct are common,occurring in 18%-23% of cases,but Mirizzi syndrome underlying an anomalous cystic duct is an important clinical consideration. Here,we present an unusual case of typeⅠMirizzi syndrome with an uncommon anomalous cystic duct,namely,a low lateral insertion of the cystic duct with a common sheath of cystic duct and common bile duct.

Diagnosis and management of cystic duct leakage after laparoscopic cholecystectomy: report of 3 cases

BACKGROUND; Operative complications after laparo- scopic cholecystectomy (LC) vary. Abdominal pain and other symptoms caused by fluid accumulation in the opera- tive area are not uncommon. Cystic duct (CD) leakage is one of the main sources of the fluid. This study was to eva- luate the procedures used in the diagnosis and management of CD leakage after LC. METHOD: The clinical materials of 3 patients with CD leakage after LC were studied retrospectively. RESULTS: Three female patients underwent LC for chronic cholecystitis associated with stones. Their clinical symp- toms were worsened of pre-existed cardiac arrhythmia, bile draining out from drainage tube, and biliary spillage from umbilical incision, respectively. Final diagnosis was made at the 1st, 2nd and 20th post-operative day. Two of the 3 patients were treated laparoscopically. Their opened CD stumps were closed with an endo-loop, with the abdomen irrigated and drained. The other patient was drained with the percutaneous technique, and a biliary stent was inserted under endoscopy. All patients recovered well. CONCLUSIONS: The clinical manifestations of CD leakage are different. Ascites can be found by B-ultrasound. Final diagnosis is dependent on magnetic resonance cholangiog- raphy and/or endoscopic retrograde cholangiopancreatog- raphy. Minimally invasive techniques can be applied to this complication safely and effectively. Reoperarion for closure of the opened CD stump can be fulfilled under laparosco- py. Endoscopic drainage must be accompanied with effec- tive abdominal drainage.

Double Cystic Duct Not Detected by Imaging But Diagnosed on Intraoperative Dissection in Laparoscopic Cholecystectomy: A Case Report, Hatwan Hospital-Sulaimani Province-Kurdistan-Iraq

The incidence rate of bile duct injury during laparoscopic cholecystectomy has not been changed for many years. This may be because of biliary tree abnormalities, as variation in cystic duct anatomy is quite common. One of the extremely rare anomalies is a double cystic duct. An old lady underwent laparoscopic cholecystectomy for symptomatic gallstones. Without any clue for this anomaly in preoperative checkup, we found two cystic ducts during the laparoscopy. Operation completed laparoscopically, with smooth early and later postoperative checkups till now.

Laparoscopic cholecystectomy plus common bile duct exploration for extrahepatic bile duct stones and postoperative recurrenceassociated risk factors

BACKGROUND There remain controversies regarding the surgical treatment of extrahepatic bile duct stones(EHBDSs)in clinical practice.AIM To explore the curative effect of laparoscopic cholecystectomy(LC)plus common bile duct exploration(CBDE)for the surgical treatment of EHBDSs and to analyze the risk factors that affect postoperative stone recurrence.METHODS Eighty-two patients with EHBDSs admitted between March 2017 and March 2023 were selected.Among them,patients treated with open choledocholithotomy plus LC or open cholecystectomy(OC)were set as the control group(n=40),and those treated with LC plus CBDE served as the observation group(n=42).The surgical outcomes of the two groups were compared,the surgical complications and Gas-trointestinal Quality of Life Index(GIQLI)scores were counted,and the one-year prognostic recurrence was recorded.Independent factors for postoperative re-currence were determined using univariate and multivariate analyses.RESULTS The two groups were comparable in the stone residual rate(P>0.05).The ope-ration time(P<0.05),intraoperative bleeding(P<0.05),and total complication rate(P=0.005)were lower in the observation group than in the control group.The observation group exhibited a marked increase in the GIQLI score,which was higher than the control group(P<0.05).A lower one-year recurrence rate was determined in the observation group vs the control group(P=0.027).Sphincter of Oddi dysfunction[odds ratio(OR)=5.712,P=0.007]and the treatment scheme of open choledocholithotomy plus LC or OC(OR=6.771,P=0.008)were the independent risk factors for one-year recurrence in patients after surgery.CONCLUSION LC plus CBDE for patients with EHBDSs can reduce stone residuals,intraoperative bleeding,complications,and postoperative recurrence.

Clinical efficacy and safety of selective trans-cystic intra-operative cholangiography in primary suture following three-port laparoscopic common bile duct exploration

Background Intra-operative cholangiography has been shown to be a sensitive and specific method of demonstrating bile duct stones. This study investigated the feasibility, safety, and clinical value of selective trans-cystic intra-operative cholangiography in primary suture following three-port laparoscopic common bile duct exploration, and identified the factors that positively predict the presence of common bile duct stones. Methods From January 2008 to January 2011, 252 of 1013 patients undergoing laparoscopic cholecystectomy received selective trans-cystic intra-operative cholangiography and primary suture following three-port laparoscopic common bile duct exploration. Their clinical data were analyzed retrospectively. Results All operations were successful and none was converted to open surgery. The intra-operative cholangiography time was （8.3±2.5） minutes, and the operative duration was （105.4±23.1） minutes. According to selective intra-operative cholangiography, the positive predictive values of current jaundice, small gallstones （〈0.5 cm） and dilated cystic duct （〉0.3 cm）, dilated common bile duct （〉0.8 cm）, history of jaundice or gallstone pancreatitis, abnormal liver function test, and preoperative demonstration of suspected common bile duct stones on imaging were 87%, 25%, 42%, 15%, 32%, and 75% for common bile duct stones, respectively. Patients with several factors suggestive of common bile duct stones yielded higher numbers of positive cholangiograms. Unexpected stones were found in 13 patients （5.2%） by intra-operative cholangiography. The post-operative hospital stay was （4.7±2.2） days. Post-operative bile leakage occurred in two cases, and these patients recovered by simple drainage for 3-7 days without re-operation. Of the 761 patients who underwent laparoscopic cholecystectomy alone, 5 （0.7%） presented with a retained common bile duct stone requiring intervention. The median follow-up was 12 months, and only one patient who once suffered from bile leakage presented with obstructive jaundice due to bile duct stenosis 6 months postoperatively. The other patients recovered without any serious complications. Conclusions Selective intra-operative cholangiography yields acceptably high positive results. It is a safe, effective, and minimally invasive approach in patients with suspected choledocholithiasis and primary suture following three-port laparoscopic common bile duct exploration.

Primary duct closure versus T-tube drainage after laparoscopic common bile duct exploration:a meta-analysis

Background and aims:Laparoscopic common bile duct exploration(LCBDE)is considered a safe and effective method for the removal of bile duct stones.However,the choice of primary duct closure(PDC)or T-tube drainage(TTD)technique after LCBDE is still controversial.This study aimed to compare the safety and effectiveness of PDC and TTD after LCBDE.Methods:Studies published before May 1,2021 in Pub Med,Web of Science,and Cochrane Library databases were searched to screen out randomized controlled trials(RCTs)and cohort studies to compare PDC with TTD.Meta-analyses of fixed effect and random effect models were performed using Rev Man 5.3.Results:A total of 1865 patients were enrolled in six RCTs and ten cohort studies.Regarding RCTs,the PDC group was significantly better than the TTD group in terms of operation time,total postoperative complications,postoperative hospital stay,and hospitalization expenses(all P<0.05).Based on cohort studies of the subgroup,the PDC group had shorter operation time,shorter postoperative hospital stay,less intraoperative blood loss,and limited total postoperative complications.Statistically,there were no significant differences in bile leakage,retained stones,stone recurrence,bile duct stricture,postoperative pancreatitis,other complications,or postoperative exhaust time between the TTD and PDC groups.Conclusions:Based on the available evidence,compared with TTD,PDC is safe and effective,and can be used as the first choice after transductal LCBDE in patients with choledocholithiasis.