fistula-in-ano is a common problem. Ligation of intersphincteric fistula tract (LIFT) is a new addition to the list of operations available to deal with complex fistula-in-ano.
Objectivewe sought to qualitatively analyze studies describing LIFT for crpytoglandular fistula-in-ano and determine its efficacy.
Data sourcesMEDLINE (Pubmed, Ovid), Embase, Scopus and Cochrane Library were searched.
Study selectionall clinical trials which studied LIFT or compared LIFT with other methods of treatment for anal fistulae, prospective observational studies, clinical registry data and retrospective case series which reported clinical healing of the fistula as the outcome were included. Case reports, studies reporting a combination with other technique, modified technique, abstracts, letters and comments were excluded.
Interventionthe intervention was ligation of intersphincteric fistula tract in crpytoglandular fistula-in-ano.
Main outcome measureprimary outcome measured was success rate (fistula healing rate) and length of follow-up.
fístula anal é um problema comum. A ligadura interesfincteriana do trajeto fistuloso (LIFT) é uma nova adição à lista de cirurgias disponíveis para tratar a fístula anal complexa.
Objetivobuscou-se analisar qualitativamente estudos descrevendo o uso de LIFT para fístula anal criptoglandular e determinar a sua eficácia.
Fontes de dadosas bases de dados MEDLINE (Pubmed, Ovid), Embase, Scopus e Biblioteca Cochrane foram pesquisadas.
Seleção dos estudostodos os ensaios clínicos que estudaram LIFT ou compararam LIFT com outros métodos de tratamento da fístula anal, estudos observacionais prospectivos, dados de registros clínicos e série de casos retrospectivos que relataram a cura clínica da fístula anal como desfecho foram incluídos. Relatos de casos, estudos que relatam uma combinação com outra técnica, técnica modificada, resumos, cartas e comentários foram excluídos.
Intervençãoa intervenção foi ligadura interesfincteriana do trajeto fistuloso em fístula anal criptoglandular.
Medida do desfecho principala medida do desfecho principal foi a taxa de sucesso (taxa de cura da fístula) e período de seguimento.
Fistula-in-ano is a common condition but a potentially complex disease process. A fistula can be found in 26–38% of all anorectal abscesses,1,2 and is characterized by chronic purulent drainage or cyclical pain associated with abscess re-accumulation followed by intermittent spontaneous decompression.3 Most are of cryptoglandular origin.4,5 Fistula-in-ano are more common in men than women.6,7
Fistula-in-ano is categorized on the basis of location relative to the anal sphincter muscles according to the Parks classification: inter-sphincteric, trans-sphincteric, supra-sphincteric, or extra-sphincteric.8 A fistula-in-ano can be “simple” or “complex”. Submucosal, low (traversing less than 30% of anal sphincter muscle) inter-sphincteric and low trans-sphincteric fistulas are considered simple. Fistula-in-ano is considered complex if found to have any of the following characteristics: tract crosses more than 30–50% of external sphincter, anterior fistula in a female, presence of multiple tracts, recurrent fistula, preexisting incontinence, local irradiation and Crohn's disease.9,10
The goal of surgical management is to effectively eradicate current and recurrent septic foci, associated epithelialized tracts and preserve continence. No single technique achieves these aims for all anal fistulas. It is often necessary to balance the degree of sphincter division and continence disturbance. An ideal procedure for treating a fistula-in-ano should be minimally invasive with minimal failure rates and morbidity.
Ligation of the intersphincteric fistula track (LIFT) has recently been described by Rojanasakul et al. from Thailand.11 Since the initial description in 2006, several studies on LIFT have been reported in literature with variable results and indications. Our objective to this study was to perform a systematic review to comprehensively summarize existing literature exploring the efficacy of LIFT in treating fistula-in-ano.
MethodsSearch strategyA systematic review of all literature relevant to efficacy of Ligation of intersphincteric fistulous track (LIFT), published between January 2005 and February 2013 was carried out using PubMed, Embase, Cochrane Database, Science Citation Index, CINAHL, National Health Service Centre for Reviews and Dissemination, and Google Scholar. Searches were performed using a combination of Medical Subject Headings (MeSH) terms and text words ‘fistula-in-ano’, ‘complex’, ‘inter-sphincteric’, ‘ligation’, ‘recurrence’, ‘incontinence’, ‘follow-up’. Manual reference checks of accepted papers in recent reviews and included papers were performed to supplement the electronic searches.
DefinitionsFistulae with multiple tracts were defined as fistulae with single primary and multiple secondary openings. A successful outcome was defined by the complete healing of the surgical intersphincteric wound and external opening. Recurrence was defined as a non-healing wound or re-appearance of an external opening with persistent discharge or re-appearance of a fistula after the initial wound had healed. In trials with patients with multiple tracts, the procedure was considered successful only if all the tracts were closed.
Inclusion criteriaAll randomized/non-randomized, controlled/non-controlled clinical trials, which studied LIFT or compared LIFT with other methods of treatment for anal fistulae, prospective observational studies, clinical registry data and retrospective case series which reported clinical healing of the fistula as the outcome were included, as were conference proceedings.39–44
Exclusion criteriaCase reports, reviews, abstracts, letters and comments were excluded. We excluded three studies reporting the usage of bioprosthetic grafts to reinforce LIFT (BioLIFT procedure) for management of complex anal fistulae12–14 and another reporting the use of LIFT for patients with perianal sinus after stapled hemorrhoidopexy15 was also excluded. Patients from studies where LIFT patients underwent an additional procedure (advancement flap or fibrin glue) along with the LIFT16 were also excluded from the review as were studies where the mean or median follow-up was less than two months. Patients with rectovaginal, anovaginal, rectourethral, or ileal-pouch vaginal fistulas were also not included as were studies on LIFT that looked at outcome measures other than fistula healing rates, e.g., incontinence or septic complications and did not report healing rates. Two studies which reported a modification to standard LIFT procedure17,18 were also excluded. When multiple articles or abstracts on LIFT from the same author/institution were analyzed, only the most recent publication was chosen for review if the same cohort of patients were analyzed in an earlier report.
Data extractionIn total, there were five investigators involved. Data on type of trial, total number of patients treated, follow-up period, overall success rate with LIFT, total number of patients having complex fistulae, multiple tracts, single tracts and recurrent disease, total number of tracts with tract closure rate, sepsis or abscess formation in the postoperative period were extracted from the included studies by the reviewers. To guard against reviewer bias, all data were extracted separately by all reviewers. The names of the authors were blinded and only the material and methods and results section were reviewed. Any discrepancies were settled after discussions and consensus between the reviewers. All data and results of statistical tests were extracted from the papers onto a proforma specifically designed for this study. For particular outcomes that were evaluated, if the data were not specifically reported, it was regarded as not reported or missing and no assumptions were made regarding the missing data. Analysis of some variables was not possible because of the lack of both uniformity and the quantity of the data reported. These variables were the impact of seton insertion before LIFT procedure, role of antibiotics, objective pain assessment after the procedure and the efficacy of multiple LIFT procedures in the same patient. The methodological quality of the studies that met the selection criteria was assessed and evaluated by the authors using the Downs and Black Quality Index score system.47 This is a validated scoring checklist for assessing the quality of both randomized clinical trials and non randomized studies. It consists of several items distributed among five subscales: reporting, external validity, bias, confounding and power. Downs and Black score ranges were given corresponding quality levels: excellent (26–28), good (20–25) and fair (15–19). Studies that scored poor (<=14) were excluded, except where it was the only available evidence. The authors individually reviewed each included article for quality (based on the Downs and Black checklist) using a quality scoring sheet. The authors independently rated all the studies, recorded final scores for each article and resolved any differences by discussion.
Outcome measuresPrimary outcome measured was success rate (fistula healing rate) of LIFT procedure. Success was defined as closure of all secondary openings, an absence of fistula drainage, and an absence of abscess formation. Secondary outcome measured were development of incontinence and recurrence. Recurrence was defined as an abscess spontaneously discharging or requiring surgical drainage, or a recurrent fistula either at the same site or at a different site.
Systematic reviewA total of 51 studies on LIFT were found (Fig. 1), of which twenty-two studies fulfilled the inclusion criteria19–40 (Table 1). Among the included studies, one was a randomized control trial, fifteen were prospective studies and six were retrospective case series.
Characteristics of included studies.
References | Year published | Type of study | Sex M/F | Median age in years. (Range in years) | Total no of patients | Methodology of assessment | Downs & Black score | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Pre-op. seton insertion | Pre-op | Antibiotic | Operative position | Anaesthesia | Duration of admission | |||||||||
MRI | EUS | Pre-op | Post-op | |||||||||||
Rojanasakul 19 | 2007 | PS | 14/4 | NR (26–72) | 18 | NR | NR | NR | NR | 18 | PJK | LR | ON | Good |
Shanwani et al. 20 | 2010 | PS | 32/13 | 41.5 (27–56) | 45 | 0 | 0 | 12 | NR | 45 | PJK | LR | DC | Good |
Bleier et al. 21 | 2010 | PS | 20/19 | 49 (NR) | 39 | NR | NR | NR | NR | NR | PJK | GA/LR/LA | NR | Good |
Aboulian et al. 22 | 2011 | RCS | 17/7 | 39 (NR) | 25 | 17 | NR | NR | 25 | 25 | PJK | GA/LR/LA | DC | Good |
Ooi et al. 23 | 2011 | PS | 17/8 | 40 (21–67) | 25 | NR | 18 | 0 | NR | 25 | PJK | NR | ON | Good |
Sileri et al. 24 | 2011 | PS | 10/8 | NR (4–62) | 18 | 3 | 18 | 18 | 18 | 18 | L | GA | DC | Good |
Tan et al. 25 | 2011 | RCS | 77/16 | 40 (16–71) | 93 | 16 | 0 | 93 | NR | 93 | L/PJK | NR | DC | Good |
Christoforidis et al. 26 | 2011 | PS | 8/3 | 41 (24–61) | 11 | 7 | NR | NR | NR | NR | NR | GA | DC | Fair |
Espin et al. 27 | 2011 | PS | 13/16 | NR (26–83) | 29 | 24 | NR | NR | NR | NR | NR | NR | NR | Fair |
Iachino et al. 28 | 2011 | PS | NR | 61.8 (NR) | 31 | NR | NR | NR | NR | NR | NR | NR | NR | Fair |
Giarratano et al. 29 | 2011 | PS | 6/12 | NR | 18 | NR | NR | 18 | NR | NR | NR | NR | NR | Fair |
Franceschilli et al. 30 | 2011 | PS | 8/3 | NR | 11 | 3 | NR | 11 | NR | 11 | NR | NR | NR | Fair |
Alfred et al. 31 | 2011 | PS | NR | NR | 17 | NR | NR | 17 | NR | NR | NR | GA | NR | Fair |
Koh et al. 32 | 2011 | PS | 7/12 | 38 (NR) | 19 | 18 | 0 | 19 | NR | NR | NR | NR | ON | Fair |
Lo et al. 33 | 2012 | PS | 19/6 | 48 (22–64) | 25 | 13 | NR | NR | 25 | NR | PJK | GA/LR | ON | Fair |
Tan et al. 34 | 2012 | RCS | 21/3 | 41 (16–75) | 24 | 24 | 0 | 24 | NR | 24 | L/PJK | NR | NR | Good |
Mushaya et al. 35 | 2012 | RCT | 17/8 | 47.5 (25–70.1) | 25 | 1 | 25 | 25 | 0 | 0 | PJKa Lb | GA | DC | Excellent |
Ulrik et al. 36 | 2012 | RCS | 57/36 | 43 (21–76) | 93 | 70 | NR | NR | NR | NR | PJK | GA/LR/LA | NR | Good |
Abcarian et al. 37 | 2012 | PS | NR | NR (22–70) | 40 | NR | NR | 1 | NR | NR | PJK | GA/LR | NR | Good |
Liu et al. 38 | 2013 | RCS | 28/10 | 42 (26–58) | 38 | 29 | NR | NR | 38 | 38 | PJK | GA/LR | DC | Good |
Lehmann et al. 39 | 2013 | PS | 9/8 | 49 (30–76) | 17 | 4 | NR | NR | 17 | 0 | NR | GA | DC (7) | Good |
Van Onkelen et al. 40 | 2013 | RCS | 13/9 | 45 (17–59) | 22 | NR | 22 | 0 | 22 | NR | PJK | GA | NR | Good |
PS, prospective study; RCS, retrospective case series; RCT, randomized control trial.
NR, not reported/cannot be concluded from the data provided.
Pre-operative bowel preparation – MBP, mechanical bowel preparation (pre-operative), BE, Bowel enema (pre-operative).
MRI (Magnetic resonance imaging) or EUS (Endo anal ultrasound).
Operative position: Lithotomy (L); Prone jack knife (PJK); a used for Anterior fistula; b used for Posterior fistula.
Anaesthesia: General anaesthesia (GA); Loco-regional (LR); Local anaesthesia (LA).
Duration of admission: Day care (DC); Overnight (ON).
Downs and Black score ranges: excellent (26–28); good (20–25); fair (15–19); poor (<=14).
Because of the heterogeneity (randomized control, retrospective and prospective studies, inclusion of complex as well as noncomplex fistulae in different studies) amongst included studies, we could not perform a weighted analysis to get a summary estimate of the efficacy of the procedure. Hence, the success rate of different parameters was expressed as a range.
ResultsWe have provided a narrative synthesis of the findings from the included studies, structured around the type of outcome. A total of 683 patients were analyzed (Table 1) with a follow-up range of 0–67 months (Table 2). The LIFT procedure had a success rate (fistula healing rate) ranging from 40% to 94.4% (479/676) (Table 3). The abscess formation rate ranged from 5.6% to 60% (197/676). The number of complex fistulae (reported in 19/22 studies) studied was 447, while those of recurrent fistulae (reported in 16/22 studies) studied was 197, single tract fistulae (reported in 16/22 studies) was 490 and multiple tract fistulae (reported in 11/22 studies) was 64. However, the individual success rate for these fistulae could not be assessed from the data available. No incontinence or change in continence were reported in 18/21 studies analyzed, while one study reported temporary incontinence to gas (2 patients) and another study reported gas (12 patients), liquid incontinence (2 patients) and both liquid and gas incontinence (1 patient).27,36
Characteristics of included studies.
Reference | No. patients with complex fistula | No. patients with IBD | No. fistulas with multiple tracts | No. recurrent fistula treated | Follow-up (range in months), patients followed up (%), method of follow-up | Success/Total patients (Healing rates %) | Abscess/sepsis No. (%) | Other complications | Further treatment given for recurrence | Median healing time (wks), range (weeks) | Median time to recurrence (weeks), range (weeks) |
---|---|---|---|---|---|---|---|---|---|---|---|
Rojanasakul 19 | 5 | 0 | 0 | 0 | (1–6.5), 100, C | 17/18 (94.4) | 1 (5.6) | NR | Repeat LIFT (1/1) | NR, (1–8) | NR |
Shanwani et al. 20 | 12 | 0 | 4 | 5 | (2–4), 100, C | 37/45 (82.2) | 8 (17.7) | None | Repeat LIFT (5/8) | 7, (4–10) | NR, (12–32) |
Bleier et al. 21 | 10 | NR | 7 | 29 | (0–14.5), 90, NR | 20/35 (57) 4 pts NR | 15 (42.8) | Anal fissure (1/35)Chronic anal pain (1/35) | NR | NR | 10, (2–38) |
Aboulian et al. 22 | 9 | NR | 2 | 8 | (2–13), 100, C | 17/25 (68) | 8 (32) | Vaginal fungal infections (2/25) | Fistulotomy (1/8)Repeat LIFT (1/8)Fibrin plug (1/8)I&D (2/8)Awaiting operation (3/8) | NR | NR |
Ooi et al. 23 | 13 | 0 | 3 | 10 | (1–10.7), 100, C | 17/25 (68) | 7 (28) | NR | I&D+Seton (7/7) | 6, (3–17) | NR, (7–20) |
Sileri et al. 24 | 18 | 0 | 1 | 4 | (4–10), 100, C | 15/18 (83.3) | 3 (16.7) | Hemorrhoidal thrombosis (1/18) | Fistulotomy (1/18)Seton+AFP (2/18) | NR | NR |
Tan et al. (2011) 25 | 64 | NR | 10 | 26 | (1–21.2), 100, C | 80/93 (86) | 13 (13.9) | NR | Fistulotomy (4)Repeat LIFT (1)Adv flap (1) | 4, (1–12) | 22, (15–33) |
Christoforidis et al. 26 | 11 | NR | NR | 3 | (1.2–9.5), 100, NR | 6/11 (54.5) | 5 (45.4) | NR | Fistulotomy (1) | NR | NR |
Espin et al. 27 | 19 | NR | 0 | NR | (12–26), 100, NR | 19/29 (65) | 10 (35) | Temporary gas incontinence (2/10) | Fistulotomy (1) | NR, (2.7–9.7) | NR |
Iachino et al. 28 | 31 | NR | 6 | NR | (1–12), 100, C, EUS | 27/31 (87) | 4 (13) | NR | NR | NR | NR |
Giarratano et al. 29 | 18 | NR | NR | NR | (6–11), NR, C | 16/18 (88.9) | 2 (11.1) | None | NR | NR | NR |
Franceschilli et al. 30 | 11 | NR | 1 | 4 | 3, 100, C, EUS | 8/11 (72) | 3 (28) | None | NR | NR | NR |
Alfred et al. 31 | 11 | NR | NR | NR | 13 | 13/17 (76.5) | 4 (24.5) | NR | NR | NR | NR |
Koh et al. 32 | 18 | NR | NR | 4 | (0.5–18.5), 100, C | 12/19 (63) | 7 (37) | None | Fistulotomy (2) | NR | NR |
Lo et al. 33 | 25 | NR | 0 | 14 | (1–21.5), 100, C | 23/25 (89) | 2 (11) | None | Fibrin glue (1)Drainage+Seton (1) | 2, (1–8) | NR |
Tan et al. (2012) 34 | 24 | 0 | NR | 0 | (4–67), 100, C | 15/24 (62.5) | 9 (37.5) | NR | Fistulotomy (4/9)Seton (4/9)I&D (1/9)ERAF (2/9)Repeat LIFT (1/9) | NR | NR |
Mushaya et al. 35 | 25 | 0 | 1 | 2 | (8.4–31.3), 96, C | 19/25 (76) | 5 (20) | Bleeding (1/25) | NR | NR | 16, NR |
Ulrik et al. 36 | 93 | 0 | 16 | 30 | (44–55), 100, C | 37/93 (40) –primary LIFT44/93 (47) – repeat LIFT | 56 (60) | Gas incontinence (12)Liquid incontinence (2)Liquid & gas incontinence (1) | Seton (20)Fistulotomy (11)LIFT (13)Abscess Drainage (9)Fistula plug (2)Advancement flap (1) | NR | 28, NR |
Abcarian et al. 37 | NR | 1 | NR | 27 | (0.5–16), 95, C | 29/40 (74) | 10 (25) | NR | NR | NR | NR |
Liu et al. 38 | 38 | NR | 13 | 18 | (3–44) NR, C, TC[26 pts >12 months follow-up (68%)] | 23/38 (61) | 15 (39) | Vaginal fungal infections (2) | Curettage (2)Fistulotomy (2)Repeat LIFT (1)Fistula plug (2) | 8, (4–36) | 16, (0–48) |
Lehmann et al. 39 | 17 | NR | 0 | 17 | (8–26), 88, C, EUS | 11/17 (65) | 6 (40) | Local haematoma (1)Subcutaneous infection (1) | NR | 54, (NR) | NR |
Van Onkelen et al. 40 | 0 | 0 | 0 | 10 | (3–35), 100, C, TC | 18/22 (82) | 4 (18) | None | Fistulotomy (4/4) | NR | NR |
IBD, Inflammatory bowel disease; Follow-up methods, clinical examination (C); EUS, Endoscopic ultrasound; TC, Telephone communication; NC, Nil change in continence; NR, Not reported; I&D, Incision and Drainage; ERAF, Endorectal advancement flap.
Success rate of LIFT procedure in different parameters.
No. | Parameter | No of studies analyzed | Total no. (reported) | Successful cases | Range of success rates (%) |
---|---|---|---|---|---|
1 | Overall | 22 | 683 | 479 | 40–94 |
2 | Studies with minimum follow up >6 months | 5 | 182 | 102 | 40–88.9 |
3 | Complex fistula | 19 | 461 | NR | NR |
4 | Recurrent fistula | 16 | 211 | NR | NR |
5 | Single tract fistula | 15 | 490 | NR | NR |
6 | Multiple tract fistula | 11 | 64 | NR | NR |
Fistula healing rate=40–94% (479/683).
Abscess formation (sepsis/suppuration)=5.6–60% (197/683).
No single technique is appropriate for the treatment of all fistula-in-ano and the surgeon's experience and judgement should guide treatment decision. LIFT is a recent procedure with one randomized controlled trial published on it so far, although there are a few under way. The other studies published so far are only cohort studies and retrospective case series. While the studies analyzed in this review are heterogeneous and the number of patients in these studies is small, their systematic analysis provides some useful insight into the role of LIFT in the management of fistulae-in-ano (Fig. 2).
Fistulotomy continues to be the procedure of choice for simple low fistulas, where the tract is submucosal, intersphincteric or located in the lower third of the external anal sphincter.1,10,41,42
On the other hand, surgical treatments for high and complex fistulas may result in variable degree of anal sphincter impairment. Surgical options, such as flap repair, fibrin glue injection, seton drainage and fistula track plug insertion have been proposed with wide ranging and often disappointing success rates.43–46 Usually less invasive approaches do not jeopardize continence, but healing rates can be very low. Reported recurrence and incontinence rates range from 0% to 32% and from 0% to 63%, respectively.
The LIFT procedure combines two important concepts: removal of the infected cryptoglandular tissue through the intersphincteric approach and closure of the internal orifice with negligible trauma to the sphincters. Essential steps of the procedure include incision at the intersphincteric groove, identification of the intersphincteric tract and ligation of the intersphincteric tract close to the internal opening. All granulation tissue is debrided and the defect in the external sphincter muscle is sutured at. This technique prevents the entry of faecal material into the fistula tract and eliminates the formation of a septic nidus in the intersphincteric space to allow healing of the fistula-in-ano.19 In the initial publication by Rojanasakul et al., a success rate of 94% was reported with no case of incontinence. Fistula healing rates range from 40% to 94% with variable follow-up as shown in Table 2. Others have confirmed the effectiveness of LIFT although with lower rates of success.
The reported success rate of LIFT among the prospective studies, with a minimum follow-up greater than 6 months, varied between 40% and 88.9%. In the six retrospective case series analyzed, the success rate was between 40% and 86%. From the only randomized control study, we can observe that the success rate was 76%. These results are moderate yet impressive considering that the procedure is minimally invasive and less morbid with little risk of incontinence. However further prospective randomized trials studies with longer follow-up periods are warranted to further validate these findings.
One important observation was that even when the LIFT procedure fails to completely eradicate the fistula, it was able to “downstage” the original anatomy of a trans-sphincteric fistula to either an intersphincteric sinus or fistula. This medialization of the external opening to the intersphincteric wound simplifies subsequent management. Intersphincteric sinuses can be managed locally by the application of silver nitrate, whereas an intersphincteric fistula can often be laid open. In those patients with complete failures it is imperative to perform a thorough reevaluation before subsequent surgical management. It is recommended that a seton is placed for 6–12 weeks if there is evidence of acute inflammation, purulence or excessive drainage.23
Thirteen studies (Table 1) looked at the use of setons prior to LIFT. None of them found any significant changes in closure rates. Further studies are needed to evaluate the role of the seton in the LIFT procedure.
LIFT seems to be very safe in terms of morbidity. Among the studies, we observed a single episode of haemorrhoidal thrombosis, bleeding, anal fissure and chronic anal pain, while two were reported to have vaginal fungal infections. Continence is consistently preserved.
Limitations of the studyAll the studies included in this analysis are of small sample size. In addition there is absence of long-term follow-up in the available studies. Perhaps more importantly though is the failure of gauging the impact of the LIFT procedure on continence and lack of objective measurement of evidence of fistula healing (endorectal ultrasound or magnetic resonance imaging). However, the systematic analysis provides us with an insight into the initial results of a new procedure with encouraging outcomes.
ConclusionDespite the LIFT technique having been adopted in many centres around the world, there is a paucity of information regarding the patterns of failures and recurrences after the LIFT procedure and their subsequent management.
The initial results with LIFT are promising, with success rate of up to 40–94% in complex fistulae-in-ano. Findings from our study reflect a simple and safe procedure with little morbidity and low risk of incontinence. Although the literature is limited, this review provides the most accurate estimate, based on the data currently available, as to the probability of success for patients with complex fistula-in-ano with the use of LIFT procedure.
Conflicts of interestThe authors declare no conflicts of interest.