Abstract
Background
The efficacy of adjuvant antibiotic therapy in reducing the rate of fistula following incision and drainage (I and D) of cryptoglandular anorectal abscesses remains controversial. This study evaluated the effect of adjuvant antibiotic therapy on fistula formation rate.
Methods
This retrospective study included all consecutive adult patients who underwent I and D for a cryptoglandular anorectal abscess between January 2011 and December 2024 at a university-affiliated institution. Demographic, clinical, and microbiological culture data were collected. The intervention assessed was adjuvant antibiotic therapy administration for a minimum of 7 days following I and D. The primary outcome compared fistula formation rates at 12 months after I and D between those who received adjuvant antibiotic therapy and those who did not. Secondary outcomes assessed the factors associated with fistula formation.
Results
Of the 770 patients who met inclusion criteria, 60.5% received adjuvant antibiotic therapy. The overall rate of fistula was 6.8%. The overall median time to diagnosis was 15.4 weeks (interquartile range [IQR]: 7.7–31.3). No differences in the fistula formation rate or time to diagnosis were observed between the two groups. Fistula formation was significantly associated with abscess location, whereas diabetes mellitus was less common among patients who developed fistula. In addition, no patient whose abscess culture yielded skin-derived microorganisms developed a fistula. Age > 40 years and intersphincteric abscess were associated with fistula formation in multivariate analysis, while diabetes mellitus demonstrated a negative association.
Conclusions
In this retrospective study, adjuvant antibiotic therapy was not associated with a decreased risk of fistula formation following abscess I and D.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10151-025-03264-7.
Keywords: Anorectal abscess, Anal fistula, Antibiotics, Anorectal abscess microbiology
Introduction
Anal fistula presents significant challenges for patients, impacting their comfort, emotional well-being, social activities, and overall quality of life. The management of complex cases is particularly demanding and represents a core pathology of colorectal surgery practice.
Timely incision and drainage (I and D) is the primary standard of care for anorectal abscess, but some patients may develop a fistula following I and D. The incidence of fistula formation following abscess drainage varies in literature, with rates reported up to 50% [1]. According to the cryptoglandular hypothesis, first articulated by Parks, fistulae are considered a progression from acute infection of the anal gland to a chronic inflammatory state [2–4]. This theory continues to underpin our understanding of the etiology in most patients, while conditions such as inflammatory bowel disease and malignancy represent a smaller subset of the etiology of fistula.
In this context, adjuvant antibiotic therapy has garnered interest for its theoretical potential to halt disease progression. Current clinical guidelines generally recommend against the routine administration of antibiotics after abscess drainage [1]. Nevertheless, data from retrospective observational studies indicate that antibiotics are still administered to approximately 45–80% of patients [5–8]. This discrepancy between guideline recommendations and real-world practice may be attributed to potential reporting bias of the benefit of antibiotics and their role in preventing fistula formation following abscess drainage.
To date, only three prospective randomized controlled trials have specifically investigated the role of adjuvant antibiotic therapy in this setting, yielding conflicting results and leaving the question open for further research [9–11]. Thus, the aim of this study was to evaluate the value of adjuvant antibiotic therapy in preventing fistula formation following I and D of anorectal abscess.
Method
Study design and setting
This retrospective study was conducted at a public university-affiliated institution in the State of Kuwait between January 2011 and December 2024. Approval for the study protocol was granted by the institutional ethics committee of the Ministry of Health, and given the retrospective study design, the requirement for written informed consent was waived. The research methodology and reporting were guided by the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) framework [12]. The corresponding STROBE checklist is included in the Supplementary Digital Content.
Study participants
All consecutive patients aged ≥ 18 years who underwent I and D for a cryptoglandular anorectal abscess in the operating room were identified from the institution’s operating room registry and included in the study.
Exclusion criteria
Patients who were < 18 years of age, those with a history of inflammatory bowel disease, concurrent necrotizing soft tissue infection, the presence of fistula at the time of index surgery, abscess secondary to prior intervention (e.g., fillers and anabolic steroid injections), or trauma were excluded.
The intervention
The intervention assessed was the administration of adjuvant antibiotic therapy following I and D. Adjuvant antibiotic therapy was defined as the administration of oral antibiotics for a minimum of 7 days postoperatively. The regimens consisted of monotherapy or combination therapy, including beta-lactams, fluoroquinolones, lincosamides, nitroimidazoles, or oxazolidinones. The selection of specific antibiotics was at the discretion of the operating surgeon, with choices tailored to ensure appropriate coverage against anorectal flora.
Data collection
Patient data were extracted from the institutional medical records, including operative registry, outpatient clinic visits, and emergency department visits. The variables collected included demographic and perioperative characteristics, including age, sex, smoking status, comorbidities, abscess location, and administration of adjuvant antibiotic therapy. Microbiological culture results were included when intraoperative samples were collected. All patients were scheduled for follow-up at the surgical outpatient clinic within 1 month of discharge to examine for a postoperative check. Further follow-up was scheduled as clinically indicated, with instructions to return to the clinic if new symptoms were observed.
Study outcomes
The primary outcome was to compare the rate of fistula formation after abscess drainage between patients who received adjuvant antibiotic therapy and those who did not. Fistula formation was defined as the occurrence of a communicating tract between the anal canal and external perianal skin at the site of the anorectal abscess within 12 months of surgery, as confirmed by physical examination and/or imaging.
Patients were stratified into two groups: adjuvant and nonadjuvant antibiotic groups. Baseline demographics, comorbidities, abscess location, and microbiological analysis details were compared between the two groups.
Secondary outcomes aimed to determine perioperative factors that were associated with fistula formation. These factors were compared between patients with and without fistula. Multivariate logistic regression analysis was performed to identify the independent predictors of fistula formation.
A subgroup analysis was performed to evaluate the association between fistula formation and antibiotic use, comparing adjuvant and nonadjuvant antibiotic groups stratified by the class of adjuvant antibiotic administered. In addition, the available culture results were reviewed and compared between patients who developed fistula and those who did not, to assess the potential associations between the cultured microorganisms and fistula formation.
Statistical methods
Continuous variables did not follow a normal distribution according to the Shapiro–Wilk test and were reported as medians with interquartile ranges (IQR) and compared using the Mann–Whitney U-test. Categorical variables were presented as frequencies (percentages) and were compared using the Chi-squared or Fisher’s exact test, as appropriate. Variables demonstrating clinical relevance or statistical significance in the univariate analysis were subsequently included in a multivariate regression model to assess independent associations with fistula formation. Statistical significance was set at p < 0.05. All statistical analyses were performed using IBM SPSS statistics version 29.0.1.0 (IBM Corp., Armonk, NY).
Results
Overview and demographics
Figure 1 depicts the flowchart of the study participants. In total, 900 patients were assessed for eligibility, and 770 patients met the inclusion criteria; of these, 466 (60.5%) received adjuvant antibiotic therapy and 304 (39.5%) did not. Table 1 describes the demographic and perioperative characteristics stratified by adjuvant antibiotic therapy use.
Fig. 1.
Flow diagram of the study participants
Table 1.
Comparison of demographic and perioperative characteristics stratified by adjuvant antibiotic therapy
| Adjuvant antibiotic group (n = 466) | Nonadjuvant antibiotic group (n = 304) | p-Value | |
|---|---|---|---|
| Age (median, IQR), years | 46.0 (36.0–55.0) | 44.0 (36.0–55.0) | 0.304 |
| Sex | 0.515 | ||
| Male | 379 (81.3%) | 241 (79.3%) | |
| Female | 87 (18.7%) | 63 (20.7%) | |
| Ethnicity | 0.976 | ||
| Arab | 358 (76.8%) | 232 (76.3%) | |
| Southeast Asian | 105 (22.5%) | 70 (23.0%) | |
| Other | 3 (0.6%) | 2 (0.7%) | |
| Active smokersa | 48 (13.7%) | 52 (21.4%) | 0.014 |
| Diabetes mellitus | 104 (22.3%) | 54 (17.8%) | 0.144 |
| Ischemic heart disease | 29 (6.2%) | 16 (5.3%) | 0.639 |
| Congestive heart failure | 9 (1.9%) | 5 (1.6%) | 1.00 |
| Peripheral vascular disease | 6 (1.3%) | 0 (0.0%) | 0.087 |
| Chronic obstructive pulmonary disease | 1 (0.2%) | 1 (0.3%) | 1.00 |
| Chronic kidney disease | 10 (2.1%) | 6 (2.0%) | 1.00 |
| History of prior anorectal abscess | 49 (10.7%) | 37 (12.4%) | 0.484 |
| Abscess location | 0.122 | ||
| Perianal | 353 (75.8%) | 248 (81.6%) | |
| Ischiorectal | 99 (21.2%) | 48 (15.8%) | |
| Intersphincteric | 8 (1.7%) | 7 (2.3%) | |
| Horseshoe | 6 (1.3%) | 1 (0.3%) | |
| Associated cellulitis | 184 (39.5%) | 118 (38.8%) | 0.880 |
aData available for 594 (77.1%) patients
The baseline demographic characteristics were similar between the two groups. The overall burden of comorbidity was low and did not differ between the groups, with most patients reporting no chronic medical conditions (74.2% versus 78.9%, p = 0.715). The adjuvant antibiotic group had fewer smokers than the nonadjuvant antibiotic group (13.7% versus 21.4%, p = 0.014). A prior history of anorectal abscess was reported in 10.7% of patients in the adjuvant antibiotic group and 12.4% in the nonadjuvant antibiotic group (p = 0.484).
Abscess location did not influence the decision to administer adjuvant antibiotic therapy, with a comparable distribution of abscess locations in both groups (p = 0.122). Perianal abscess accounted for most cases (75.8% versus 81.5%), followed by ischiorectal (21.2% versus 15.8%), and intersphincteric (1.7% versus 2.3%). Horseshoe abscesses were uncommon in both groups (1.3% versus 0.3%).
Rate of fistula formation
With a median follow-up period of 68.1 (2.0–289.9) weeks, the overall fistula formation rate during the study period was 6.8%, with most cases (69.2%) diagnosed within 6 months of abscess I and D. The overall median time to clinical diagnosis of fistula was 15.4 weeks (IQR: 7.7–31.3). Table 2 compares the rate and time to clinical diagnosis of fistula between the adjuvant and nonadjuvant antibiotic groups, showing no difference in incidence rate (7.1% versus 6.3%, p = 0.664) or median time to fistula formation (13.7 weeks versus 23.1 weeks, p = 0.104). There were 433 (56.2%) patients who had at least 12 months of follow-up. Within this subgroup, the fistula formation rate remained consistent (7.4%) with the rate observed in the full cohort, with no difference between the adjuvant and nonadjuvant antibiotic groups (8.5% versus 5.6%, p = 0.343).
Table 2.
Comparison of postoperative fistula stratified by adjuvant antibiotic therapy
| Total (n = 770) | Adjuvant antibiotic group (n = 466) | Nonadjuvant antibiotic group (n = 304) | p-Value | |
|---|---|---|---|---|
| Postoperative fistula formation rate | 52 (6.8%) | 33 (7.1%) | 19 (6.3%) | 0.664 |
| Median time to clinical diagnosis of fistula, (IQR) weeks | 15.4 (7.7–31.3) | 13.7 (7.4–23.6) | 23.1 (10.7–39.1) | 0.104 |
Factors associated with fistula formation
Table 3 compares the factors associated with fistula formation. Baseline demographics and comorbidities were largely comparable between patients who formed a fistula and those who did not; however, diabetes mellitus was significantly less common among patients who formed a fistula (9.6% versus 21.3%, p = 0.049). In addition, abscess location was significantly associated with fistula formation, with ischiorectal (26.9% versus 18.5%) and intersphincteric (9.6% versus 1.4%) abscess demonstrating higher rates of fistula formation than perianal abscess.
Table 3.
Univariate analysis of factors associated with fistula formation
| Fistula n = 52 |
No fistula n = 718 |
p-Value | |
|---|---|---|---|
| Age (median, IQR), years | 47.5 (40.0–54.0) | 46.0 (36.0–55.0) | 0.155 |
| Sex | 0.856 | ||
| Male | 41 (78.8%) | 578 (80.6%) | |
| Female | 11 (21.2%) | 139 (19.4%) | |
| Ethnicity | 0.459 | ||
| Arab | 44 (84.6%) | 546 (76.0%) | |
| Southeast Asian | 8 (15.4%) | 167 (23.3%) | |
| Other | 0 (0.0%) | 5 (0.7%) | |
| Active smoker | 7 (17.1%) | 93 (16.8%) | 1.00 |
| Diabetes mellitus | 5 (9.6%) | 153 (21.3%) | 0.049 |
| Ischemic heart disease | 3 (5.8%) | 42 (5.8%) | 1.00 |
| Congestive heart failure | 2 (3.8%) | 12 (1.7%) | 0.243 |
| Peripheral vascular disease | 1 (1.9%) | 5 (0.7%) | 0.344 |
| Chronic obstructive pulmonary disease | 0 (0.0%) | 2 (0.3%) | 1.00 |
| Chronic kidney disease | 0 (0.0%) | 16 (2.2%) | 0.618 |
| Associated cellulitis | 18 (34.6%) | 284 (39.6%) | 0.557 |
| Abscess location | 0.002 | ||
| Perianal | 33 (63.5%) | 568 (79.1%) | |
| Ischiorectal | 14 (26.9%) | 133 (18.5%) | |
| Intersphincteric | 5 (9.6%) | 10 (1.4%) | |
| Horseshoe | 0 (0.0%) | 7 (1.0%) | |
| Culturea | 0.061 | ||
| Skin-derived organisms | 0 (0.0%) | 46 (12.3%) | |
| Gut-derived organisms | 28 (94.8%) | 284 (75.7%) | |
| No growth | 5 (15.2%) | 45 (12.0%) | |
| Adjuvant antibiotic therapy | 33 (63.5%) | 433 (60.3%) | 0.664 |
aData available for 408 (53.0%) patients
Another important observation was that none of the patients who grew skin-derived organisms only developed a fistula.
In the multivariate logistic regression analysis, age > 40 years [odds ratio (OR) = 2.809, 95% confidence interval (CI) 1.361–5.780] and intersphincteric abscess (OR = 10.539, 95% CI 3.224–34.454) were significantly associated with fistula formation. In contrast, diabetes mellitus was associated with a reduced risk of fistula formation (OR = 0.251, 95% CI 0.086–0.730) (Table 4).
Table 4.
Multivariate logistic regression analysis of factors associated with fistula formation
| Odds ratio | 95% confidence interval | p-Value | ||
|---|---|---|---|---|
| Lower | Upper | |||
| Age > 40 years | 2.809 | 1.361 | 5.780 | 0.005 |
| Female sex | 1.289 | 0.627 | 2.650 | 0.490 |
| Diabetes mellitus | 0.251 | 0.086 | 0.730 | 0.011 |
| Abscess locationa | 0.000 | |||
| Ischiorectal abscess | 1.936 | 0.967 | 3.878 | 0.062 |
| Intersphincteric abscess | 10.539 | 3.224 | 34.454 | < 0.001 |
| History of anorectal abscess | 1.018 | 0.407 | 2.549 | 0.969 |
| Adjuvant antibiotic therapy | 1.062 | 0.576 | 1.956 | 0.848 |
| Associated cellulitis | 0.804 | 0.428 | 1.510 | 0.497 |
aReference: perianal abscess
Subgroup analysis by antibiotic class
Table 5 reports the subgroup analysis between the adjuvant and nonadjuvant antibiotic groups stratified by the class of adjuvant antibiotic administered. No statistically significant differences were observed among the groups with regard to fistula formation.
Table 5.
Subgroup analysis of the associations of fistula formation between adjuvant and nonadjuvant antibiotic groups stratified by the class of adjuvant antibiotic administered
| Antibiotic class | Fistula | No fistula | p-Value |
|---|---|---|---|
| Beta-lactams | 5 (20.8%) | 47 (14.2%) | 0.370 |
| Amoxicillin/clavulanate | |||
| Piperacillin/tazobactam | |||
| Cefuroxime | |||
| Cephalexin | |||
| Fluoroquinolones | 2 (9.5%) | 26 (8.4%) | 0.694 |
| Ciprofloxacin | |||
| Levofloxacin | |||
| Lincosamides | 11 (36.7%) | 188 (39.7%) | 0.848 |
| Clindamycin | |||
| Nitroimidazoles | 3 (13.6%) | 38 (11.8%) | 0.735 |
| Metronidazole | |||
| Oxazolidinones | 0 (0.0%) | 2 (0.7%) | 1.00 |
| Linezolid | |||
| Combined agents | 12 (23.1%) | 132 (18.4%) | 0.460 |
| Ciprofloxacin and metronidazole | |||
| Ciprofloxacin and clindamycin | |||
| Clindamycin and metronidazole |
Microbiological analysis
Cultures were obtained from 408 (53.0%) patients, yielding 527 organisms. Among the patients sampled, 50 (12.3%) showed no microbial growth, 192 (47.0%) had monomicrobial infection, and 166 (40.7%) had polymicrobial infection.
Table 6 compares the microbiological cultures retrieved between patients who developed fistula and those who did not. Escherichia coli and Klebsiella pneumoniae were the most common gram-negative organisms in both groups, with a higher prevalence in patients who developed fistula, but this did not reach statistical significance. Notably, none of the patients who grew Staphylococcus spp. developed a fistula (0.0% versus 11.5%, p = 0.036).
Table 6.
Comparison of the microbiological profiles of patients who developed fistula and those who did not
| Organism recovered | Fistula n = 33 |
No fistula n = 375 |
p-Value |
|---|---|---|---|
| Gram-negative bacteria | |||
| Enterobacteriaceae | |||
| Escherichia coli | 21 (63.6%) | 184 (49.1%) | 0.146 |
| Klebsiella pneumoniae | 8 (24.2%) | 64 (17.1%) | 0.339 |
| Other Enterobacteriaceae | 0 (0.0%) | 13 (3.5%) | 0.612 |
| Other gram-negative bacilli | 1 (3.0%) | 8 (2.1%) | 0.536 |
| Gram-positive bacteria | |||
| Staphylococcus spp. | 0 (0.0%) | 43 (11.5%) | 0.036 |
| Streptococcus spp. | 2 (6.1%) | 56 (14.9%) | 0.200 |
| Enterococcus spp. | 1 (3.0%) | 14 (3.7%) | 1.00 |
| Anaerobes | |||
| Bacteroides spp. | 4 (12.1%) | 76 (20.3%) | 0.361 |
| Prevotella spp. | 3 (9.1%) | 18 (4.8%) | 0.236 |
| Other anaerobes | 1 (3.0%) | 9 (2.4%) | 0.574 |
| Candida spp. | 0 (0.0%) | 1 (0.3%) | 1.00 |
Discussion
In this study, the rate of fistula formation at 12 months following I and D of anorectal abscess was 6.8%, and adjuvant antibiotic therapy did not appear to confer any benefit.
The fistula rate observed in our study aligns with contemporary literature, yet trends toward the lower end of published estimates [11]. Limited data directly address the role of adjuvant antibiotic therapy, with variability in methodological approaches, including antibiotic selection, treatment duration, follow-up intervals, and blinding. Consistent with our findings, Sozener et al. found no significant difference in the fistula formation rate following a 10-day course of adjuvant antibiotic therapy [9]. Similarly, a retrospective study by Nunoo-Mensah did not identify a difference in a cohort in which nearly half of the patients received adjuvant antibiotic therapy, reporting an overall fistula rate of 32% with a median follow-up of 5 weeks [7].
Conversely, adjuvant antibiotic therapy was found to reduce fistula formation in one randomized controlled trial and three retrospective studies, although the strength of this association remains uncertain. Ghahramani et al. randomized patients to a 7-day course of adjuvant antibiotic therapy and concluded that it reduced fistula formation. However, the 3-month follow-up period of their study may have missed subsequent cases [10]. Our study observed a median time to clinical diagnosis of fistula of 15 weeks, which may account for the differences in the reported outcomes. Other observational studies have reported similar beneficial effects of adjuvant antibiotic therapy [5, 6, 8]. In 2019, a systematic review and meta-analysis of six studies, including the two randomized trials, concluded that 5–10 days of adjuvant antibiotic therapy reduced the odds of fistula formation by 36% [13]. This discrepancy underscores the necessity of comprehensive longitudinal surveillance in assessing the rate of fistula formation and indicates that short-term studies may not fully capture the actual scale of the disease burden.
Most recently, a randomized trial by Nasara et al. found no significant difference in fistula formation at 12 months following a 7-day course of adjuvant antibiotic therapy after abscess drainage, further supporting our findings [11]. On the contrary, Blondin et al. reported a lower rate of fistula formation associated with antibiotic use in a retrospective propensity analysis, although the overall incidence of fistula formation was high at 65% [8].
The secondary analysis identified several results relevant to future risk stratification and management strategies. Older age and abscess location were associated with subsequent fistula formation, while diabetes mellitus appeared to have a protective effect.
Literature investigating factors associated with fistula formation following abscess drainage demonstrates considerable variability in the results. Lohsiriwat et al. noted a higher fistula rate among patients younger than 40 years [6], whereas Sahnan et al. observed that although abscesses were more common in men, women had a higher rate of progression to fistula. This difference was attributed to sex differences in the incidence rates of superficial skin infections rather than cryptoglandular infections [14]. The present study did not demonstrate similar associations between young age or sex and fistula formation. On the contrary, multivariate regression analysis demonstrated age > 40 years to be linked to fistula formation.
Diabetes mellitus as a protective factor aligns with other reports, including a retrospective study by Lohsiriwat et al., who also noted that the absence of diabetes increased the risk of fistula formation [6, 14]. One plausible hypothesis is that patients with diabetes may be predisposed to superficial soft-tissue infections rather than to cryptoglandular pathology.
Another observation was the association between abscess location and fistula formation, with ischiorectal and intersphincteric abscesses linked to a higher proportion of subsequent fistula formation. Notably, the intersphincteric location maintained statistical significance in the multivariate analysis. Other studies have reported similar relationships between abscess location and the risk of fistula [9, 14, 15]. This likely represents the more complex drainage pathways of these spaces, where incomplete or misdirected drainage may facilitate the formation of persistent tracts and the subsequent development of a fistula.
Gut-derived organisms have been implicated in the pathogenesis of fistula formation, suggesting that the abscess communicates with the anal canal. In this study, patients with abscess cultures yielding gut-derived organisms were those who subsequently developed fistula, whereas none of the patients with skin-derived organisms developed fistula. This observation aligns with previous research that has reported an association between gut-derived organisms and fistula formation. These findings further support the cryptoglandular theory, which posits that obstruction of the anal glands leads to the formation of fistula. Conversely, the presence of skin-derived organisms has been associated with infections of obstructed apocrine glands, which are less likely to result in fistula formation [15–18].
Limitations
This study is limited by its retrospective design, lack of standardized postoperative pathways, variability in the antibiotics administered, and follow-up period. While not all patients had long-term follow-up, this is not unexpected considering that following anorectal abscess drainage, patients seldom return to the hospital for extended follow-up assessment unless new symptoms arise. Given the accessibility of our public hospital, it is reasonable to infer that patients experiencing new symptoms would have sought further medical evaluation. In addition, patients who underwent I and D in the emergency department were not included.
Despite these limitations, this study augments the existing evidence base by including a large, real-world cohort, capturing contemporary antibiotic prescribing practices, and delineating the natural history of anorectal abscess following drainage, thereby enhancing the generalizability of its findings.
Conclusions
In this retrospective cohort study of patients who underwent I and D for anorectal abscess, adjuvant antibiotic therapy did not appear to reduce the risk of subsequent fistula formation. Further prospective randomized studies with standardized long-term surveillance are needed to clarify whether adjuvant antibiotic therapy affects the risk of fistula.
Supplementary Information
Below is the link to the electronic supplementary material.
Author contributions
Study conception and design: JA, SA, NA, HA, and FA. Acquisition of data: JA, SA, NA, HA, and FA. Analysis and interpretation of data: JA and FA. Drafting of manuscript: JA, SA, NA, HA, and FA. Critical revision of manuscript: JA, SA, NA, HA, and FA.
Funding
This study did not receive any funding.
Data availability
The data generated and analyzed for the current study are not publicly available but may be obtained from the corresponding author upon reasonable request.
Declarations
Conflict of interest
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial or nonfinancial interest in the subject matter or materials discussed in this manuscript. The authors declare no competing interests.
Ethical approval/consent to participate
The institutional ethical committee of the Ministry of Health approved this study, and the requirement for written consent was waived owing to the retrospective design of this study.
Clinical trial number
Not applicable.
Consent to publish
Not applicable.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data generated and analyzed for the current study are not publicly available but may be obtained from the corresponding author upon reasonable request.