Introduction

Sepsis is a life-threatening condition characterized by organ dysfunction resulting from a dysregulated immune response to infection [1]. Sepsis and septic shock represent major global health issues, affecting millions annually and causing death in approximately one out of every 4 individuals [2]. The global incidence of sepsis is estimated to range from 276 to 678 cases per 100,000 people annually, with mortality rates between 22.5% and 26.7%. Vulnerable populations include the elderly, pregnant women, neonates, hospitalized patients, intensive care unit (ICU) patients, individuals with compromised immune systems, and those with chronic medical conditions [3].

Vitamin D, a secosteroid, was once considered solely responsible for maintaining calcium and phosphorus balance in bones. Recent research, however, has revealed its role in immunomodulation, cell proliferation, and differentiation following vitamin D administration [4]. A retrospective cohort study by Braun, which analyzed 1,325 samples, found that ICU patients with vitamin D levels below 15 ng/mL exhibited a significant association with higher mortality rates among sepsis patients [5]. Other studies have also linked reduced serum vitamin D levels to conditions such as diabetic foot ulcers, suggesting that inflammation and increased infection susceptibility may be involved in the pathomechanism [6,7].

The vitamin D receptor (VDR) is expressed in macrophages, lymphocytes, and monocytes. When stimulated by 25-hydroxyvitamin D (25(OH)D), these cells can increase the secretion of antimicrobial peptides like cathelicidin. Cathelicidin is effective against various pathogens, including Gram-positive and Gram-negative bacteria, fungi, and microbes present in the skin, respiratory, and digestive tracts. Patients with 25(OH)D levels below 20 ng/mL are unable to produce sufficient cathelicidin, thereby increasing their susceptibility to nosocomial infections such as pneumonia and sepsis [8]. Furthermore, vitamin D binding to its receptor has been implicated in the pathogenesis of foot ulceration in individuals with diabetes [9]. There is also growing evidence that various VDR polymorphisms may play roles in a range of diseases, including hypertension, non-alcoholic fatty liver disease, cancer, and obesity [10].

Genetic polymorphisms, which are common variations in DNA sequences among populations, can affect biological functions. Recent studies have identified several polymorphisms in the VDR gene; however, their impact on protein function and VDR signaling remains incompletely understood. Among these, the FokI polymorphism, located in the translation initiation region of the VDR gene, produces VDR proteins with different structures. A study by Zeljic et al. [11] in Serbia involving 100 ICU sepsis patients found that the VDR FokI polymorphism (rs2228570) was associated with increased mortality within the first 28 days of sepsis.

This study focused on the FokI polymorphism in the VDR gene due to its unique potential to influence vitamin D metabolism and its significant impact on VDR functionality. This polymorphism results in the production of different VDR protein forms that alter the body’s response to vitamin D. Although other polymorphisms such as ApaI, BsmI, and TaqI were considered, they were not prioritized because of limited evidence supporting their clinical significance in sepsis. The ability of the FokI polymorphism to potentially affect vitamin D dosing and therapeutic responses, particularly in sepsis patients, renders it a more pertinent target for analysis.

Despite an expanding body of literature on the role of vitamin D in sepsis, several key gaps remain. Prior studies on vitamin D levels in ICU-treated sepsis patients have been constrained by small sample sizes, methodological variability, and the absence of standardized protocols for vitamin D measurement and supplementation [12,13]. Moreover, many studies have not accounted for potential genetic variations in the VDR gene, particularly the FokI polymorphism, which may influence vitamin D metabolism and immune responses. These limitations have contributed to inconsistent findings, making it challenging to draw definitive conclusions about the clinical implications of vitamin D deficiency in sepsis management. In contrast, our study addresses these gaps by performing a comprehensive meta-analysis that includes only studies with rigorous methodological designs, such as large sample sizes and consistent measurement protocols, while also examining the role of VDR gene polymorphisms in modulating vitamin D effects in sepsis patients.

This study differs from previous systematic reviews and meta-analyses in several ways. First, while earlier reviews have predominantly focused on vitamin D levels and sepsis outcomes, our review uniquely incorporates an analysis of the VDR FokI polymorphism, which may modulate vitamin D effects and contribute to variability in sepsis susceptibility and outcomes. Second, previous studies often suffered from insufficient sample sizes or methodological inconsistencies, issues we addressed by including only studies that met stringent inclusion criteria in accordance with Cochrane’s guidelines, even if some were of poor quality, and by addressing heterogeneity through subgroup analysis or meta-regression when necessary. Finally, this review provides a detailed risk of bias assessment using the Newcastle-Ottawa scale, which evaluates the influence of study design and methodology on the findings, allowing for a more nuanced interpretation of the evidence. Overall, our aim is to offer a comprehensive and reliable understanding of the relationships between vitamin D levels, the VDR FokI polymorphism, and sepsis risk and mortality.

Materials and Methods

Eligibility Criteria

The inclusion criteria for articles were (1) study type: Only studies published in English and available as full-text articles were considered. The selection included randomized controlled trials, cohort studies, case-control studies, and observational studies that focused on the relationship between vitamin D levels, VDR FokI gene polymorphism, and sepsis risk or mortality. (2) Patient demographics: Studies involving human subjects of any age, gender, or ethnicity were included. Priority was given to studies involving sepsis patients treated in an ICU setting. Neonates, adults, and elderly patients were considered as long as the data were relevant to the analysis. (3) Vitamin D and VDR FokI gene polymorphism: Studies measuring serum 25(OH)D levels and assessing the relationship between vitamin D deficiency and sepsis outcomes were included. Specifically, studies analyzing the VDR FokI gene polymorphism (rs2228570) were incorporated. Although other SNPs such as ApaI, BsmI, and TaqI were considered where available, the primary focus remained on FokI. (4) Variables to be collected: Eligible studies measured factors such as body mass index, age, gender, and comorbidities (e.g., diabetes or hypertension) that could influence vitamin D levels and sepsis outcomes. Data on sepsis severity (e.g., sequential organ failure assessment score) and inflammatory markers such as C-reactive protein were also considered. (5) Outcomes: Only studies that reported on the relationship between vitamin D levels, VDR polymorphisms, and sepsis mortality or morbidity were included. Studies providing quantitative data on the correlation between these factors and sepsis risk, hospital or ICU length of stay, or inflammatory markers were also considered.

The exclusion criteria for articles were (1) case reports and reviews: Case reports, narrative reviews, and meta-analyses were excluded because the focus was on original research providing primary data. (2) Non-human studies: Animal studies and studies that did not involve human participants were excluded. (3) Inadequate data: Studies that did not report on the relationship between vitamin D levels and VDR polymorphisms in sepsis patients or lacked sufficient data to perform a meta-analysis (e.g., no sample size, lack of control groups) were excluded. (4) Language and accessibility: Studies not published in English or those without full-text access were excluded. (5) Study design limitations: Articles that did not meet the inclusion criteria due to methodological issues, such as failure to control for important confounders or poor study quality (e.g., high risk of bias as per the Newcastle-Ottawa scale) were excluded from the meta-analysis.

Information Sources

A systematic literature review was conducted using electronic databases including PubMed, Embase, ProQuest, and the Cochrane Library for the period from 1996 until 2025, incorporating studies of varying quality. Keywords used in the search included “sepsis AND (Vitamin D OR 25(OH)D OR 25-Hydroxyvitamin D)” and “VDR FokI polymorphism OR Vitamin D receptor FokI gene variant.”

Selection Process

The selection process began with a keyword search in various databases to identify relevant studies, followed by the removal of duplicate entries. Titles and abstracts were then screened, and full-text evaluations were conducted to determine eligibility. Studies containing relevant data were systematically analyzed and included in the meta-analysis, as depicted in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram (Figure 1).

Data Synthesis

Data from the selected studies were critically analyzed and synthesized to explore the relationship between vitamin D levels, VDR FokI gene polymorphism, and sepsis risk or mortality. The data were organized into 3 primary subtopics: (1) sepsis patients with VDR FokI gene polymorphism, (2) vitamin D levels in sepsis patients, and (3) the relationship between vitamin D levels and VDR FokI polymorphism in sepsis patients. The synthesis process followed these steps.

Data extraction

Two independent reviewers extracted data using a standardized form. Extracted data included study design, sample size, participant demographics (e.g., age, gender), vitamin D levels (25[OH]D), VDR FokI genotype (TT, CT, CC), and sepsis-related outcomes (e.g., sepsis risk, mortality). Discrepancies were resolved by consensus.

Statistical analysis

A meta-analysis was performed to quantitatively assess the relationship between vitamin D levels and sepsis outcomes. The pooled effect size for continuous variables (e.g., vitamin D levels) was calculated as the mean difference (MD) with 95% confidence intervals (CIs). The association between VDR FokI genotype (TT, CT, CC) and sepsis risk was analyzed using odds ratios (ORs) with 95% CIs, and the significance of pooled estimates was determined using the Z-statistic (p-value).

Heterogeneity assessment

Given the variability in study designs and populations, heterogeneity was evaluated using I² statistics. An I²-value greater than 50% indicated substantial heterogeneity. A random-effects model was applied for studies with significant heterogeneity (I²>50%), while a fixed-effects model was used for studies with low heterogeneity.

Risk of bias

The risk of bias for each study was assessed using the ROB2 tool, which examines 5 domains: (1) randomization process, (2) deviations from intended intervention, (3) missing outcome data, (4) outcome measurement, and (5) selection of reported results. Studies with a high risk of bias were excluded from the analysis.

Sensitivity analysis

A sensitivity analysis was conducted by sequentially removing individual studies to determine if any single study disproportionately affected the overall results.

Publication bias

Publication bias was evaluated using funnel plots and the Egger test. A symmetrical funnel plot suggested no significant publication bias, whereas asymmetry indicated potential bias that could affect interpretation.

Statistical software

All analyses were performed using Review Manager (RevMan) software ver. 5.4 (Cochrane), with a significance threshold set at p<0.05.

Additional statistical data

Where available, subgroup analyses based on patient demographics (e.g., age, gender, comorbidities) were performed to examine potential effect modifiers on the relationship between vitamin D and sepsis outcomes. Additionally, if data on vitamin D supplementation were available, its potential impact on sepsis-related outcomes in patients with vitamin D deficiency was analyzed.

Results

Study Selection

A total of 267 records were initially identified from various databases, including PubMed (n=89), Embase (n=77), ProQuest (n=101), Cochrane Library (n=0), and LILACS (n=0). After screening, 136 records were deemed relevant for further evaluation. Following duplicate removal, 131 unique records remained. Further review excluded 117 records due to non-original research (n=84) or lack of full-text availability (n=33), leaving 19 reports for eligibility assessment. Of these, 11 reports were excluded because they did not focus on sepsis, vitamin D, or the VDR FokI variable. Ultimately, 8 studies were included in the review and meta-analysis. Specifically, 7 articles were excluded due to their focus on topics unrelated to sepsis—namely, Cafiero et al. [14] on periodontal disease; Gupta et al. [15] on tuberculosis disease–human immunodeficiency virus; Mokhtar et al. [16] on congenital heart disease; Ni et al. [17] on pregnancy; Rasheed et al. [18] on mycosis fungoides; Zununi Vahed et al. [19] on kidney transplant; and Zacharioudaki et al. [20] on viral infection in infants—as well as Al-Daghri et al. [21] on cardiometabolic health in type 2 diabetes mellitus (T2DM), Kazemian et al. [22] on breast cancer, Mohseni et al. [23] on the impact of vitamin D supplementation on inflammatory markers and total antioxidant capacity in women with breast cancer, Neyestani et al. [24] in 2013 on the influence of VDR FokI genotypes on the effectiveness of vitamin D supplementation on glycemic, lipidemic, and inflammatory biomarkers in T2DM patients, and Sanwalka et al. [25] on the effect of VDR gene FokI polymorphism on bone mass accrual in Indian girls with low calcium intake. Ultimately, 7 relevant articles were identified and underwent data extraction and meta-analysis (Figure 1).

Risk of Bias in Studies

The risk of bias in the 8 reviewed articles was assessed using the Newcastle-Ottawa scale. The evaluation was conducted across 8 domains, with results presented in a table using red, yellow, and green symbols. All 7 articles demonstrated low bias in the 5 assessed domains, as indicated by green symbols (Figure 2) [11,26–32].

Vitamin D Deficiency in Sepsis Patients

Studies investigating the relationship between vitamin D levels and the FokI polymorphism in relation to sepsis risk and mortality have produced varying results. A study by Abouzeid et al. [26] in Egypt reported significantly lower vitamin D levels in sepsis cases compared to controls (17.5±4.4 ng/mL vs. 36.7±6.5 ng/mL). The FokI FF genotype was associated with a significantly increased risk of sepsis (OR, 3.7; 95% CI, 1.4–10.2) and mortality (OR, 3.7; 95% CI, 1.4–10.2). Tayel et al. [27] at Menoufia University Hospitals observed similar results in neonates, noting lower vitamin D levels in neonates with sepsis (8.7±0.7 ng/mL vs. 19.1±4.7 ng/mL) and an increased sepsis risk associated with the TT genotype (OR, 4.804; 95% CI, 1.4–16.4). In Serbia, Zeljic et al. [11] reported that the homozygous CC genotype increased sepsis risk, although no significant relationship with mortality was found. In contrast, Shaheen et al. [28] in Egypt observed no significant association between vitamin D levels, FokI polymorphism, and sepsis risk or mortality. Similarly, Das et al. [29] in India found no association between the FokI polymorphism and neonatal sepsis, despite lower vitamin D levels in cases compared to controls (12.23 ng/mL vs. 30.32 ng/mL) (Table 1) [11,26–32].

A study by Yang et al. [30] in China indicated that both the FokI FF and Ff genotypes, as well as the f allele, significantly increased sepsis risk, while Bozgul et al. [31] in Turkey found that the CC genotype was associated with a decreased risk of mortality (OR, 0.41; 95% CI, 0.17–0.92). Additionally, a study by Xiao et al. [32] focused on these genetic variations and their potential to predict susceptibility to neonatal sepsis. This study is significant because it links genetic polymorphisms with serum biomarkers (such as 25(OH)D and sTREM-1), which could serve as diagnostic tools for neonatal sepsis.

The Relationship Between Sepsis Severity and Vitamin D Levels

Comparison of vitamin D levels between sepsis patients and healthy control groups

A meta-analysis comparing vitamin D levels between sepsis patients and healthy control groups found that vitamin D levels were lower in sepsis patients than in controls, with a MD of –4.17 (95% CI, –7.87 to –0.47) ng/mL. Although significant heterogeneity was observed among the studies (tau²=17.75, I²=100%), the overall effect was statistically significant, with a Z value of 2.21 and p=0.03 (Figure 3) [26–30].

The distribution of VDR FokI genotypes (T/T, C/T, C/C) between sepsis patients and the control group

A meta-analysis of the risk associated with the CC c VDR FokI genotypes between sepsis patients and control groups revealed a higher risk in the sepsis group compared to controls, with a risk difference of 1.39 (95% CI, 0.70–2.73). However, the overall effect was not statistically significant, with a Z value of 0.95 and p=0.34. The analysis also demonstrated significant heterogeneity (tau²=0.81, I²=91%), suggesting that these results should be interpreted with caution (Figure 4) [11,26–32].

For the CT genotype, the risk in the sepsis group was higher than in the control group, with a risk ratio of 0.75 (95% CI, 0.47–1.20). Despite a Z value of 1.19 and a reported p-value of 0.001, the overall effect was not statistically significant. Moderate heterogeneity was observed (tau₂=0.29, I²=71%), which suggests that these results can be interpreted with somewhat greater confidence compared to previous analyses (Figure 5) [11,26–32].

The analysis of the TT genotype indicated that a lower risk in the sepsis group compared to controls, with a risk ratio of 1.04 (95% CI, 0.78–1.39). However, this difference was not statistically significant, as indicated by a Z value of 0.27 and p=0.78. Significant heterogeneity was observed (tau₂=0.09, I²=58%), warranting cautious interpretation of these results (Figure 6).

Discussion

We assessed the risk of bias for each study included in the meta-analysis using the Newcastle-Ottawa scale, which evaluates studies across 5 key domains. Each domain was categorized as low risk, high risk, or unclear risk. This evaluation allowed us to assess the credibility and quality of the studies in our systematic review and meta-analysis. The scale examines aspects based on predefined criteria such as the adequacy of the case definition, representativeness of the cases, selection and definition of controls, comparability of cases and controls, ascertainment of exposure, the consistency of ascertainment methods for cases and controls, and the non-response rate. Overall, the risk of bias was primarily low, although a few studies raised concerns in specific domains—such as unclear randomization or missing outcome data—which may have impacted the results despite their inclusion based on eligibility criteria.

The results of this study indicate that vitamin D levels in sepsis patients are consistently lower than in the control group. This finding aligns with the established role of vitamin D as an immunomodulator that contributes to the body’s immune response. Vitamin D enhances the activity of innate immune cells, including macrophages and neutrophils, while reducing the release of pro-inflammatory cytokines. Consequently, lower vitamin D levels may impair the body’s ability to combat infections, thereby increasing the risk of sepsis.

The FokI polymorphism in the VDR gene is a functional variant rather than a silent one. Occurring in the translation region of the VDR gene, it leads to the production of 2 different forms of the VDR protein. The “F” allele produces a longer VDR protein, whereas the “f” allele results in a shorter form. This functional difference is believed to affect the receptor’s ability to bind vitamin D, thereby influencing the immune system’s response. Studies suggest that this polymorphism may alter VDR activity, affecting the body’s ability to modulate immune responses and potentially increasing susceptibility to conditions such as sepsis. Therefore, the FokI polymorphism is considered functional because it can modify receptor activity and the immune system’s responsiveness to vitamin D.

This study also indicates that VDR gene polymorphisms, particularly FokI, may be associated with sepsis risk, although there is variability in the results across studies. For example, some studies—such as those by Abouzeid et al. [26] and Yang et al. [30]—found that the FF genotype significantly increased the risk of sepsis. In contrast, other studies, including those by Das et al. [29] and Shaheen et al. [28], did not observe a significant association. This variation could be attributed to differences in population characteristics, analytical methods, and sample sizes used in each study.

The meta-analysis results support the finding that vitamin D levels are lower in sepsis patients compared to the control group (standard MD, –4.17; 95% CI, –7.87 to –0.47) (Figure 3) [26–30]. The potential role of vitamin D in the pathophysiology of sepsis is further underscored by observations that patients with severe sepsis exhibit significantly lower levels of vitamin D compared to those with mild sepsis or healthy individuals [33,34]. Vitamin D plays a critical immunomodulatory role in both innate and adaptive immunity by enhancing the production of antimicrobial peptides (such as cathelicidin and defensins), suppressing pro-inflammatory cytokines (tumor necrosis factor-α and interleukin [IL]-6), and increasing anti-inflammatory cytokines (IL-10) [35]. In sepsis, dysregulation of the immune response—marked by hyper-inflammatory reactions and immunosuppression—is a key factor in morbidity and mortality. Consequently, low vitamin D levels may exacerbate this condition by reducing the body’s capacity to fight infections [33,36,37]. Several mechanisms may explain the reduced vitamin D levels in sepsis patients, including pre-existing vitamin D deficiency due to comorbidities like kidney or liver disease, increased utilization of vitamin D during the immune response, and organ dysfunction that disrupts the conversion of vitamin D to its active form [37,38].

Although some studies found an association between the FokI polymorphism and sepsis risk, our meta-analysis shows that the risk associated with the genotype is not statistically significant (CC: p-value=0.53; CT: p-value=0.46; TT: p-value=0.3) (Figures 4–6). In this regard, Lu et al. [39] also supported the view that the relationship between FokI and sepsis risk is not significant—particularly when FokI is considered among genetic variants that do not meet strong or moderate credibility criteria. The analysis also revealed significant heterogeneity, indicating that these results should be interpreted with caution. This variability may result from local genetic factors, differing mutation patterns in the VDR gene across populations, or the interaction between genetic and environmental influences.

The relationship between vitamin D levels and susceptibility to sepsis may also be influenced by genetic factors, including variations in the gene encoding VDR [11,30,40]. Among these, the FokI polymorphism is one of the most extensively studied, as it is believed to affect VDR function and, in turn, the body’s immune response. However, although low vitamin D levels have been consistently identified as a risk factor that exacerbates sepsis, the evidence regarding a direct relationship between the FokI polymorphism and sepsis risk remains inconclusive [28,30,40].

Additionally, the findings of this study have important implications for the management of patients at risk for sepsis. Detecting low vitamin D levels and identifying VDR gene polymorphisms may serve as useful preventive or diagnostic measures to improve sepsis management. Vitamin D supplementation in high-risk populations, such as neonates or patients with immune deficiencies, could represent a potential therapeutic approach, although further research is needed to substantiate this strategy.

However, several limitations must be acknowledged. The high heterogeneity observed suggests that methodological variations, sample sizes, and population characteristics have influenced the results. Furthermore, not all studies provided detailed information on parameters that might affect outcomes—such as nutritional status, comorbidities, or medications received by the patients. Therefore, further research using prospective designs and better control of confounding factors is warranted.

Several limitations must be considered when interpreting this study’s results. First, high heterogeneity was observed across the studies included in the meta-analysis, indicating variability in study designs, populations, and measurement methods. This heterogeneity suggests that the findings may not be universally applicable and that the results should be interpreted with caution. Factors such as methodological differences (e.g., varying protocols for measuring vitamin D levels, differences in the timing of these measurements, and diverse inclusion criteria for sepsis patients) likely contribute to this variability. Second, some studies had relatively small sample sizes, which may limit both the statistical power and the generalizability of the results. While larger studies could help clarify these trends, small sample sizes might lead to overestimated or underestimated effects. Another important limitation is the insufficient reporting of potential confounding variables—such as comorbid conditions (e.g., diabetes, obesity), medications, and nutritional status—that could affect both vitamin D levels and sepsis outcomes. Without controlling for these factors, drawing definitive conclusions about the causal relationship between vitamin D deficiency and sepsis risk is challenging. Lastly, variability in the assessment of VDR polymorphisms (i.e., differences in reporting genotypic distributions and a limited focus on the FokI polymorphism) may have influenced the consistency of the results. It is also important to note that the relationship between the FokI polymorphism and sepsis risk remains inconclusive, and further studies with more standardized genotyping methods are necessary to confirm these findings. Overall, while this study provides valuable insights into the potential role of vitamin D and VDR polymorphisms in sepsis, future research should address these limitations by incorporating larger, more consistent datasets, accounting for potential confounders, and using more standardized methodologies.

Conclusion

This study demonstrates that vitamin D levels in sepsis patients are significantly lower than those in the control group, underscoring the potential role of vitamin D as a risk factor in the development of sepsis. Moreover, although several studies have identified an association between VDR gene polymorphisms—particularly FokI—and an increased risk of sepsis, the meta-analysis did not reveal a statistically significant relationship, with high heterogeneity observed across the studies.

HIGHLIGHTS

• Sepsis patients were found to have significantly lower vitamin D levels, suggesting that hypovitaminosis D may be a risk factor.

• This study also identifies a potential link between the VDR FokI gene polymorphism and increased sepsis risk.

• These findings underscore the importance of early detection of vitamin D deficiency as a preventive strategy in at-risk populations.

Supplementary Material

Article information

Ethics Approval

Not applicable.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Funding

None.

Availability of Data

All data generated or analyzed during this study are included in this published article. For other data, these may be requested through the corresponding author.

Authors’ Contributions

Conceptualization: all authors; Data curation: WJ; Formal analysis: all authors; Funding acquisition: WJ; Investigation: WJ; Methodology: WJ; Project administration: all authors; Resources: all authors; Software: all authors; Supervision: SRT, HS, AAA; Validation: SRT, HS, AAA; Visualization: WJ; Writing–original draft: WJ; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow for systematic studies.

Figure 2.

Risk of bias analysis using the Newcastle-Ottawa scale with 8 domains.

Figure 3.

Forest plots comparing vitamin D levels between cases and controls. SD, standard deviation; SMD, standard mean difference; IV, intravenous; CI, confidence interval.

Figure 4.

Forest plot comparing the distribution of the CC VDR FokI genotype. M-H, Mantel-Haenszel; CI, confidence interval; df, degrees of freedom.

Figure 5.

Forest plot comparing the distribution of the CT VDR FokI genotype. M-H, Mantel-Haenszel; CI, confidence interval; df, degrees of freedom.

Figure 6.

Forest plot comparing the distribution of the TT VDR FokI genotype. M-H, Mantel-Haenszel; CI, confidence interval; df, degrees of freedom.

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