Soluble CD14 (Presepsin) in the early prediction of bacterial type in Early Onset Neonatal Sepsis in Preterm Neonates

Soluble CD14 (Presepsin) in the early prediction of bacterial type in Early Onset Neonatal Sepsis in Preterm Neonates | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Soluble CD14 (Presepsin) in the early prediction of bacterial type in Early Onset Neonatal Sepsis in Preterm Neonates Mariam John Amin Ibrahim, Ahmed Nasser Ibrahim Elkholy, Heba Mohamed Atif Ismail, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6874629/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Identifying the type of bacterial infection in a timely manner is crucial for the successful treatment of newborns with early-onset sepsis. However, blood culture results are often delayed, highlighting the urgent need for an early biomarker to predict the causative organism. Presepsin (P-SEP) has recently gained attention as a promising biomarker, generated as a component of the immune system's reaction to bacterial infection. It acts as an early warning sign of sepsis in newborns and can be identified in the first phases of inflammation. Purpose: to assess the predictive efficacy of soluble CD14 (presepsin) in identifying the type of bacterial organism in preterm newborns with early onset neonatal sepsis. Methods: thirty-six newborns with risk factors for early-onset sepsis were included in this prospective observational study, and initial CRP negative, they were further subdivided into probable & proven sepsis, based on the initial blood culture results. Serum presepsin levels, CRP and blood culture analyses were performed on all neonates. Results: Patients with gram-negative infections had significantly elevated P-SEP levels initially on the first day and at follow-up on the third day. At a cutoff value of ≥ 970 ng/L, serum P-SEP on day 3 yielded a 100% positive predictive value, an 87.5% sensitivity, a 100% specificity, and an 88.8% negative predictive value to predict gram negative bacterial infection Conclusion: Presepsin evaluation in preterm neonates with early-onset sepsis serves as a valuable early marker for identifying the type of bacterial infection present. Health sciences/Biomarkers Health sciences/Medical research predictive Soluble CD14 Presepsin early onset Neonatal Sepsis Preterm Neonates blood culture gram negative bacteria Figures Figure 1 Figure 2 Figure 3 Figure 4 What is known- what is new? Over the past few years, the clinical significance of presepsin has been extensively explored across different types of infections, including surgical infections, burns, and febrile neutropenia. Presepsin has been identified as a useful early diagnostic indicator for neonatal sepsis of both early and late onsets. The delay in obtaining blood culture results, especially in countries with low incomes, often compels clinicians to initiate empirical antibiotic therapy rather than targeted treatment based on the specific bacterial infection. This delay in appropriate management can negatively impact neonatal outcomes. Presepsin levels have been reported to be higher in infections caused by Gram-negative bacteria compared to Gram-positive ones. In the current study, we confirmed this finding and established a cutoff value that can help differentiate between Gram-negative and Gram-positive infections, enabling more precise selection of appropriate antibiotic therapy. INTRODUCTION Throughout the first month of life, neonatal sepsis, a serious health issue, presents with infection-related symptoms, either with or without bacteremia. Severe septicaemia can occur when infectious bacteria infiltrate into the bloodstream or they can cause specific infections including, urinary tract infections, osteomyelitis, arthritis, pneumonia, and meningitis. [ 1 ] After preterm birth and difficulties connected to the labor and delivery process (as birth asphyxia), the third most common cause of infant mortality is neonatal sepsis. It causes 42% of deaths in the first week of life and 13% of all neonatal deaths. [ 2 ] Unlike older patients, early stages of neonatal sepsis have a variety of noninfectious diseases and extremely vague presentations which may be confused with it. The limited value of laboratory tests including blood culture (gold standard) because of its limited sensitivity, low positivity rates, some traits of the neonatal population, as well as shifting typical reference ranges throughout the neonatal period make early detection of neonatal sepsis more difficult [ 3 ] Despite the usefulness of numerous diagnostic and treatment options, doctors caring for infected neonates in the age of multi-drug resistance, particularly in low- and middle-income countries, confront numerous obstacles when making judgements. They are still in need of new specific diagnostic and prognostic markers to identify the type of organism in infected patients who would benefit from targeted antibiotic therapy rather than empirical antibiotics. [ 3 , 4 ] As a bacterial molecular pattern recognition receptor, CD14 can recognize a variety of ligand groups from pathogens that are both Gram-positive and Gram-negative, including Lipopolysaccharides (LPS) from Gram-negative bacteria and peptidoglycans and lipoteichoic acid from Gram-positive bacteria. [ 5 ] It facilitates the toll-like receptor 4's processing of the endotoxin signal, which causes the discharge of several cytokines and encourages the initiation of a systemic inflammatory reaction. [ 6 ] Monocytes and macrophages, which are inflammatory cells, exhibit 2 types of CD14: a membrane-bound CD14 (mCD14) found on these cells and a soluble CD14 (sCD14), which is created when the membrane form of CD14 is shed in the plasma. The body's reaction to a bacterial infection includes the production of presepsin (P-SEP), a fragment with a size of 13 kDa called soluble CD14 subtype, (sCD14-ST) that is produced when plasma proteases cleave sCD14. [ 7 ] P-SEP is thought to promote monocyte phagocytosis and interact with B and T cells to modify a particular immunological response, while its exact role is still unknown. In the early phases of inflammation and sepsis, it dramatically rises in the bloodstream. As a result, P-SEP appeared to be an appropriate biomarker for the early diagnosis of EOS. [ 8 , 9 , 10 ] AIM OF THE WORK To assess the predictive efficacy of soluble CD14 (presepsin) in identifying the type of bacterial organism in preterm newborns with early onset neonatal sepsis. PATIENTS AND METHODS This research was an observational prospective study. It was conducted at NICUs of Ain-Shams University Hospital, Cairo, Egypt, from October of 2021 and October of 2022. The study received approval from the faculty of medicine's Research Ethics Committee, Ain Shams university no. MS 619/2021. Each patient's parents provided their informed consent to be recruited in the study. No personal data was used in the study. The participants had the right to withdraw at any point in the study. The present study included 36 newly born infants preterm having a minimum of one Risk factor for maternal and newborn infections or clinical signs that point to the possibility of early-onset sepsis but with an initial CRP negative result. Preterm neonates with the following characteristics were considered neonatal risk factors: respiratory discomfort that begins more than four hours after birth, The necessity of mechanical ventilation Apnoea seizures, aberrant vitals or signs of shock, changes in reactivity or behaviour, altered muscular tone, such as floppiness, newborn encephalopathy symptoms, feeding issues or intolerance, Hypoxia , jaundice 24 hours after birth, Cardiopulmonary resuscitation was required, anomalies in the temperature (less than 36°C or more than 38°C) that cannot be attributed to environmental sources, abnormal coagulation (International Normalised Ratio >2.0), thrombocytopenia, or excessive bleeding that cannot be explained, Oliguria that lasts longer than 24 hours after birth, either hyperglycemia or hypoglycemia, metabolic acidosis (base deficit of at least 10 mmol/L), Infection symptoms that are localised (e.g., dermal or ocular). [11] Maternal ‘risk factors of sepsis : invasive bacterial infection that was either confirmed or suspected during childbirth or in the 24 hours prior to and following delivery, needing parenteral antibiotic treatment. Infection in another child, either suspected or confirmed in case of a multiple pregnancy. A prior infant that had an invasive group B streptococcal infection. Infection, bacteriuria, or colonisation of maternal group B streptococci during the present pregnancy. Rupture of the membranes prior to labour. Premature delivery after spontaneous labour (before to 37 weeks gestation). Suspected or verified membrane rupture in a premature birth lasting more than eighteen hours. High intrapartum fever or chorioamnionitis, either confirmed or suspected. Pregnancy-related procedures like amniocentesis and cervical cerclage [11] . Neonates with serious congenital malformation, fetal hydrops, perinatal asphyxia and confirmed intrauterine infections (herpes, syphilis, CMV, rubella, and toxoplasmosis) were excluded from the study [12] . The laboratory findings were concealed from the treating physicians, and two physicians categorised the newborns according to the definitions of infections and risk factors. Patients were classified as septic or not if both clinicians agreed. All neonates included in this study had positive risk factors for infection and initial routine sepsis markers (CRP 6 mg/dl at follow-up on day 3 of life, despite negative blood culture. All participating patients received empirical antibiotic therapy according to the protocol in children hospitals' NICUs (ampicillin and gentamycin) until culture and sensitivity results appeared. Every patient underwent the following procedures: Complete history taking: Antenatal, Natal and Postnatal histories. Gestational age estimation and Anthropometric measurementswere done at time of admission. Clinical examinationwas performed For symptoms and signs of suspected sepsis. General Examination: (Vital data, blood glucose levels, mental status, and exclusion of dysmorphic features) Local Examination: Chest: signs of respiratory distress, need for respiratory support and surfactant, Cardiovascular: capillary perfusion time, and the need for inotropic support, Abdomen: signs of feeding intolerance and abdominal girth and Central nervous system: Head circumference, fontanelles, muscle tone, reflexes, posture, and convulsions. Laboratory investigations done included blood culture (BACTEC), peripheral blood smear examination and complete blood count (CBC), human presepsin (P-SEP) was determined using the enzyme linked immunosorbent assay (ELISA) technique, and CRP was measured using a highly sensitive C-reactive protein . Blood samples were withdrawn from all cases prior to beginning antibiotic medication for culture, CBC with differential, CRP and P-SEP. These biomarkers were measured again at 72 hours. Blood samples were withdrawn by the most skilled personnel in the facility, and no samples were stored to be used in any further research. Statistical Analysis: The acquired data was coded, entered, and analysed using Microsoft Excel software. The data was then analysed using the Statistical Package for the Social Sciences (SPSS) program, version 28.0. Categorical variables were displayed as numbers and proportions, whereas quantitative continuous variables were displayed as mean and standard deviation for parametric data and median and interquartile range for nonparametric data. To determine whether differences and associations were significant, the following tests were employed: the normality of data was assessed by visual inspection of their histograms, skewness and kurtosis statistics and standard errors. Levene's test was used to confirm that the variances in the samples were equal (homogeneity of variance); for parametric data, independent continuous variables were compared using the student's t-test.; the one-sample Kolmogorov-Smirnov or Shapiro-Wilk tests were used to test the variables; the variable is not normally distributed if (p value) < 0.05; and the variances are not equal if (p value) < 0.05. The P-value, or probability level, was set at less than 0.05 for outcomes that were statistically significant and less than 0.001 for those that were highly significant. Where appropriate, values for the 95 percent confidence interval (95% CI) and odds ratio (OR) were shown. Receiver Operating Characteristic (ROC) curves for P-SEP were analysed in order to identify the area under the curve (AUC) and the most accurate cut-off values. After that, all other research variables, including sensitivity, specificity, LR+, LR-, positive predictive value (PPV), and negative predictive value (NPV), were assessed, in order to predict type of organism. For each parameter, an exact 95% CI was computed. An optimum test index is indicated by an AUC of 1.0; a diagnostic test with no relevance has an AUC of 0.5. A diagnostic test is generally considered low value if its ROC-AUC falls between 0.5 and 0.7, medium value if it falls between 0.7 and 0.9, and excellent value if it falls beyond 0.9. A significant statistical difference was demonstrated by a P<0.01 value. Ethics approval The study received approval from the faculty of medicine's Research Ethics Committee, Ain Shams university no. MS 619/2021. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, as adopted by the World Medical Association for research involving human participants. Each patient's parents provided their informed consent to be recruited in the study. No personal data was used in the study. The participants had the right to withdraw at any point in the study. RESULTS A total of 125 newborns were qualified to take part in our research, 99 were excluded due to the presence of congenital anomalies, presence of intrauterine infections, declining to participate or lost follow up (Figure 1) More than half of the case, 61.11% of them were males and 38.88% were females. Mean ± SD of the gestational age was 32.58 ± 2.43. The mean ± SD of the mother ages was 29.31 ± 5.01, and most of the deliveries were by caesarean sections. Forty-four percent of the septic newborns had positive blood culture results; eight out of sixteen culture-proven EOS had gram-negative bacteria (50%) and seven out of sixteen had gram-positive bacteria (43.7%); The organism that was most common was coagulase-negative Staphylococcus. (4cases; 25%), klebsiella came next (3 cases, 18.7%), Enterococci (2 cases; 12.5%), Acinetobacter (2 cases ; 12.5%), One case with Staphylococcus aureus (6.3%), MRSA (o1 case; 6.3%), Enterobacter aerogenes (one case; 6.3%), Candida parapsilosis (one case; 6.3%), and a mix of Klebsiella and Acinetobacter (one case; 6.3%) (Table 1, figure 2) . Patients with gram-negative infections had substantially greater P-SEP levels at baseline (day 1) and follow-up (day 3), than those with gram-positive infections (t = 2.352, p = 0.035; t = 3.810, p = 0.002 respectively). (Table 2) . Further analysis of the presepsin levels on day1 and day 3 indicate that P-SEP on day 1 produced 75 percent sensitivity, 85.7% specificity, 85.7% positive predictive value, and 77.4% negative predictive value, and a cutoff value of > 920 ng/L, with an area under the curve of 0.813 (95% confidence interval 0.582-1.043). Serum P-SEP on day three, however, produced a 87.5% sensitivity, 100% specificity, 100% positive predictive value, and 88.8% negative predictive value, and an area under the curve of 0.946 (95% confidence interval 0.830-1.063) at a threshold value of > 970 ng/L. It is apparent that P-SEP on day 3 achieved a better performance in the prediction of gram-negative infections in EOS over the P-SEP on day 1 (Table 3, figure3,4). Table 1 : Demographic data, anthropometric measures and blood culture results among septic neonates. Septic neonates N % Neonatal Data Sex Male 22 61.11% Female 14 38.88% Gestational age by expected date of delivery (wks.) Mean ± SD 32.58 ± 2.43 Birth weight (kg.) d Median (Range) 1.63 (1.0-3.67) APGAR at 1 min d Median (Range) 6 (0-8) Maternal Data Mode of Delivery CS 28 77.8% NVD 8 22.2% Culture organism No Growth 20 55.6% CONS 4 25.0% Klebsiella 3 18.8% Acinetobacter 2 12.5% Acinetobacter / Klebsiella 1 6.3% Staphylococcus aureus 1 6.3% MRSA 1 6.3% Enterococci 2 12.5% Enterobacter aerogenes 1 6.3% Candida parapsilosis 1 6.3% Abbreviations: SD, standard deviation. CS, cesarean section; NVD, normal vaginal delivery; APGAR, appearance pulse grimace activity respiration; d = Shapiro-Wilk test shows non-normal distribution. MRSA: methicillin-resistant staphylococcus aureus, CONS: coagulase negative staphylococcus. Table 2: P-SEP level according to Blood cultures result in septic neonates. Gram positive Cocci (N = 7) Gram negative bacilli (N = 8) Independent T test p-value P-SEP at baseline (ng/L) 780.0 ± 176.54 1028.75 ± 225.54 2.352 0.035 a P-SEP at follow up (ng/L) 754.28 ± 179.89 1041.25 ± 107.62 3.810 0.002 a Abbreviations: P-SEP, presepsin; a = p-value is significant < 0.05 . Table 3: Receiver-operating characteristics (ROC) curve analyses of presepsin as a predictor for gram-negative infections in patients with EOS. cutoff AUC SE 95% CI Sensitivity Specificity PPV NPV P-SEP in day 1 (ng/L) ≥ 920 0.813 0.117 0.582-1.043 75% 85.7% 85.7% 77.4% P-SEP in day 3 (ng/L) ≥ 970 0.946 0.059 0.830-1.063 87.5% 100% 100% 88.8% Abbreviations: P-SEP, presepsin; AUC, area under the curve; PPV, positive predictive value; CI, confidence interval, SE, standard error;NPV, negative predictive value; Discussion In the NICU, premature newborns are far more susceptible to systemic infections. They struggle to fight infections because of their underdeveloped immune systems, which may be further weakened by a number of preterm birth-related conditions. [13] . Because sepsis symptoms are vague, diagnosing "suspected sepsis" in newborns in the NICU is one of the most frequent and difficult diagnoses. The establishment of the type of bacterial infection is a timely crucial key point in proper management of preterm neonates which help tailor the appropriate antibiotic that should be used. The poor diagnostic performance of currently utilized laboratory indicators and the regrettable delay in bacterial culture data (The gold standard for diagnosing sepsis in newborns) make it challenging to design precise antibiotic therapy. Neonatal sepsis may be excluded with the help of sepsis screening panels and grading systems based on numerous laboratory data, but their positive predictive value is low, and their ability to predict organisms is not well proven [14] . Although studies have shown that traditional laboratory diagnostic tools, as, total white blood cell count, platelet count, absolute neutrophil count, and I/T ratio, are unreliable in diagnosing EOS, clinicians have historically relied on them [15] . Numerous cytokines and acute-phase reactants were examined in relation to newborn sepsis. The most popular standard acute phase reactant in NICUs for diagnosing newborn sepsis is CRP. [16] . All of these markers have been utilized to indicate the probability of EOS; however, the identification of the specific causative organism relies solely on blood cultures. This process is often delayed, particularly in low-income countries, limiting timely and targeted management. Therefore, finding a sepsis marker with a useful positive predictive value—that is, one that can identify a high chance of sepsis in neonates who need antimicrobial drugs shortly after birth—is crucial. Furthermore, it would be helpful if it can identify the likely organism in every septic newborn. [14] . The human P-SEP level has gained popularity as a diagnostic tool for both full-term and preterm newborns with EOS within the past ten years. [10, 17] . The relationship between the type of causative organism and various sepsis biomarkers has not been extensively studied. Therefore, we aimed to explore this aspect using presepsin (P-SEP) as a potential indicator. The diagnostic potential of P-SEP in identifying the causal organism type in preterm newborns with early-onset neonatal sepsis who originally showed negative routine sepsis indicators (CRP < 6 mg/L) was specifically examined in this study. 44.4% of sepsis (proven sepsis) cases in the current study had positive blood culture results, while 55.6% of sepsis cases were negative (probable sepsis). The gram-negative bacteria were found in 8 of 16 EOS (50%) who were culture-proven, while gram-positive bacteria were detected in 7 of 16 culture-proven EOS (43.7%), and 1 of 16 culture-proven EOS was candida (6.3%). These findings agree with earlier studies, which reported that gram-negative EOS occurred most frequently among preterm babies [18, 19] . Despite that the gram-negative infections were the most frequent in our study, Coagulase-negative staphylococcus accounted for 25% of the total, with Klebsiella and Acinetobacter coming in second and third, respectively, at 18.8% and 12.5%. These findings agree with those reported by Lee et al., who discovered that the most prevalent bacteria obtained from blood was coagulase-negative staphylococcus (CoNS) [20] . Similarly, Iskandar et al., reached the same results, stating that the most prevalent organism in patients with EOS were CoNS and Enterobacter gergoviae, while Klebsiella pneumonia was the most prevalent bacterium in patients with late-onset sepsis, followed by CoNS [21] . In contrast with our results, Hornik et al., found that Escherichia coli and group B streptococci were the pathogens most identified in EOS in preterms [18] . Regarding the relationship between P-SEP and blood culture results, P-SEP levels at days 1 and 3 were significantly higher in bacterial infections that were gram-negative than those that were gram-positive. (p = 0.035 and 0.002, respectively). Furthermore, P-SEP at follow up on day 3 of admission showed very good performance for prediction of gram-negative infection, at a cutoff value of ≥ 970 ng/L [87.5% sensitivity, specificity 100%, PPV 100 %, NPV 88.8%]. However, at the cutoff value ≥ 920 ng/L, the P-SEP level at baseline on admission had [sensitivity 75%, specificity 85.7%, PPV = 85.7%, NPV = 77.4%]. In comparison to the P-SEP on day 1, the P-SEP on day 3 had better performance, having a PPV of 100% vs. 85.7% and a sensitivity of 87.5% vs. 75%. These results were in line with those of Masson et al., who found that patients with Gram-negative bacterial infections had greater baseline P-SEP levels (946 ng/L) than patients with Gram-positive infections [22] . Mahmoud Zayed et al. found that gram-positive infections had greater P-SEP levels at days 1, 3, and 6 of life than gram-negative infections, which is inconsistent to our findings. [23] . But according to some prior studies, there is no discernible difference between gram-positive and gram-negative infections in terms of P-SEP on days 1 and 3 [24, 25] . The 13 kDa subtype of the soluble CD14 on the N-terminal segment is the presepsin we have been measuring in our study. CD14 is expressed on the membrane of phagocytic cells and serves as a pattern recognition receptor (PRR) for lipopolysaccharide (LPS)/LPS-binding protein (LPS-LBP) complexes. Together with the bacteria that are ingested, CD14 is internalized during phagocytosis. It is then cleaved via phago-lysosomal processing and is released into the plasma as presepsin. The presence of lipopolysaccharide (LPS), a characteristic part of Gram-negative bacteria, may help to explain why infections brought on by Gram-negative bacteria have higher presepsin levels than those produced by Gram-positive bacteria [26] . Finally, it is important to take into account a number of noteworthy limitations of this research. Firstly, The study we conducted was carried out in a single center with a minimal sample size, limiting the generalizability of our findings. Along with the limited amount of data available, and discrepancies about normal reference values of P-SEP especially in preterm babies, due to different measurement techniques. Conclusion Presepsin evaluation in preterm neonates with early-onset sepsis serves as a valuable early marker for identifying the type of bacterial infection present. Abbreviations AUC: area under the curve After that, all other research variables, including sensitivity, specificity, CBC: complete blood count CI: confidence interval CMV: Cytomegalovirus. CONS: coagulase negative staphylococcus. CRP: C- reactive protein ELISA: enzyme linked immunosorbent assay EOS: early onset sepsis kDa: kilodalton LPS-LBP: lipopolysaccharide/LPS-binding protein complexes LPS: Lipopolysaccharides mCD14: membrane-bound CD14 MRSA: methicillin-resistant staphylococcus aureus NICUs: neonatal intensive care units. NPV: negative predictive value OR: odds ratio P-SEP: Presepsin pattern recognition receptor (PRR) for PPV: positive predictive value ROC: Receiver Operating Characteristic sCD14-ST : soluble CD14 subtype soluble CD14 (sCD14 SPSS: Statistical Package for the Social Sciences program Declarations Competing interests The authors declare that they have no conflicts of interest. Ethics approval The study received approval from the faculty of medicine's Research Ethics Committee, Ain Shams university no. MS 619/2021. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, as adopted by the World Medical Association for research involving human participants. Each patient's parents provided their informed consent to be recruited in the study. No personal data was used in the study. The participants had the right to withdraw at any point in the study. Consent to participate Each patient's parents provided their informed consent to be recruited in the study. No personal data was used in the study. The participants had the write to withdraw at any point in the study. Funding: This research received no external funding. Author Contribution All authors contributed to the formulation of the study design. AE was responsible for the collection of clinical data. The first draft of the manuscript was prepared by MI and AE. All authors reviewed and commented on previous versions of the manuscript and have read and approved the final version. Acknowledgement We gratefully acknowledge all the participants who generously contributed to this study. Their involvement was invaluable to the success of our research. Data Availability The data supporting this study are available from the corresponding author upon reasonable request. References Pemde, H., and Dutta, A. K. (2008). Symposium on AIIMS protocols in neonatology–III. 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Klinger, G., Levy, I., Sirota, L., Boyko, V., Reichman, B., Lerner-Geva, L., and Network, I. N. (2009). Epidemiology and risk factors for early onset sepsis among very-low-birthweight infants. American Journal of Obstetrics and Gynecology , 201 (1), 38-e1. Lee, S. M., Chang, M., and Kim, K.-S. (2015). Blood culture proven early onset sepsis and late onset sepsis in very-low-birth-weight infants in Korea. Journal of Korean Medical Science , 30 (Suppl 1), S67–S74. Iskandar, A., Arthamin, M. Z., Indriana, K., Anshory, M., Hur, M., Di Somma, S., and Network, G. (2019). Comparison between presepsin and procalcitonin in early diagnosis of neonatal sepsis. The Journal of Maternal-Fetal & Neonatal Medicine , 32 (23), 3903–3908. Masson, S., Caironi, P., Fanizza, C., Thomae, R., Bernasconi, R., Noto, A., Oggioni, R., Pasetti, G. S., Romero, M., and Tognoni, G. (2015). Circulating presepsin (soluble CD14 subtype) as a marker of host response in patients with severe sepsis or septic shock: data from the multicenter, randomized ALBIOS trial. Intensive Care Medicine , 41 (1), 12–20. Mahmoud Zayed, K., Abd ELmoez Ali Saad, A., Mohamed Amin, W., and Gamal Abo El-Nasr, M. (2020). Diagnostic value of presepsin in detection of early-onset neonatal sepsis. Al-Azhar Journal of Pediatrics , 23 (2), 825–851. Asmaa, O. A., Hanan, H., AL-Shaimaa, M. S., and Atya, A. M. A. (2018). Presepsin: A Anew Marker for Early Diagnosis of Septicemia. The Medical Journal of Cairo University , 86 (9), 2237. Değirmencioğlu, H., Ozer Bekmez, B., Derme, T., Öncel, M. Y., Canpolat, F. E., and Tayman, C. (2019). Presepsin and fetuin-A dyad for the diagnosis of proven sepsis in preterm neonates. BMC Infectious Diseases , 19 (1), 1–7. Koizumi, Y., Sakanashi, D., Mohri, T., Watanabe, H., Shiota, A., Asai, N., Kato, H., Hagihara, M., Murotani, K., Yamagishi, Y., Suematsu, H., & Mikamo, H. (2020). Can presepsin uniformly respond to various pathogens? - an in vitro assay of new sepsis marker. BMC immunology, 21(1), 33. https://doi.org/10.1186/s12865-020-00362-z Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6874629","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":485301007,"identity":"a1b29a3e-b663-441d-8023-4a8c96148ba6","order_by":0,"name":"Mariam John Amin Ibrahim","email":"data:image/png;base64,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","orcid":"","institution":"Ain Shams University","correspondingAuthor":true,"prefix":"","firstName":"Mariam","middleName":"John Amin","lastName":"Ibrahim","suffix":""},{"id":485301008,"identity":"192f943a-1faf-4f59-adde-7bf5746a76fb","order_by":1,"name":"Ahmed Nasser Ibrahim Elkholy","email":"","orcid":"","institution":"El Mahalla General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"Nasser Ibrahim","lastName":"Elkholy","suffix":""},{"id":485301009,"identity":"8155de4d-e77a-4222-99eb-7959112d5cee","order_by":2,"name":"Heba Mohamed Atif Ismail","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"prefix":"","firstName":"Heba","middleName":"Mohamed Atif","lastName":"Ismail","suffix":""},{"id":485301010,"identity":"624d9cb3-1fdb-4ceb-b9a8-4c43d26ae84b","order_by":3,"name":"Dalia Fathi Ali El Sherif","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"prefix":"","firstName":"Dalia","middleName":"Fathi Ali El","lastName":"Sherif","suffix":""}],"badges":[],"createdAt":"2025-06-11 19:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6874629/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6874629/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87034577,"identity":"9771cb5b-d626-40b1-bd8a-dde5ee0858f0","added_by":"auto","created_at":"2025-07-18 13:10:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23533,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003econsort of the studied neonates\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6874629/v1/6243910f2cd51cb1de707701.png"},{"id":87034578,"identity":"b9d3cf6a-40a7-46f0-bb82-78ec371d4adc","added_by":"auto","created_at":"2025-07-18 13:10:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":65245,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBlood culture results in septic neonates.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6874629/v1/375c59a1458f0a90eac95170.png"},{"id":87034582,"identity":"b0335006-1521-46aa-a045-8e993f7ebc44","added_by":"auto","created_at":"2025-07-18 13:10:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":52822,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe overall model quality of P-SEP as a predictor for infections with gram negative organisms in EOS.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6874629/v1/04f91e006405b1d1579fc87f.png"},{"id":87035866,"identity":"83865a0d-a994-4aca-9f44-8b2a0b064e95","added_by":"auto","created_at":"2025-07-18 13:18:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":59013,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROC curve for prediction of infections with gram negative organisms in EOS.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6874629/v1/dddf57ec466747e3d97460c1.png"},{"id":88846047,"identity":"d395c8a4-83af-4394-827a-596c55241c10","added_by":"auto","created_at":"2025-08-12 04:01:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1951255,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6874629/v1/c7eb857a-ab2d-4be4-8fc9-c56ab0f5254c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Soluble CD14 (Presepsin) in the early prediction of bacterial type in Early Onset Neonatal Sepsis in Preterm Neonates","fulltext":[{"header":"What is known- what is new?","content":"\u003cul\u003e\n \u003cli\u003eOver the past few years, the clinical significance of presepsin has been extensively explored across different types of infections, including surgical infections, burns, and febrile neutropenia.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePresepsin has been identified as a useful early diagnostic indicator for neonatal sepsis of both early and late onsets. The delay in obtaining blood culture results, especially in countries with low incomes, often compels clinicians to initiate empirical antibiotic therapy rather than targeted treatment based on the specific bacterial infection. This delay in appropriate management can negatively impact neonatal outcomes.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePresepsin levels have been reported to be higher in infections caused by Gram-negative bacteria compared to Gram-positive ones. In the current study, we confirmed this finding and established a cutoff value that can help differentiate between Gram-negative and Gram-positive infections, enabling more precise selection of appropriate antibiotic therapy.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eThroughout the first month of life, neonatal sepsis, a serious health issue, presents with infection-related symptoms, either with or without bacteremia. Severe septicaemia can occur when infectious bacteria infiltrate into the bloodstream or they can cause specific infections including, urinary tract infections, osteomyelitis, arthritis, pneumonia, and meningitis. \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAfter preterm birth and difficulties connected to the labor and delivery process (as birth asphyxia), the third most common cause of infant mortality is neonatal sepsis. It causes 42% of deaths in the first week of life and 13% of all neonatal deaths. \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eUnlike older patients, early stages of neonatal sepsis have a variety of noninfectious diseases and extremely vague presentations which may be confused with it. The limited value of laboratory tests including blood culture (gold standard) because of its limited sensitivity, low positivity rates, some traits of the neonatal population, as well as shifting typical reference ranges throughout the neonatal period make early detection of neonatal sepsis more difficult \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eDespite the usefulness of numerous diagnostic and treatment options, doctors caring for infected neonates in the age of multi-drug resistance, particularly in low- and middle-income countries, confront numerous obstacles when making judgements. They are still in need of new specific diagnostic and prognostic markers to identify the type of organism in infected patients who would benefit from targeted antibiotic therapy rather than empirical antibiotics. \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAs a bacterial molecular pattern recognition receptor, CD14 can recognize a variety of ligand groups from pathogens that are both Gram-positive and Gram-negative, including Lipopolysaccharides (LPS) from Gram-negative bacteria and peptidoglycans and lipoteichoic acid from Gram-positive bacteria. \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e It facilitates the toll-like receptor 4's processing of the endotoxin signal, which causes the discharge of several cytokines and encourages the initiation of a systemic inflammatory reaction. \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eMonocytes and macrophages, which are inflammatory cells, exhibit 2 types of CD14: a membrane-bound CD14 (mCD14) found on these cells and a soluble CD14 (sCD14), which is created when the membrane form of CD14 is shed in the plasma. The body's reaction to a bacterial infection includes the production of presepsin (P-SEP), a fragment with a size of 13 kDa called soluble CD14 subtype, (sCD14-ST) that is produced when plasma proteases cleave sCD14. \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eP-SEP is thought to promote monocyte phagocytosis and interact with B and T cells to modify a particular immunological response, while its exact role is still unknown. In the early phases of inflammation and sepsis, it dramatically rises in the bloodstream. As a result, P-SEP appeared to be an appropriate biomarker for the early diagnosis of EOS. \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAIM OF THE WORK\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the predictive efficacy of soluble CD14 (presepsin) in identifying the type of bacterial organism in preterm newborns with early onset neonatal sepsis.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cp\u003eThis research was an observational prospective study. It was conducted at NICUs of Ain-Shams University Hospital, Cairo, Egypt, from October of 2021 and October of 2022.\u003c/p\u003e\n\u003cp\u003eThe study received approval from the faculty of medicine\u0026apos;s Research Ethics Committee, Ain Shams university no. MS 619/2021. Each patient\u0026apos;s parents provided their informed consent to be recruited in the study. No personal data was used in the study. The participants had the right to withdraw at any point in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe present study included 36 newly born infants preterm having a minimum of one Risk factor for maternal and newborn infections or clinical signs that point to the possibility of early-onset sepsis but with an initial CRP negative result. Preterm neonates with the following characteristics were considered neonatal risk factors: respiratory discomfort that begins more than four hours after birth, The necessity of mechanical ventilation Apnoea seizures, aberrant vitals or signs of shock, changes in reactivity or behaviour,\u0026nbsp;altered muscular tone, such as floppiness, newborn encephalopathy symptoms, feeding issues or intolerance, Hypoxia , jaundice 24 hours after birth, Cardiopulmonary resuscitation was required, anomalies in the temperature (less than 36\u0026deg;C or more than 38\u0026deg;C) that cannot be attributed to environmental sources, abnormal coagulation (International Normalised Ratio \u0026gt;2.0), thrombocytopenia, or excessive bleeding that cannot be explained, Oliguria that lasts longer than 24 hours after birth, either hyperglycemia or hypoglycemia, metabolic acidosis (base deficit of at least 10 mmol/L), Infection symptoms that are localised (e.g., dermal or ocular).\u0026nbsp;\u003csup\u003e[11]\u003c/sup\u003e \u003cu\u003eMaternal \u0026lsquo;risk factors of sepsis\u003c/u\u003e:\u0026nbsp;invasive bacterial infection that was either confirmed or suspected during childbirth or in the 24 hours prior to and following delivery, needing parenteral antibiotic treatment. Infection in another child, either suspected or confirmed in case of a multiple pregnancy. A prior infant that had an invasive group B streptococcal infection. Infection, bacteriuria, or colonisation of maternal group B streptococci during the present pregnancy. Rupture of the membranes prior to labour. Premature delivery after spontaneous labour (before to 37 weeks gestation). Suspected or verified membrane rupture in a premature birth lasting more than eighteen hours. High intrapartum fever or chorioamnionitis, either confirmed or suspected.\u0026nbsp;Pregnancy-related procedures like amniocentesis and cervical cerclage\u0026nbsp;\u003csup\u003e[11]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eNeonates with serious congenital malformation, fetal hydrops, perinatal asphyxia and confirmed intrauterine infections (herpes, syphilis, CMV, rubella, and toxoplasmosis) were excluded from the study\u0026nbsp;\u003csup\u003e[12]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe laboratory findings were concealed from the treating physicians, and two physicians categorised the newborns according to the definitions of infections and risk factors. Patients were classified as septic or not if both clinicians agreed.\u003c/p\u003e\n\u003cp\u003eAll neonates included in this study had positive risk factors for infection and initial routine sepsis markers (CRP\u0026lt; 6), they were followed up for 72 hours, where they were divided into 2 subgroups: proven sepsis (n = 16) who had positive blood culture and probable sepsis (n = 20) groups who had\u0026nbsp;increased CRP \u0026gt; 6 mg/dl at follow-up on day 3 of life, despite negative blood culture. All participating patients received empirical antibiotic therapy according to the protocol in children hospitals\u0026apos; NICUs (ampicillin and gentamycin) until culture and sensitivity results appeared.\u003c/p\u003e\n\u003cp\u003eEvery patient underwent the following procedures:\u0026nbsp;\u003cem\u003eComplete history taking:\u0026nbsp;\u003c/em\u003eAntenatal, Natal and Postnatal histories. \u003cem\u003eGestational age estimation and Anthropometric measurementswere done at time of admission. Clinical examinationwas performed\u0026nbsp;\u003c/em\u003eFor symptoms and signs of suspected sepsis. General Examination: (Vital data, blood glucose levels, mental status, and exclusion of dysmorphic features) Local Examination: \u003cem\u003eChest:\u003c/em\u003e signs of respiratory distress, need for respiratory support and surfactant, \u003cem\u003eCardiovascular:\u0026nbsp;\u003c/em\u003ecapillary perfusion time, and the need for inotropic support, \u003cem\u003eAbdomen:\u0026nbsp;\u003c/em\u003esigns of feeding intolerance and abdominal girth and \u003cem\u003eCentral nervous system:\u0026nbsp;\u003c/em\u003eHead circumference, fontanelles, muscle tone, reflexes, posture, and convulsions. \u003cem\u003eLaboratory investigations done included blood\u003c/em\u003e culture (BACTEC), peripheral blood smear examination and complete blood count (CBC), human presepsin (P-SEP) was determined using the enzyme linked immunosorbent assay (ELISA) technique, and CRP was measured using a highly sensitive C-reactive protein . Blood samples were withdrawn from all cases prior to beginning antibiotic medication for culture, CBC with differential, CRP and P-SEP. These biomarkers were measured again at 72 hours. Blood samples were withdrawn by the most skilled personnel in the facility, and no samples were stored to be used in any further research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis:\u003c/strong\u003e The acquired data was coded, entered, and analysed using Microsoft Excel software. The data was then analysed using the Statistical Package for the Social Sciences (SPSS) program, version 28.0.\u003c/p\u003e\n\u003cp\u003eCategorical variables were displayed as numbers and proportions, whereas quantitative continuous variables were displayed as mean and standard deviation for parametric data and median and interquartile range for nonparametric data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTo determine whether differences and associations were significant, the following tests were employed:\u0026nbsp;\u003c/strong\u003ethe normality of data was assessed by visual inspection of their histograms, skewness and kurtosis statistics and standard errors. Levene\u0026apos;s test was used to confirm that the variances in the samples were equal (homogeneity of variance); for parametric data, independent continuous variables were compared using the student\u0026apos;s t-test.; the one-sample Kolmogorov-Smirnov or Shapiro-Wilk tests were used to test the variables; the variable is not normally distributed if (p value) \u0026lt; 0.05; and the variances are not equal if (p value) \u0026lt; 0.05.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe P-value, or probability level, was set at less than 0.05 for outcomes that were statistically significant and less than 0.001 for those that were highly significant. Where appropriate, values for the 95 percent confidence interval (95% CI) and odds ratio (OR) were shown.\u003c/p\u003e\n\u003cp\u003eReceiver Operating Characteristic (ROC) curves for P-SEP were analysed in order to identify the area under the curve (AUC) and the most accurate cut-off values. After that, all other research variables, including sensitivity, specificity, LR+, LR-, positive predictive value (PPV), and negative predictive value (NPV), were assessed, in order to predict type of organism. For each parameter, an exact 95% CI was computed.\u003c/p\u003e\n\u003cp\u003eAn optimum test index is indicated by an AUC of 1.0; a diagnostic test with no relevance has an AUC of 0.5. A diagnostic test is generally considered low value if its ROC-AUC falls between 0.5 and 0.7, medium value if it falls between 0.7 and 0.9, and excellent value if it falls beyond 0.9. A significant statistical difference was demonstrated by a P\u0026lt;0.01 value.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study received approval from the faculty of medicine\u0026apos;s Research Ethics Committee, Ain Shams university no. MS 619/2021. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, as adopted by the World Medical Association for research involving human participants. Each patient\u0026apos;s parents provided their informed consent to be recruited in the study. No personal data was used in the study. The participants had the right to withdraw at any point in the study.\u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 125 newborns were qualified to take part in our research, 99 were excluded due to the presence of congenital anomalies, presence of intrauterine infections, declining to participate or lost follow up (Figure 1)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMore than half of the case, 61.11% of them were males and 38.88% were females. Mean \u0026plusmn; SD of the gestational age was 32.58 \u0026plusmn; 2.43. The mean \u0026plusmn; SD of the mother ages was 29.31 \u0026plusmn; 5.01, and most of the deliveries were by caesarean sections.\u003c/p\u003e\n\u003cp\u003eForty-four percent of the septic newborns had positive blood culture results; eight out of sixteen culture-proven EOS had gram-negative bacteria (50%) and seven out of sixteen had gram-positive bacteria (43.7%); The organism that was most common was coagulase-negative Staphylococcus. (4cases; 25%), klebsiella came next (3 cases, 18.7%), Enterococci (2 cases; 12.5%), Acinetobacter (2 cases ; 12.5%), One case with Staphylococcus aureus (6.3%), MRSA (o1 case; 6.3%), Enterobacter aerogenes (one case; 6.3%), Candida parapsilosis (one case; 6.3%), and a mix of Klebsiella and Acinetobacter (one case; 6.3%) \u003cstrong\u003e(Table 1, figure 2)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003ePatients with gram-negative infections had substantially greater P-SEP levels at baseline (day 1) and follow-up (day 3), than those with gram-positive infections (t = 2.352, p = 0.035; t = 3.810, p = 0.002 respectively). \u003cstrong\u003e(Table 2)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eFurther analysis of the presepsin levels on day1 and day 3 indicate that P-SEP on day 1 produced 75 percent sensitivity, 85.7% specificity, 85.7% positive predictive value, and 77.4% negative predictive value, and a cutoff value of \u0026gt; 920 ng/L, with an area under the curve of 0.813 (95% confidence interval 0.582-1.043). Serum P-SEP on day three, however, produced a 87.5% sensitivity, 100% specificity, 100% positive predictive value, and 88.8% negative predictive value, and an area under the curve of 0.946 (95% confidence interval 0.830-1.063) at a threshold value of \u0026gt; 970 ng/L. It is apparent that P-SEP on day 3 achieved a better performance in the prediction of gram-negative infections in EOS over the P-SEP on day 1 (Table 3, figure3,4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003cstrong\u003e: Demographic data, anthropometric measures and blood culture results among septic neonates.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 275px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeptic neonates\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeonatal Data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e61.11%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e38.88%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGestational age by expected date of delivery (wks.)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e32.58 \u0026plusmn; 2.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBirth weight (kg.) \u003csup\u003ed\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (Range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e1.63 (1.0-3.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAPGAR at 1 min \u003csup\u003ed\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (Range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e6 (0-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMaternal Data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMode of\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDelivery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e77.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNVD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e22.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCulture organism\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo Growth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e55.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCONS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e25.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKlebsiella\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e18.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcinetobacter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e12.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcinetobacter / Klebsiella\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e6.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStaphylococcus aureus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e6.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMRSA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e6.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnterococci\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e12.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnterobacter aerogenes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e6.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 278px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCandida parapsilosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e6.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: SD, standard deviation. \u003csub\u003e\u0026nbsp;\u003c/sub\u003eCS, cesarean section; NVD, normal vaginal delivery; APGAR, appearance pulse grimace activity respiration; \u003csup\u003ed\u003c/sup\u003e = Shapiro-Wilk test shows non-normal distribution. MRSA: methicillin-resistant staphylococcus aureus, CONS: coagulase negative staphylococcus.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: P-SEP level according to Blood cultures result in septic neonates.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGram positive Cocci\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N = 7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGram negative bacilli\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N = 8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIndependent T test\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-SEP at baseline (ng/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e780.0 \u0026plusmn; 176.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1028.75 \u0026plusmn; 225.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e2.352\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.035\u003c/strong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-SEP at follow up (ng/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e754.28 \u0026plusmn; 179.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e1041.25 \u0026plusmn; 107.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e3.810\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: P-SEP, presepsin; \u003csup\u003ea\u0026nbsp;\u003c/sup\u003e= p-value is significant \u0026lt; 0.05 .\u0026nbsp;\u003c/p\u003e\n\u003cp id=\"_Toc127061186\"\u003e\u003cstrong\u003eTable 3:\u003c/strong\u003e Receiver-operating characteristics (ROC) curve analyses of presepsin as a predictor for gram-negative infections in patients with EOS.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"554\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ecutoff\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSensitivity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpecificity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePPV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNPV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-SEP in day 1 (ng/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026ge; 920\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e0.813\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.582-1.043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e75%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e85.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e85.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e77.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-SEP in day 3 (ng/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026ge; 970\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e0.946\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.830-1.063\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e87.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e88.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: P-SEP, presepsin; AUC, area under the curve; PPV, positive predictive value; CI, confidence interval, SE, standard error;NPV, negative predictive value;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the NICU, premature newborns are far more susceptible to systemic infections. They struggle to fight infections because of their underdeveloped immune systems, which may be further weakened by a number of preterm birth-related conditions. \u003csup\u003e[13]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eBecause sepsis symptoms are vague, diagnosing \u0026quot;suspected sepsis\u0026quot; in newborns in the NICU is one of the most frequent and difficult diagnoses. The establishment of the type of bacterial infection is a timely crucial key point in proper management of preterm neonates which help tailor the appropriate antibiotic that should be used. The poor diagnostic performance of currently utilized laboratory indicators and the regrettable delay in bacterial culture data (The gold standard for diagnosing sepsis in newborns) make it challenging to design precise antibiotic therapy. Neonatal sepsis may be excluded with the help of sepsis screening panels and grading systems based on numerous laboratory data, but their positive predictive value is low, and their ability to predict organisms is not well proven \u003csup\u003e[14]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough studies have shown that traditional laboratory diagnostic tools, as, total white blood cell count, platelet count, absolute neutrophil count, and I/T ratio, are unreliable in diagnosing EOS, clinicians have historically relied on them \u003csup\u003e[15]\u003c/sup\u003e. Numerous cytokines and acute-phase reactants were examined in relation to newborn sepsis. The most popular standard acute phase reactant in NICUs for diagnosing newborn sepsis is CRP. \u003csup\u003e[16]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAll of these markers have been utilized to indicate the probability of EOS; however, the identification of the specific causative organism relies solely on blood cultures. This process is often delayed, particularly in low-income countries, limiting timely and targeted management.\u003c/p\u003e\n\u003cp\u003eTherefore, finding a sepsis marker with a useful positive predictive value\u0026mdash;that is, one that can identify a high chance of sepsis in neonates who need antimicrobial drugs shortly after birth\u0026mdash;is crucial. Furthermore, it would be helpful if it can identify the likely organism in every septic newborn. \u003csup\u003e[14]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe human P-SEP level has gained popularity as a diagnostic tool for both full-term and preterm newborns with EOS within the past ten years. \u003csup\u003e[10, 17]\u003c/sup\u003e.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe relationship between the type of causative organism and various sepsis biomarkers has not been extensively studied. Therefore, we aimed to explore this aspect using presepsin (P-SEP) as a potential indicator. The diagnostic potential of P-SEP in identifying the causal organism type in preterm newborns with early-onset neonatal sepsis who originally showed negative routine sepsis indicators (CRP \u0026lt; 6 mg/L) was specifically examined in this study.\u003c/p\u003e\n\u003cp\u003e44.4% of sepsis (proven sepsis) cases in the current study had positive blood culture results, while 55.6% of sepsis cases were negative (probable sepsis). The gram-negative bacteria were found in 8 of 16 EOS (50%) who were culture-proven, while gram-positive bacteria were detected in 7 of 16 culture-proven EOS (43.7%), and 1 of 16 culture-proven EOS was candida (6.3%). These findings agree with earlier studies, which reported that gram-negative EOS occurred most frequently among preterm babies\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003csup\u003e[18, 19]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eDespite that the gram-negative infections were the most frequent in our study, Coagulase-negative staphylococcus accounted for 25% of the total, with Klebsiella and Acinetobacter coming in second and third, respectively, at 18.8% and 12.5%. These findings agree with those reported by\u0026nbsp;\u003cstrong\u003e\u003cem\u003eLee et al.,\u003c/em\u003e\u003c/strong\u003e who discovered that the most prevalent bacteria obtained from blood was coagulase-negative staphylococcus (CoNS)\u0026nbsp;\u003csup\u003e[20]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSimilarly, \u003cstrong\u003e\u003cem\u003eIskandar et al.,\u003c/em\u003e\u003c/strong\u003e reached the same results, stating that the most prevalent organism in patients with EOS were CoNS and Enterobacter gergoviae, while Klebsiella pneumonia was the most prevalent bacterium in patients with late-onset sepsis, followed by CoNS\u0026nbsp;\u003csup\u003e[21]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn contrast with our results, \u003cstrong\u003e\u003cem\u003eHornik et al.,\u003c/em\u003e\u003c/strong\u003e found that Escherichia coli and group B streptococci were the pathogens most identified in EOS in preterms \u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e[18]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eRegarding the relationship between P-SEP and blood culture results, P-SEP levels at days 1 and 3 were significantly higher in bacterial infections that were gram-negative than those that were gram-positive. (p = 0.035 and 0.002, respectively).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurthermore, P-SEP at follow up on day 3 of admission showed very good performance for prediction of gram-negative infection, at a cutoff value of \u0026ge; 970 ng/L [87.5% sensitivity, specificity 100%, PPV 100 %, NPV 88.8%]. However, at the cutoff value \u0026ge; 920 ng/L, the P-SEP level at baseline on admission had [sensitivity 75%, specificity 85.7%, PPV = 85.7%, NPV = 77.4%].\u003c/p\u003e\n\u003cp\u003eIn comparison to the P-SEP on day 1, the P-SEP on day 3 had better performance, having a PPV of 100% vs. 85.7% and a sensitivity of 87.5% vs. 75%.\u003c/p\u003e\n\u003cp\u003eThese results were in line with those of Masson et al., who found that patients with Gram-negative bacterial infections had greater baseline P-SEP levels (946 ng/L) than patients with Gram-positive infections \u003csup\u003e[22]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMahmoud Zayed et al.\u003c/strong\u003e found that gram-positive infections had greater P-SEP levels at days 1, 3, and 6 of life than gram-negative infections, which is inconsistent to our findings. \u003csup\u003e[23]\u003c/sup\u003e. But according to some prior studies, there is no discernible difference between gram-positive and gram-negative infections in terms of P-SEP on days 1 and 3 \u003csup\u003e[24, 25]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe 13 kDa subtype of the soluble CD14 on the N-terminal segment is the presepsin we have been measuring in our study. CD14 is expressed on the membrane of phagocytic cells and serves as a pattern recognition receptor (PRR) for lipopolysaccharide (LPS)/LPS-binding protein (LPS-LBP) complexes. Together with the bacteria that are ingested, CD14 is internalized during phagocytosis. It is then cleaved via phago-lysosomal processing and is released into the plasma as presepsin. The presence of lipopolysaccharide (LPS), a characteristic part of Gram-negative bacteria, may help to explain why infections brought on by Gram-negative bacteria have higher presepsin levels than those produced by Gram-positive bacteria \u003csup\u003e[26]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eFinally, it is important to take into account a number of noteworthy limitations of this research. Firstly, The study we conducted was carried out in a single center with a minimal sample size, limiting the generalizability of our findings. Along with the limited amount of data available, and discrepancies about normal reference values of P-SEP especially in preterm babies, due to different measurement techniques.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePresepsin evaluation in preterm neonates with early-onset sepsis serves as a valuable early marker for identifying the type of bacterial infection present. \u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAUC: area under the curve After that, all other research variables, including sensitivity, specificity,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCBC: complete blood count\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCI: confidence interval\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCMV: Cytomegalovirus.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CONS: coagulase negative staphylococcus.\u003c/p\u003e\n\u003cp\u003eCRP: C- reactive protein\u003c/p\u003e\n\u003cp\u003eELISA: enzyme linked immunosorbent assay\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEOS: early onset sepsis\u003c/p\u003e\n\u003cp\u003ekDa: kilodalton\u003c/p\u003e\n\u003cp\u003eLPS-LBP: \u0026nbsp;lipopolysaccharide/LPS-binding protein complexes\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLPS: Lipopolysaccharides\u0026nbsp;\u003c/p\u003e\n\u003cp\u003emCD14: membrane-bound CD14\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRSA: methicillin-resistant staphylococcus aureus\u003c/p\u003e\n\u003cp\u003eNICUs: neonatal intensive care units.\u003c/p\u003e\n\u003cp\u003eNPV: negative predictive value\u003c/p\u003e\n\u003cp\u003eOR: odds ratio\u003c/p\u003e\n\u003cp\u003eP-SEP: Presepsin\u003c/p\u003e\n\u003cp\u003epattern recognition receptor (PRR) for\u003c/p\u003e\n\u003cp\u003ePPV: positive predictive value\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eROC: Receiver Operating Characteristic\u0026nbsp;\u003c/p\u003e\n\u003cp\u003esCD14-ST : soluble CD14 subtype\u003c/p\u003e\n\u003cp\u003esoluble CD14 (sCD14\u003c/p\u003e\n\u003cp\u003eSPSS: Statistical Package for the Social Sciences program\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003ch2\u003eEthics approval\u003c/h2\u003e\n\u003cp\u003eThe study received approval from the faculty of medicine\u0026apos;s Research Ethics Committee, Ain Shams university no. MS 619/2021. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, as adopted by the World Medical Association for research involving human participants. Each patient\u0026apos;s parents provided their informed consent to be recruited in the study. No personal data was used in the study. The participants had the right to withdraw at any point in the study.\u003c/p\u003e\n\u003ch2\u003eConsent to participate\u003c/h2\u003e\n\u003cp\u003eEach patient\u0026apos;s parents provided their informed consent to be recruited in the study. No personal data was used in the study. The participants had the write to withdraw at any point in the study.\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eAll authors contributed to the formulation of the study design. AE was responsible for the collection of clinical data. The first draft of the manuscript was prepared by MI and AE. All authors reviewed and commented on previous versions of the manuscript and have read and approved the final version.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eWe gratefully acknowledge all the participants who generously contributed to this study. Their involvement was invaluable to the success of our research.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data supporting this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cstrong\u003ePemde, H., and Dutta, A. K. 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(2017).\u0026nbsp;\u003c/strong\u003ePresepsin for the detection of early-onset sepsis in preterm newborns. \u003cem\u003ePediatric Research\u003c/em\u003e, \u003cem\u003e81\u003c/em\u003e(2), 329\u0026ndash;334.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMelville, J. M., and Moss, T. J. M. (2013).\u003c/strong\u003e The immune consequences of preterm birth. \u003cem\u003eFrontiers in Neuroscience\u003c/em\u003e, \u003cem\u003e7\u003c/em\u003e, 79.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePolin, R. A., Newborn, C. on F. and, Papile, L.-A., Baley, J. E., Bhutani, V. K., Carlo, W. A., Cummings, J., Kumar, P., Tan, R. C., and Wang, K. S. (2012).\u0026nbsp;\u003c/strong\u003eManagement of neonates with suspected or proven early-onset bacterial sepsis. \u003cem\u003ePediatrics\u003c/em\u003e, \u003cem\u003e129\u003c/em\u003e(5), 1006\u0026ndash;1015.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePierrakos, C., Velissaris, D., Bisdorff, M., Marshall, J. C., and Vincent, J.-L. (2020).\u003c/strong\u003e Biomarkers of sepsis: time for a reappraisal. \u003cem\u003eCritical Care\u003c/em\u003e, \u003cem\u003e24\u003c/em\u003e(1), 1\u0026ndash;15.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePerrone, S., Lotti, F., Longini, M., Rossetti, A., Bindi, I., Bazzini, F., Belvisi, E., Sarnacchiaro, P., Scapellato, C., and Buonocore, G. (2018).\u003c/strong\u003e C reactive protein in healthy term newborns during the first 48 hours of life. \u003cem\u003eArchives of Disease in Childhood-Fetal and Neonatal Edition\u003c/em\u003e, \u003cem\u003e103\u003c/em\u003e(2), F163\u0026ndash;F166.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eBotondi, V., D\u0026rsquo;Adamo, E., Plebani, M., Trubiani, O., Perrotta, M., Di Ricco, L., Spagnuolo, C., De Sanctis, S., Barbante, E., \u0026amp; Strozzi, M. C. (2022).\u003c/strong\u003e Perinatal presepsin assessment: a new sepsis diagnostic tool? \u003cem\u003eClinical Chemistry and Laboratory Medicine (CCLM)\u003c/em\u003e, \u003cem\u003e60\u003c/em\u003e(8), 1136\u0026ndash;1144.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eHornik, C. P., Fort, P., Clark, R. H., Watt, K., Benjamin Jr, D. K., Smith, P. B., Manzoni, P., Jacqz-Aigrain, E., Kaguelidou, F., and Cohen-Wolkowiez, M. (2012).\u003c/strong\u003e Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units. \u003cem\u003eEarly Human Development\u003c/em\u003e, \u003cem\u003e88\u003c/em\u003e, S69\u0026ndash;S74.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eKlinger, G., Levy, I., Sirota, L., Boyko, V., Reichman, B., Lerner-Geva, L., and Network, I. N. (2009).\u003c/strong\u003e Epidemiology and risk factors for early onset sepsis among very-low-birthweight infants. \u003cem\u003eAmerican Journal of Obstetrics and Gynecology\u003c/em\u003e, \u003cem\u003e201\u003c/em\u003e(1), 38-e1.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eLee, S. M., Chang, M., and Kim, K.-S. (2015).\u003c/strong\u003e Blood culture proven early onset sepsis and late onset sepsis in very-low-birth-weight infants in Korea. \u003cem\u003eJournal of Korean Medical Science\u003c/em\u003e, \u003cem\u003e30\u003c/em\u003e(Suppl 1), S67\u0026ndash;S74.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIskandar, A., Arthamin, M. Z., Indriana, K., Anshory, M., Hur, M., Di Somma, S., and Network, G. (2019).\u003c/strong\u003e Comparison between presepsin and procalcitonin in early diagnosis of neonatal sepsis. \u003cem\u003eThe Journal of Maternal-Fetal \u0026amp; Neonatal Medicine\u003c/em\u003e, \u003cem\u003e32\u003c/em\u003e(23), 3903\u0026ndash;3908.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMasson, S., Caironi, P., Fanizza, C., Thomae, R., Bernasconi, R., Noto, A., Oggioni, R., Pasetti, G. S., Romero, M., and Tognoni, G. (2015).\u0026nbsp;\u003c/strong\u003eCirculating presepsin (soluble CD14 subtype) as a marker of host response in patients with severe sepsis or septic shock: data from the multicenter, randomized ALBIOS trial. \u003cem\u003eIntensive Care Medicine\u003c/em\u003e, \u003cem\u003e41\u003c/em\u003e(1), 12\u0026ndash;20.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMahmoud Zayed, K., Abd ELmoez Ali Saad, A., Mohamed Amin, W., and Gamal Abo El-Nasr, M. (2020).\u0026nbsp;\u003c/strong\u003eDiagnostic value of presepsin in detection of early-onset neonatal sepsis. \u003cem\u003eAl-Azhar Journal of Pediatrics\u003c/em\u003e, \u003cem\u003e23\u003c/em\u003e(2), 825\u0026ndash;851.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAsmaa, O. A., Hanan, H., AL-Shaimaa, M. S., and Atya, A. M. A. (2018).\u0026nbsp;\u003c/strong\u003ePresepsin: A Anew Marker for Early Diagnosis of Septicemia. \u003cem\u003eThe Medical Journal of Cairo University\u003c/em\u003e, \u003cem\u003e86\u003c/em\u003e(9), 2237.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDeğirmencioğlu, H., Ozer Bekmez, B., Derme, T., \u0026Ouml;ncel, M. Y., Canpolat, F. E., and Tayman, C. (2019).\u003c/strong\u003e Presepsin and fetuin-A dyad for the diagnosis of proven sepsis in preterm neonates. \u003cem\u003eBMC Infectious Diseases\u003c/em\u003e, \u003cem\u003e19\u003c/em\u003e(1), 1\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eKoizumi, Y., Sakanashi, D., Mohri, T., Watanabe, H., Shiota, A., Asai, N., Kato, H., Hagihara, M., Murotani, K., Yamagishi, Y., Suematsu, H., \u0026amp; Mikamo, H. (2020). Can presepsin uniformly respond to various pathogens? - an in vitro assay of new sepsis marker. BMC immunology, 21(1), 33. https://doi.org/10.1186/s12865-020-00362-z\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"predictive, Soluble CD14, Presepsin, early onset Neonatal Sepsis, Preterm Neonates, blood culture, gram negative bacteria","lastPublishedDoi":"10.21203/rs.3.rs-6874629/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6874629/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Identifying the type of bacterial infection in a timely manner is crucial for the successful treatment of newborns with early-onset sepsis. However, blood culture results are often delayed, highlighting the urgent need for an early biomarker to predict the causative organism. Presepsin (P-SEP) has recently gained attention as a promising biomarker, generated as a component of the immune system's reaction to bacterial infection. It acts as an early warning sign of sepsis in newborns and can be identified in the first phases of inflammation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e to assess the predictive efficacy of soluble CD14 (presepsin) in identifying the type of bacterial organism in preterm newborns with early onset neonatal sepsis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003ethirty-six newborns with risk factors for early-onset sepsis were included in this prospective observational study, and initial CRP negative, they were further subdivided into probable \u0026amp; proven sepsis, based on the initial blood culture results. Serum presepsin levels, CRP and blood culture analyses were performed on all neonates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003ePatients with gram-negative infections had significantly elevated P-SEP levels initially on the first day and at follow-up on the third day. At a cutoff value of ≥ 970 ng/L, serum P-SEP on day 3 yielded a 100% positive predictive value, an 87.5% sensitivity, a 100% specificity, and an 88.8% negative predictive value to predict gram negative bacterial infection\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003e\u0026nbsp;Presepsin evaluation in preterm neonates with early-onset sepsis serves as a valuable early marker for identifying the type of bacterial infection present.\u003c/p\u003e","manuscriptTitle":"Soluble CD14 (Presepsin) in the early prediction of bacterial type in Early Onset Neonatal Sepsis in Preterm Neonates","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 13:10:10","doi":"10.21203/rs.3.rs-6874629/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c150c51d-7570-4737-9c0e-a6fb35d0309b","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51518903,"name":"Health sciences/Biomarkers"},{"id":51518904,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-08-12T03:53:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-18 13:10:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6874629","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6874629","identity":"rs-6874629","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}