MD Jérémie F Cohen
email: jeremie.cohen@inserm.fr

Antoine Ouziel

Soraya Matczak

Josephine Brice

Rene Spijker

Olivier Lortholary

Marie-Elisabeth Bougnoux

Julie Toubiana

Joséphine Brice

René Spijker

Diagnostic accuracy of serum (1,3)-beta-d-glucan for neonatal invasive candidiasis: systematic review and meta-analysis

Keywords: Systematic Review (1,3)-Beta-D-Glucan CRP: C-reactive protein NIC: Neonatal invasive candidiasis IQR: Interquartile range EORTC/MSG: European Organization for Research Neonatal invasive candidiasis, (1,3)-beta-D-glucan, diagnostic tests, sensitivity, specificity, neonates, systematic review, meta-analysis

teaching and research institutions in France or abroad, or from public or private research centers.

INTRODUCTION

Neonatal invasive candidiasis (NIC) is one of the leading causes of sepsis in neonatal intensive care units.

Candida species are the third most common infectious agents isolated in late-onset neonatal sepsis [START_REF] Stoll | Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network[END_REF], with C. albicans and C. parapsilosis accounting for 80 to 90% of neonatal fungal infections [START_REF] Steinbach | Pediatric Invasive Candidiasis: Epidemiology and Diagnosis in Children[END_REF]. In the USA, the incidence of NIC varies between 3 and 10 % for very low birth weight neonates (VLBW; 1000 -1500 g) and between 6 and 20% for extremely low birth weight neonates (ELBW; <1000 g) [START_REF] Stoll | Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network[END_REF][START_REF] Benjamin | Infection in late preterm infants[END_REF]. NIC is a severe illness, with a case-fatality rate up to 30% (4), and carries an additional risk of subsequent neurodevelopmental impairment due to Candida spp. meningoencephalitis [START_REF] Benjamin | Neonatal candidiasis: epidemiology, risk factors, and clinical judgment[END_REF]. The significant decrease of NIC incidence since the end of the 2000s is partly explained by the identification and control of its modifiable risk factors [START_REF] Aliaga | Changes in the incidence of candidiasis in neonatal intensive care units[END_REF], such as administration of broad-spectrum antibiotics, presence of a central venous catheter, exclusive parenteral nutrition, and mechanical ventilation [START_REF] Kelly | The epidemiology and diagnosis of invasive candidiasis among premature infants[END_REF].

The diagnosis of NIC remains difficult. Only 40% of neonates suspected of NIC have fever, and other clinical manifestations of neonatal sepsis such as tachycardia, poor perfusion, respiratory distress, feeding difficulties, and jaundice, are insufficiently specific [START_REF] Makhoul | Review of 49 neonates with acquired fungal sepsis: further characterization[END_REF]. Laboratory findings such as thrombocytopenia, leukocytosis, and elevated C-reactive protein (CRP) levels are not specific for candidiasis [START_REF] Makhoul | Review of 49 neonates with acquired fungal sepsis: further characterization[END_REF][START_REF] Manzoni | Is thrombocytopenia suggestive of organism-specific response in neonatal sepsis? Pediatrics international[END_REF][START_REF] Distefano | Procalcitonin serum levels in perinatal bacterial and fungal infection of preterm infants[END_REF]. NIC can only be proven by culturing Candida spp. from a normally sterile site, e.g., blood or cerebrospinal fluid samples [START_REF] De Pauw | Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group[END_REF], but the sensitivity of fungal blood culture may vary from 21 to 71%, as suggested by autopsy-proven invasive candidiasis studies in adults [START_REF] Clancy | Finding the "missing 50%" of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care[END_REF]. The sensitivity of blood culture is even lower in neonates because the blood sample obtained for culture is often less than 1 ml [START_REF] Connell | How reliable is a negative blood culture result? Volume of blood submitted for culture in routine practice in a children's hospital[END_REF]. Moreover, the delay in obtaining a positive culture result might be considered too long, usually 2 to 5 days, to enable early diagnosis and treatment [START_REF] Ellepola | Laboratory diagnosis of invasive candidiasis[END_REF]. Delays in instituting appropriate antifungal therapy may lead to an increase in morbidity and mortality [START_REF] Greenberg | Empiric antifungal therapy and outcomes in extremely low birth weight infants with invasive candidiasis[END_REF]. There is no single gold standard for determining the presence or absence of NIC. Therefore, most clinicians and researchers rely on risk stratification systems such as European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria, which grade the diagnosis of invasive fungal infection with three levels of probability (proven, probable, and possible). New biomarkers would be helpful for decision-making in neonates with sepsis. PCR based-assays for Candida have shown promising results, but clinical studies in neonates are scarce [START_REF] Trovato | Detection of fungal DNA in lysis-centrifugation blood culture for the diagnosis of invasive candidiasis in neonatal patients. Clinical microbiology and infection : the official publication of the[END_REF][START_REF] Ramos | Performance of a Quantitative PCR-Based Assay and Beta-d-Glucan Detection for Diagnosis of Invasive Candidiasis in Very-Low-Birth-Weight Preterm Neonatal Patients (CANDINEO Study)[END_REF]. Serum (1,3)-Beta-D-Glucan (BDG), a cell wall component of most pathogenic fungi, has been introduced in the revised version of EORTC/MSG diagnostic criteria for invasive candidiasis in 2008 [START_REF] De Pauw | Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group[END_REF]. Presence of BDG in the serum (Fungitell® > 80 ng/ml) allows the clinician to classify the patient as having "probable" instead of "possible" systemic fungal infection. Results of serum BDG levels can be obtained in less than 24 hours, and the amount of blood needed for the measurement of BDG is acceptable for neonates (< 100 µL).

In a recent meta-analysis in adults [START_REF] Onishi | Diagnostic accuracy of serum 1,3-beta-D-glucan for pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis[END_REF], BDG showed a summary sensitivity and specificity for detecting invasive fungal infection of 80% (95CI: 77% -82%) and 82% (81% -83%), respectively. BDG seems able to rule out invasive fungal infection in children and adults [START_REF] Guitard | Detection of beta-Dglucan for the diagnosis of invasive fungal infection in children with hematological malignancy[END_REF][START_REF] Karageorgopoulos | beta-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis[END_REF][START_REF] Angebault | Prospective Evaluation of Serum beta-Glucan Testing in Patients With Probable or Proven Fungal Diseases[END_REF], but there is limited data for its use in neonates, and a diagnostic accuracy systematic review and meta-analysis is lacking. The accuracy of BDG deserves being investigated in neonates because of specific risk factors and epidemiology of Candida infections, and higher rates of dissemination and end-organ damage in this population [START_REF] Benjamin | Neonatal candidemia and end-organ damage: a critical appraisal of the literature using meta-analytic techniques[END_REF]. This study aimed to determine the diagnostic accuracy of BDG in NIC.

METHODS

This systematic review was reported following the Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies statement (Appendix 1) [START_REF] Mcinnes | Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement[END_REF]. This study was registered

Eligibility criteria

We included published and unpublished studies which compared BDG (Fungitell® assay, Associates of Cape Cod, Inc., Falmouth, MA) with any reference standard that defined groups of patients with ordinal certainty of NIC (e.g., EORTC/MSG criteria) and included fungal blood culture. We included prospective and retrospective cross-sectional studies, randomised controlled trials, and case-control studies. We excluded studies in which another diagnostic kit than Fungitell® (e.g., GKT®) was evaluated, and case series with less than 10 participants. We included only studies reported in English, French, and Spanish.

Literature search strategy

The search strategy was developed in consultation with an information specialist (RS). We searched Medline via Pubmed using the search strategy described in Appendix 2. The search was adapted to search Embase via Ovid. We did not use methodological filters to identify diagnostic studies because such filters may result in the omission of relevant studies [START_REF] Leeflang | Use of methodological search filters to identify diagnostic accuracy studies can lead to the omission of relevant studies[END_REF], but used the Cochrane Neonatal group's standard search strategy for the neonatal population (available at neonatal.cochrane.org). We handsearched reference lists of included studies, of guidelines for the management of candidiasis, and of previous reviews about BDG [START_REF] Onishi | Diagnostic accuracy of serum 1,3-beta-D-glucan for pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis[END_REF][START_REF] Karageorgopoulos | beta-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis[END_REF][START_REF] He | A systematic review and meta-analysis of diagnostic accuracy of serum 1,3-beta-D-glucan for invasive fungal infection: Focus on cutoff levels[END_REF][START_REF] Pappas | Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America[END_REF][START_REF] Cuenca-Estrella | ESCMID* guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures[END_REF][START_REF] Hope | ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp. Clinical microbiology and infection : the official publication of the[END_REF]. We also searched for eligible articles using the "similar articles" function in PubMed [START_REF] Angebault | Prospective Evaluation of Serum beta-Glucan Testing in Patients With Probable or Proven Fungal Diseases[END_REF]

Study selection

First, two review authors (AO, JFC) independently excluded studies that were not related to NIC or BDG on the basis of the titles and abstracts identified by the search strategy. Then, two review authors (AO, JFC) retrieved the full text of relevant articles and independently evaluated them for inclusion using predetermined inclusion criteria.

Data extraction and management

For each included study, the following set of data was extracted using a pro forma: first author, year of publication or presentation, inclusion criteria, study setting, study design, reference standard used, number of participants, participant characteristics, threshold values for BDG investigated in the study report, data needed to assess methodological quality, and numbers to construct 2 x 2 tables (number of true positives, true negatives, false positives, and false negatives) at predefined positivity thresholds of 80 pg/ml (as recommended by the manufacturer) and 120 pg/ml. When study authors did not provide such numbers, we either calculated these numbers based on the reported estimates of sensitivity and specificity, or attempted to contact the authors to obtain additional information. According to the clinical and biological data available for each study, we reclassified participants according to the following three risk categories: proven NIC, probable NIC, and possible or excluded NIC. Data extraction was performed by one author (AO) and checked by a second (JT). One review author (JFC) acted as arbiter in case of discrepancies.

Assessment of methodological quality

Methodological quality assessment involved the use of the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [START_REF] Whiting | QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies[END_REF]. For each study, we scored risk of bias and concerns regarding applicability according to the four domains of QUADAS-2 (i.e., patient selection, index test, reference standard, and flow and timing).

Statistical analysis and data synthesis

Based on data from the 2 x 2 tables, we displayed estimates of sensitivity and specificity on forest plots and in the receiver-operating characteristic (ROC) space to represent the variability in diagnostic test accuracy within and between studies. We used Stata/SE version 13 (StataCorp, College Station, TX) to fit the hierarchical bivariate model [START_REF] Reitsma | Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews[END_REF], which allows for calculating summary estimates of sensitivity and specificity and the associated 95% confidence intervals, at prespecified positivity thresholds of 80 pg/ml and 120 pg/ml.

In our main analysis, participants with proven and probable NIC were considered as having NIC (reference standard positives), while participants with possible or excluded NIC were considered as not having NIC (reference standard negatives). In an additional analysis, we estimated the sensitivity of BDG to detect proven NIC cases, at a prespecified threshold of 80 pg/ml. We also carried out a sensitivity analysis by including only studies judged at low risk of bias.

RESULTS

Results of the search

The database literature search was performed on July 25, 2019 (last update). A chart displaying the flow of studies through the review appears in Figure 1. Searching in Medline and Embase identified 1697 unique records. We excluded a total of 1674 reports on the basis of their title, abstract or both. After evaluating the full text of 23 studies, we excluded 18 (Appendix 3). Additional searches allowed us to include three other studies [START_REF] Tabl | 1-3)-β-D-glucan in Neonatal Candidemia and its Reactivity with Bacterial Blood Stream Infection[END_REF][START_REF] Cliquennois | Diagnostic accuracy of Beta-D-Glucan for detecting invasive candidiasis in neonates[END_REF][START_REF] Cohen | Intérêt du (1,3)-béta-D-glucane pour le diagnostic de candidose invasive chez le nouveau-né[END_REF]. Overall, we included eight studies in our systematic review and meta-analysis [START_REF] Ramos | Performance of a Quantitative PCR-Based Assay and Beta-d-Glucan Detection for Diagnosis of Invasive Candidiasis in Very-Low-Birth-Weight Preterm Neonatal Patients (CANDINEO Study)[END_REF][START_REF] Tabl | 1-3)-β-D-glucan in Neonatal Candidemia and its Reactivity with Bacterial Blood Stream Infection[END_REF][START_REF] Cliquennois | Diagnostic accuracy of Beta-D-Glucan for detecting invasive candidiasis in neonates[END_REF][START_REF] Cohen | Intérêt du (1,3)-béta-D-glucane pour le diagnostic de candidose invasive chez le nouveau-né[END_REF][START_REF] Cornu | Evaluation of the (1,3)-beta-Dglucan assay for the diagnosis of neonatal invasive yeast infections[END_REF][START_REF] Goudjil | 1-3)-beta-D-glucan levels in candidiasis infections in the critically ill neonate. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies[END_REF][START_REF] Mackay | Serum 1,3-betaD-Glucan assay in the diagnosis of invasive fungal disease in neonates[END_REF][START_REF] Montagna | Diagnostic performance of 1-->3-beta-d-glucan in neonatal and pediatric patients with Candidemia[END_REF]. [START_REF] Cornu | Evaluation of the (1,3)-beta-Dglucan assay for the diagnosis of neonatal invasive yeast infections[END_REF][START_REF] Mackay | Serum 1,3-betaD-Glucan assay in the diagnosis of invasive fungal disease in neonates[END_REF]. NIC risk factors and colonisation by Candida spp. were often taken into consideration 10 when defining probable NIC [START_REF] Cliquennois | Diagnostic accuracy of Beta-D-Glucan for detecting invasive candidiasis in neonates[END_REF][START_REF] Cohen | Intérêt du (1,3)-béta-D-glucane pour le diagnostic de candidose invasive chez le nouveau-né[END_REF][START_REF] Cornu | Evaluation of the (1,3)-beta-Dglucan assay for the diagnosis of neonatal invasive yeast infections[END_REF][START_REF] Goudjil | 1-3)-beta-D-glucan levels in candidiasis infections in the critically ill neonate. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies[END_REF][START_REF] Mackay | Serum 1,3-betaD-Glucan assay in the diagnosis of invasive fungal disease in neonates[END_REF]. The number of proven NIC cases ranged from 4 to 15 per study, for a total of 60.

Characteristics of included studies

Methodological quality of included studies

Table 3 summarises quality assessment of the studies included in the review (see detailed quality assessment in Appendix 4). Two of the studies were judged as being of low overall risk of bias (≥ 3 QUADAS-2 items) [START_REF] Cliquennois | Diagnostic accuracy of Beta-D-Glucan for detecting invasive candidiasis in neonates[END_REF][START_REF] Goudjil | 1-3)-beta-D-glucan levels in candidiasis infections in the critically ill neonate. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies[END_REF]. Five studies avoided clinical selection of participants and therefore included a representative spectrum of patients. Interpretation of the results of the reference standard was made with blinding of the result of the BDG in 3 of 8 studies. There was low concern about applicability for patient selection, the index test, and the reference standard, except for the two case-control studies [START_REF] Tabl | 1-3)-β-D-glucan in Neonatal Candidemia and its Reactivity with Bacterial Blood Stream Infection[END_REF][START_REF] Montagna | Diagnostic performance of 1-->3-beta-d-glucan in neonatal and pediatric patients with Candidemia[END_REF].

Summary estimates of accuracy

The meta-analysis included eight studies encompassing 465 participants in total. At an 80 pg/ml positivity threshold, sensitivity varied from 75% to 100% and specificity from 47% to 100% (Figure 2A); bivariate meta-analysis showed a summary sensitivity of 89% (80% -94%) and a summary specificity of 60% (54% -66%) (Figure 3A). At a 120 pg/ml positivity threshold, sensitivity varied from 65% to 100% and specificity from 66% to 100% (Figure 2B); the summary estimates of sensitivity and specificity of BDG were 81% (71% -88%) and 80% (67% -88%), respectively (Figure 3B).

Additional analyses

When restricting the meta-analysis to patients with proven NIC, and using a positivity threshold of 80 pg/ml, BDG had a summary sensitivity of 99% (93% -100%); only 2 out of 60 cases of proven NIC would have been missed by BDG (Appendix 5).

We initially planned a sensitivity analysis restricted to studies judged at low risk of bias in at least three QUADAS-2 domains, but only two studies fulfilled this quality criterion. We investigated the impact of study quality by restricting the meta-analysis to non-case-control studies. Compared with the overall results (summary sensitivity and specificity of 89% and 60%, respectively), at a threshold of 80 pg/ml, sensitivity was lower and specificity was stable when considering exclusively the six non-case-control studies (summary sensitivity and specificity of 85% and 59%, respectively).

DISCUSSION

Main findings

NIC is a serious illness for which diagnosis is particularly difficult. In this meta-analysis, including eight studies encompassing 465 patients, summary sensitivity and specificity of BDG were 89% (80% -94%) and 60% (54% -66%) at an 80 pg/ml threshold, and 81% (71% -88%) and 80% (67% -88%) at a 120 pg/ml threshold. There were substantial variations in inclusion criteria and risk stratification systems across studies. In an additional analysis, we found that BDG was able to detect 99% of proven NIC cases when using an 80 pg/ml positivity threshold. In non-case-control studies, the sensitivity of BDG was lower, and specificity was stable (85% and 59%, respectively).

Comparison with previous findings

The accuracy of BDG for detecting invasive fungal infection was studied in pediatric patients with oncologic and hematologic malignancies [START_REF] Guitard | Detection of beta-Dglucan for the diagnosis of invasive fungal infection in children with hematological malignancy[END_REF]. Using an 80 pg/ml threshold, the sensitivity and specificity of BDG were 42% and 71%, respectively. Thus, BDG seems less sensitive in this type of patients than in neonates. Guitard et al. explained this lower sensitivity by the frequent use of empiric and pre-emptive echinocandins prior to BDG measurement. The authors hypothesised that echinocandins might cause false-negative BDG results by inhibiting the activity of enzyme BDG-synthase [START_REF] Guitard | Detection of beta-Dglucan for the diagnosis of invasive fungal infection in children with hematological malignancy[END_REF].

In adults, two recent systematic reviews with meta-analysis evaluated the diagnostic accuracy of BDG for detecting invasive fungal infection. At an 80 pg/ml threshold, sensitivity and specificity were 77% and 85% [START_REF] Karageorgopoulos | beta-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis[END_REF], respectively, and 78% and 81% [START_REF] He | A systematic review and meta-analysis of diagnostic accuracy of serum 1,3-beta-D-glucan for invasive fungal infection: Focus on cutoff levels[END_REF]. Again, BDG seems more sensitive in neonates, at the expense of specificity. False-positive BDG results could be explained by cellulose-containing membranes used in hemodialysis, surgical glucan-containing gauzes, administration of human blood products such as albumin and intravenous immunoglobulins, treatment with certain antibiotics such as piperacillintazobactam, and glucan-containing test tubes used the laboratory [START_REF] Clancy | Finding the "missing 50%" of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care[END_REF][START_REF] Huppler | Role of Molecular Biomarkers in the Diagnosis of Invasive Fungal Diseases in Children[END_REF]. Of note, no false positivity related to the preterm neonatal status per se has been reported.

Three studies that evaluated BDG in neonates were excluded from this review because they didn't use the Fungitell® assay but a different commercial kit (i.e., GKT® and Dynamiker Fungus® assays) [START_REF] Liu | Evaluation of a Novel Plasma (1,3)-beta-d-Glucan Detection Assay for Diagnosis of Candidemia in Pediatric Patients[END_REF][START_REF] Zhao | Platelet parameters and (1, 3)-beta-D-glucan as a diagnostic and prognostic marker of invasive fungal disease in preterm infants[END_REF][START_REF] Shabaan | Role of serum (1,3)-beta-d-glucan assay in early diagnosis of invasive fungal infections in a neonatal intensive care unit[END_REF].

Reported positivity thresholds for the GKT® assay were lower than for Fungitell® (14 pg/ml for Liu et al.

and 10 pg/ml for Zhao et al.). Sensitivity and specificity of the GKT® assay were 75% and 91%, respectively, in Liu's study, and 68% and 75%, respectively, in Zhao's. The reported threshold for the Dynamiker fungus® assay was 99 pg/ml, which seems in the same range than that of Fungitell®; its sensitivity and specificity were 64% and 95 %, respectively [START_REF] Shabaan | Role of serum (1,3)-beta-d-glucan assay in early diagnosis of invasive fungal infections in a neonatal intensive care unit[END_REF].

Strengths and limitations

In this review, two reviewers independently performed study selection, but data extraction and quality assessment was performed by one reviewer and checked by a second. Studies included in this review are not exempt from methodological weaknesses, and results should be considered with caution. Also, the number of studies (n = 8) and participants (n = 465) are rather low. This led to imprecision in metaanalysis summary estimates and impeded further analysis of potential sources of heterogeneity between studies, for example by use of meta-regression. Also, because of the lack of reported data, we were only able to analyse the accuracy of BDG at two prespecified thresholds (i.e., 80 pg/ml and 120 pg/ml).

Implications

At an 80 pg/ml threshold, BDG has a high sensitivity for detecting proven NIC (99%). When focusing on "proven and probable NIC", a less stringent outcome, sensitivity dropped to 89% in our meta-analysis, which means that one out of ten patients with "proven and probable NIC" would be missed in a strategy relying only on BDG. Although BDG has a high sensitivity for proven NIC, it has only moderate accuracy for "proven and probable NIC" combined. As a consequence, BDG should not be used as a stand-alone test to rule out NIC and eventually stop empirical antifungal treatment. We probably should incorporate BDG in a clinical decision rule combining clinical, biological and radiological information, as suggested by Benjamin et al. [START_REF] Benjamin | Neonatal candidiasis: epidemiology, risk factors, and clinical judgment[END_REF]. BDG could also be incorporated in a clinical scoring system such as the "Candida Score" developed by Leon et al. to assess the risk of invasive candida infection in non-neutropenic adults [START_REF] Leon | A bedside scoring system ("Candida score") for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization[END_REF]. We are not aware of studies assessing the clinical usefulness of BDG-based compared to such riskbased approaches.

There was high variability in reference standards and case definitions across studies. The presence of such variability highlights that the EORTC/MSG criteria seem challenging to apply in neonates. We suggest using a simplified rule-based risk stratification system relying on the presence of signs and symptoms of neonatal sepsis, risk factors for invasive candidiasis, evidence of Candida colonisation, and

Candida being cultured from a normally sterile site (Table 4). We believe a more consensual risk stratification system would increase homogeneity in case definition and help interpreting results from future studies.

More prospective multicenter cohort studies with blinding of test readers are needed. Such studies should not focus on BDG alone, but should also investigate the value of other biomarkers such as platelet and leukocyte counts, CRP, mannan and anti-mannan antibodies, and Candida PCR, for example. This would allow direct comparisons of test performance. It could also be interesting to measure BDG systematically and repeatedly in the serum and cerebrospinal fluid of newborns with NIC because BDG monitoring might allow reducing the length of antifungal therapy.

Conclusions

BDG seems a promising biomarker in the management of newborns with suspected NIC. Notably, BDG might be helpful in clinical practice to exclude NIC diagnosis. However, it seems too early to recommend its use because of the scarcity of reliable clinical data, heterogeneity in case definitions, and unstable accuracy estimates. Given the current evidence, BDG cannot be used as a stand-alone test to decide whether or not the treatment threshold for NIC is reached. Larger high-quality clinical studies in neonates with sepsis are warranted.

TABLES

Cliquennois 2018

See Table 4 Cohen 2017 See Table 4 Cornu 2018  Control group: neonates who were neither colonised nor infected with any fungal pathogen;  Probable group: neonates who had probable invasive yeast infection (IYI) suspected from clinical and biological criteria; Probable IYI was defined as receipt of more than 5 days of antifungal therapy and presence of yeast in urine (urine bag) or digestive (stool and anal swab) colonisation with clinical or biological (white blood cell count, Creactive protein [CRP])) symptoms of sepsis.  Proven group: neonates who had proven IYI. Proven IYI was defined as a positive culture for a yeast species from a normally sterile body site except urine obtained with a urine bag.

Goudjil 2012

 Infected group: patients with systemic infection, including a Candida-positive culture from a usually sterile body site: candidemia (only blood cultures positive for Candida spp.), disseminated candidiasis (blood, urine, CSF, peritoneal or pleural spaces, bone, joint or ocular sites positive for Candida spp.), renal candidiasis (urine cultures are positive for Candida spp. with ultrasound evidence of fungal lesions in the kidney);  Non-infected group: patients with symptoms of infection but without any positive fungal culture from sterile body sites.

Mackay 2011

 No fungemia: a high index of suspicion for fungemia including 3 or more risk factors; blood culture negative; white cell count (WCC), platelet count (<100 000/mm 3 ) and C-reactive protein (CRP) within normal limits; no evidence of colonisation with a fungal organism; or definite bacterial sepsis;  Possible fungemia: a high index of suspicion for fungemia including 3 or more risk factors; blood cultures negative; no evidence of colonisation; two or more of the following present: abnormal WCC, low platelet count or elevated CRP (>10);  Probable fungemia: a high index of suspicion for fungemia including 3 or more risk factors and evidence of colonisation with a fungal organism in the form of positive stool or non-sterile urine sample (collected by urine bag) for yeasts; blood cultures negative; and one or more of the following are present: abnormal WCC, low platelet count (<100 000/mm 3 ) or elevated CRP (>10);  Definite fungemia: positive culture for a fungal organism from a normally sterile site (including blood or tissue culture).

Montagna 2011

 Proven Candida bloodstream infections  Negative controls Ramos 2017  Invasive candidiasis (IC) confirmed: an episode was defined as IC confirmed if a culture of a sterile sample was found to be positive for Candida spp. or if a Candida species was detected during the autopsy of a deceased patient. Likewise, an episode was considered IC confirmed when endophthalmitis candidiasis was diagnosed by direct examination of the fundus of the eye or if fungus balls were observed by abdominal ultrasound.  IC probable: this designation was used for patients who tested negative for Candida spp. in a culture derived from blood, cerebrospinal fluid (CSF), or other sterile fluid samples but for whom (i) improvement was seen upon treatment with an antifungal(s) and/or (ii) the episode corresponded to a true IC (according to the clinician's criteria and based on the evolution) and/or (iii) the image from an echocardiogram was consistent with Candida endocarditis or a cerebral ultrasound showed micro-abscesses consistent with IC. In addition to fulfilling any of the criteria described above, one of the following conditions had to be met: colonisation by Candida spp. was detected by isolation of Candida spp. from stool, urine, bronchial aspirate, or gastric samples or a clinical diagnosis of Candida dermatitis was made; thrombocytopenia (platelet count of 100,000/mm 3 ) was diagnosed; or, after an episode of sepsis, a complication such as meningitis, endocarditis, or pyelonephritis appeared as a result of the dissemination of Candida spp. This condition was determined by clinical judgment. Mucosal candidiasis in the absence of clinical signs of IC was not considered to represent IC.

Figure 1 .

 1 Figure 1. Flow diagram of studies in the review.

Figure 2 .

 2 Figure 2. Forest plots of (1,3)-Beta-D-Glucan sensitivity and specificity for detecting neonatal

Figure 3 .

 3 Figure 3. Summary ROC plot of (1,3)-Beta-D-Glucan sensitivity and specificity for neonatal

Table 1

 1 Authors used various rules combining host, clinical and mycological criteria to define NIC status. Some of them used additional biological criteria such as CRP level, leukocytosis, and platelet count

summarises the main characteristics of the included studies. Four originated from France, one from Italy, one from Spain, one from South Africa, and one from Egypt. Five of them were retrospective (and among them, two were case-control studies), one was a single centre prospective study, and two were multicenter prospective cohort studies. A total of 465 participants were included across studies (range 13 to 155), with a median gestational age of 30 weeks of gestation (WG) (range 27 to 31.7) and a median birth weight of 1027.5 g (range 991.1 to 1811.4). Inclusion criteria varied (see detailed study characteristics in Appendix 4). Each author used case definitions derived from EORTC/MSG criteria

[START_REF] De Pauw | Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group[END_REF]

, but there was substantial heterogeneity in risk stratification systems from a study to another; only the definition of proven cases was homogeneous (i.e., Candida-positive culture from a normally sterile site; see Table

2

).

Table 1 . Characteristics of included studies

 1 : WG, weeks of gestation; BDG, Beta-D-Glucan; NIC, neonatal invasive candidiasis; NICU, neonatal intensive care unit. *Gestational age and birth weight reported as median except for Ramos and Tabl (mean). ** According to case definitions used in the original articles. ***In meta-analysis, neonates with bacteremia and controls were grouped as NIC-negatives.

	Study	Country	Inclusion criteria	Study design	N Median gestational age	Median birth weight	Risk stratification system	Fungal species when
						(weeks)*	(g)*	(n)**	identified
	Cliquennois 2018	France	Neonates suspected of	Prospective single	61	27.6	1035	Proven NIC (4)	7 C. albicans
			NIC	center cohort				Probable NIC (4)	1 C. Parapsilosis
								Possible NIC (53)	1 unspecified yeast
	Cohen 2017	France	Neonates suspected of	Retrospective	13	27.3	1020	Proven NIC (5)	4 C. albicans
			NIC, with available BDG	single centre				Probable NIC (4)	1 C. glabrata
			serum measurements	cohort				Possible NIC (4)
	Cornu 2018	France	Neonates suspected of	Retrospective	38	30	1200	Proven group (4)	16 C. albicans
			late-onset infection, with	single centre				Probable group (13)	1 C. parapsilosis
			available BDG serum	cohort				Control group (21)
			measurements
	Goudjil 2012	France	Neonates suspected of	Retrospective	61	28.5	1000	Infected group (18, including	14 C. albicans
			NIC, with available BDG	single centre				6 proven NIC)	3 C. parapsilosis
			serum measurements	cohort				Non-infected group (43)	1 C. lusitaniae
	Mackay 2011	South	Neonates suspected of	Prospective	72	31	1340	Definite fungemia (10)	4 C. albicans
		Africa	late-onset infection, with	multicenter cohort				Probable fungemia (9)	4 C. parapsilosis
			high risk of NIC					Possible fungemia (22)	1 Saccharomyces
								No fungemia (31)	cerevisiae
	Montagna 2011	Italy	Preterm neonates with	Retrospective	20	Not reported	1145	Proven Candida	6 C. albicans
			NIC, and non-infected	single centre case-				bloodstream infections (10)	3 C. parapsilosis
			preterm neonates	control				Negative controls (10)	1 C. glabrata
	Ramos 2017	Spain	Neonates suspected of	Prospective	155	27	882	IC confirmed (6)	8 C. albicans
			late-onset sepsis or	multicenter cohort				IC probable (2)	1 Candida spp
			meningitis in NICU					Controls (147)
	Tabl 2012	Egypt	Neonates with NIC,	Retrospective	45	Candidemia: 30.4	Candidemia: 1018.7	Candidemia (15)	Not reported
			neonates with bacteremia,	single center case-		Bacteremia: 30.5	Bacteremia: 991.1	Bacteremia (15)
			and healthy controls***	control		Control: 31.7	Control: 1811.4	Control (15)

Abbreviations

Table 2 . Risk stratification systems used across studies Study Risk stratification system

 2

Table 3 . Risk of bias and concerns regarding applicability of included studies Risk of bias Applicability concerns

 3

	Study	Patient	Index	Reference	Flow and	Patient	Index	Reference
		selection	test	standard	timing	selection	test	standard
	Cliquennois 2018	Low	Low	Low	Low	Low	Low	Low
	Cohen 2017

Acknowledgements:

We thank Drs Cliquennois, Cornu, Mackay, and Goudjil for having shared additional unpublished data.

Access to data: JFC had full access to the data; he is the guarantor for the data.

TRANSPARENCY DECLARATION

Protocol: The protocol of this study was registered and published on the PROSPERO website (number CRD42018089545).

Conflicts of interest: None.

Funding: There was no external funding for this study.


DOMAIN ONTOLOGY

Description of Anthropogenic

CIDOC-CRM and Extensions

Cultural Heritage Documentation TOP LEVEL ENTITIES [START_REF] Bruseker | Cultural Heritage Data Management: The Role of Formal Ontology and CIDOC CRM[END_REF]

ALIGNMENT CLASSES AND PROPERTIES C.

DOMAIN TERMINOLOGY

TOW ARDS A DOMAIN ONTOLOGY DEDICATED TO THE DESCRIPTION OF ANTHROPOGENIC TRACES in rock art

INTRODUCTION / CONTEXT

Around 178 Paleolithic caves and rock-shelters are scattered around the French territory. The former represent a particularly sensitive heritage. Their study can be quite complex, involving experts from a variety of scientific fields that can vary from a cave to another (archaeologists, geologists, climatologists, microbiologists, etc.). The collaboration of these multidisciplinary teams is however complexified by the diversity of their work supports or formats and by the disparity of the produced documents.

The question that arises concerns the semantic articulation of the analysis elements produced by the experts and therefore the structuration of heterogeneous data.

The cross-referencing of the information that is produced becomes essential for an overall understanding. A proposal based on the use of a conceptual model formalising the knowledge of the expert field is thus envisaged. This resides in a domain ontology, a knowledge model designed to meet the above-mentioned need for semantic structuration of the collected data (fig. 1).

STATE OF THE ART

Anthropogenic traces are the main reason for specialists' accorded interest in Paleolithic caves. This is also reflected in the survey methods. Oscar Fuentes thus distinguishes two types of surveys : the plastic analytical and the technical analytical survey [START_REF] Fuentes | La 3D et l' étude de l'art pariétal, ses apports et ses limites[END_REF]. The former translates the traces in an aesthetic way, the Paleolithic traces being at the heart of the study. In the second approach, they are given the same level of importance as their support, or the rock stigmas. The graphic entity thus becomes the result of a process and not the entry point.

As a bearer of an aesthetic but also symbolic value, the description of cave art is subject to interpretation. The classification of traces types often requires the creation of new terms, terms that do not always enjoy consensus. In addition, the controlled vocabulary existing in the archaeological field is insufficiently oriented towards the description of anthropogenic traces and cave art analysis in general.

METHODOLOGY

The ambition is therefore to create a domain ontology dedicated to the description of anthropogenic traces. This work is largely based on the approach developed for the domain ontology built as part of the ANR MONUMENTUM project [START_REF] Messaoudi | An ontological model for the reality-based 3D annotation of heritage building conservation state[END_REF]. In order to do so, we relied on the structure of archaeological context sheets and the scientific literature of the domain to reveal the knowledge domain and model the top-level classes of the ontology, their properties and sub-classes (fig. 2.A.). The ambition is for the domain ontology to be merged later with CIDOC-CRM, the conceptual reference model for cultural heritage information and its extensions (fig. 2.B., 2.C.).

FIRST RESULTS

This allowed us to model 5 conceptual classes, considered as being necessary and sufficient for the description of anthropic traces, as well as the properties that structure them (fig. 3) : Alteration, Support, Anthropogenic Trace, Realisation Technique, Theme.

The main question that arrised during the modelling of these concepts concerned the status of the anthropogenic traces. The latter could indeed be considered as a form of rock alteration. It was however decided that a distinction is to be made, Paleolithic graphic entities are of an incommensurably artistic, historical and cultural value. Ancient anthropogenic traces are thus at the heart of this ontology. The subclasses of these thematic concepts are thereafter structured into a conceptual mapping (fig. 4).

CONCLUSION AND PERSPECTIVES

The domain ontology can serve as a basis for an eventual information system and is a response to a need for semantic structuring of heterogeneous data. This articulation of the analyti- cal elements produced within a domain is indeed interesting from the perspective of the extraction of new knowledge resulting from data cross-referencing.

A first perspective is the implementation of the domain ontology in an information system dedicated to the study of heritage objects [START_REF] Manuel | Quantitative Analysis and semi-automatic annotation of spatialized data[END_REF] in order to structure spatialised semantic annotations. A system based on annotations made on 3D point clouds organised using a domain ontology could facilitate the crossing of these different information layers. Correlations between the domain ontology and archaeological databases can furthermore be performed using SQL/SPARQL mappings. Finally, the question of the visualisation of this data must be addressed, particularly from the perspective of information cross-referencing.

  c t / in v o lv e a ff e c t / in v o lv e p a rt ic ip a te in

Figure 3 .

 3 Figure 3. Conceptual model of the top-level classes of the domain ontology and their properties

Figure 4 .Figure 1 .

 41 Figure 4. Conceptual model of the classes tree developped in French

Figure 2 .

 2 Figure 2. Objective and adopted methodology


E Steveler
email: emilie.steveler@insa-strasbourg.fr

H Rinnert

M Vergnat

Low-temperature photoluminescence properties of Nd-doped silicon oxide thin films containing silicon nanocrystals

Keywords: Photoluminescence, neodymium, rare earth, silicon oxide, silicon nanocrystals, lowtemperature 1. Introduction

The luminescence properties of neodymium-doped silicon oxide thin films containing silicon nanocrystals (Si-nc) were studied as a function of temperature from 10 to 300 K by steady-state and time-resolved photoluminescence (PL) spectrometry. The Nd-related emission at 920 nm, induced by the 4 F3/2→ 4 I9/2 shell transitions, was obtained either with a resonant excitation at 585 nm or with an indirect excitation at 325 nm via Si-nc, which act as sensitizers. A saturation of the neodymiumrelated photoluminescence intensity has been evidenced for indirect excitation thanks to silicon nanocrystals at temperatures below 100 K. According to the Förster model of energy transfer, this saturation is explained by a decrease of the coupling efficiency between Si-nc and rare earth ions at low temperatures, induced by the increase of the silicon nanocrystals lifetime at low temperatures.

Silicon-based materials doped with rare earths (RE) ions have attracted much attention because of their potential use for optoelectronics [1]. Indeed the use of RE ions can give rise to light emissions at wavelengths from the far-infrared to the ultraviolet spectral range. The light emission from the RE generally arises from intrashell transitions of 4f electrons which are, in first order, electric dipole forbidden. Hence, a resonant excitation of the RE leads to a weak luminescence efficiency. However, an indirect excitation mechanism can lead to a strong increase of the excitation efficiency of the optically active ions. For instance, Er 3+ ions which are used in optical communications for their luminescence at 1.54 μm, can be indirectly excited in silica containing silicon nanocrystals (Si-nc), thanks to an efficient energy transfer process from Si-nc to Er 3+ ions [2,3,4,5]. The Er-related photoluminescence (PL) is thereby strongly improved since the absorption cross section of the Si-nc, which act as sensitizers, is several orders of magnitude higher than that of direct Er excitation. Similarly to the case of erbium, Nd 3+ ions present several technologically important luminescent bands including the 4 F3/2→ 4 I11/2, 4 F3/2→ 4 I9/2 and 4 F3/2→ 4 I13/2 4f-shell transitions which are, respectively, the basis of 1.05 μm Nd lasers, a second lasing transition at 900 nm, and a 1.3-1.4 μm band in the second fiber transparency window. Because of the emission of Nd 3+ ions in the near infrared range, Nd-doped materials are also of potential interest for the achievement of down-shifting or down-conversion layers, which are expected to improve the of solar cells efficiency by reducing the thermalization process of photogenerated carriers. Nd-related PL bands have been observed in silicon oxide alloys prepared by plasma-enhanced chemical vapor deposition [6], sputtering [7,8] or evaporation [9]. In a previous work [10], we demonstrated that silicon nanocrystals are efficient sensitizers of Nd 3+ ions at room temperature, but no result has been reported on the energy transfer behavior at low temperature. In the present paper, we address in the low-temperature PL properties of Nd-doped silicon oxide thin films containing Si-nc. In samples containing Si-nc as porous silicon [11] or Si-nc obtained by ionic implantation of silicon in silica [12], it has been shown that the temperature dependance of Si-nc PL intensity has a maximum around 100 K. For Si-nc obtained by laser-induced decomposition of silane [13] or by plasma-enhanced chemical vapor deposition [14], the maximum of the PL of Si-nc is observed around 150 K. The decrease of the PL intensity above 100-150 K is generally attributed to thermally activated non-radiative desexcitation processes. However, the generally observed decrease of the PL of Si-nc below 100 K is explained by a saturation effect which is due to the strong increase of the PL radiative lifetime at low temperature [15,16,17].

In this work, we studied the low-temperature PL properties of Nd-doped silicon rich silicon oxide thin films prepared by evaporation. It is demonstrated that the Nd-related PL saturates at low temperatures in presence of Si-nc, only as Nd 3+ ions are indirectly excited. The results are discussed in relation with the desexcitation and the excitation processes of the rare earth ions, in relation with the temperature dependence of the Si-nc PL properties.

Experimental details

The films were prepared by co-evaporation of SiO powder from a thermal cell and of SiO2 powder from an electron beam gun in a high-vacuum chamber with a base pressure equal to 10 -8 Torr. The deposition rate equal to 0.1 nm/s was controlled by a quartz microbalance system and the prepared samples had the composition SiO1.5. The thickness of the films was equal to 200 nm. The Nd evaporation was performed from an effusion cell, heated around 1200 °C. The Nd concentration, defined by CNd = [Nd] / [SiOx], was calibrated by adjusting the relative deposition rates of SiO powder and Nd, and was varied from 0.15 to 2 atomic %. For Nd concentrations higher than 0.5 at.% a PL quenching effect due to rare earth clustering is observed; however, no matter the Nd concentration, our photoluminescence experiments evidence the low temperature saturation of the Nd-related PL in presence of Si-nc. Thus, we only present here the results for a neodymium concentration equal to 1 atomic %. The silicon substrates were maintained at 100 °C during the deposition. The Si clusters are generated by annealing post-treatments, which involves in the demixtion of the SiOx film following the reaction SiOx  Si + SiO2. Further information on the SiOx demixtion and the formation of Si-ncs such as Fourier Transform InfraRed spectroscopy and Transmission Electron Microscopy (images and diffraction) can be found in previous publications [18,19,20]. For this study, the samples were annealed at 1100 °C during 5 minutes under a nitrogen flow in a rapid thermal furnace.

For PL intensity measurements, the samples were excited by a 30 mW He-Cd laser using the 325 nm line or by an optical parametric oscillator (OPO) laser at 420 nm or 585 nm. The OPO laser pulse frequency and the duration were typically equal to 10 Hz and 5 ns, respectively. For experiments using the OPO laser, the PL emission from the samples was obtained by integrating the time-dependent luminescence. For the time-resolved PL experiments, the samples were pumped by the 355 nm line of a frequency-tripled YAG:Nd laser. The laser pulse frequency, energy, and duration were typically equal to 10 Hz, 50 µJ, and 20 ns, respectively. The time response of the detection system was better than 1 µs. The PL signal was analyzed by a monochromator equipped with a 600 grooves/mm grating and by an InP/InGaAs photomultiplier tube cooled at 190 K, with a detection range in the 600-1700 nm range. The response of the detection systems was precisely calibrated with a tungsten wire calibration source. PL experiments were performed at temperatures between 10 K and 300 K in a cryostat cooled with liquid helium.

Results and discussion

The PL spectra of Nd-doped silicon oxide thin films containing Si-nc are presented in Fig. 1 as a function of the temperature between 10 and 300 K. The excitation line was non resonant with electronic levels of neodymium ions. These spectra show a broad band around 700 -750 nm, corresponding to the PL of Si-nc due to the quantum confinement, and the Nd-related PL band at 920 nm, corresponding to the 4 F3/2→ 4 I9/2 transition. The PL intensity of Si-nc shows a maximum between 90 and 150 K, as previously seen in the literature [11][12][13][14], and the Nd-related PL intensity reaches a maximum value for temperatures below 150 K. In order to better analyze these results, we plotted the integrated Nd-related PL intensity as a function of the temperature (Fig. 2 (a)). On the one hand, this graph shows a linear increase of the intensity of Nd 3+ ions as the temperature decreases from 300 to 100 K, due to a decrease of the non radiative recombination rate with lowering temperature. On the other hand, below 100 K, the Nd-related PL intensity saturates.

To explain this low-temperature saturation of rare earth ions, we first studied the desexcitation mechanism of the neodymium ions by extracting the decay time of the rare earth. Fig. 2 (a) also presents the decay time of Nd 3+ ions as a function of the temperature. Neodymium decay times were calculated by fitting the experimental PL decay curve at 920 nm with a single exponential decay curve. The decay time of Nd 3+ ions increases almost linearly from 125 to 310 µs as the temperature drops from 300 to 10 K. This decay time can be described by the following relation:

rad non rad Nd    1 1 1  
where Nd  is the measured decay time of Nd 3+ ions, rad  is the radiative decay time and rad non



is the non-radiative decay time. It can be assumed that the radiative decay time does not depend on the temperature, then the increase of the measured Nd decay time at low temperature is due to an increase of the non-radiative decay time. Since non-radiative processes are expected to be thermally activated, non-radiative recombination rate decreases at low temperature. This indeed leads to an increase of the non-radiative decay time at low temperature and thus an increase of measured Nd decay time. This should involve an increase of the Nd-related PL intensity, as observed by Seo et al. [6]. In the case of our samples, the observed saturation of the Nd-related PL intensity below 100 K can not therefore be explained by the desexcitation mechanism of the rare earth.

Since we previously show that the desexcitation mechanism of Nd can not be at the origin of the Nd-related PL saturation at low temperature, the excitation mechanism of Nd 3+ ions could then be the cause of this saturation. In such samples containing Si-nc, we previously demonstrated that Nd 3+ ions are indirectly excited by Si-nc thanks to an efficient energy transfer [10]. We studied then the correlation between the intensities of Si-nc and Nd 3+ ions as a function of the temperature. suggesting that these phenomena are correlated. Thus, in order to understand the evolution of the Nd-related PL intensity as a function of temperature, we studied the temperature dependence of the PL of Si-nc.

Then, from the time resolved PL spectra of Si-nc for different temperatures, we extracted the decay time of Si-nc (Fig. 2 (b)). The decay time of Si-nc was extracted using a stretchedexponential law (IPL = I0 exp (-t/τ) β ), where β was equal to 0.8. Such a law is generally used to describe the time dependance of the Si-nc PL [21,22]. On the one hand, as the temperature drops from 300 to 90 K, the decay time of Si-nc increases slowly from 90 to 260 µs because of the decrease of the non-radiative recombination rate, explaining the increase of the PL intensity. On the other hand, the decay time of Si-nc strongly increases below 90 K, reaching a value of 2 ms at 10 K.

This sharp rise is due to an important increase of the radiative decay time of Si-nc, as predicted by Calcott et al. [23]. This strong increase of the radiative decay time leads to a significant reduction of the radiative recombination efficiency, explaining the decrease of the PL intensity of Si-nc below 90 K.

According to the Förster model on the energy transfer from a donor to an acceptor [START_REF] Förster | Comparative effects of radiation[END_REF], a decrease of the radiative recombination rate of the donor leads to a decrease of the energy transfer probability. Since the radiative recombination efficiency of Si-nc strongly decreases at low temperatures, the probability of energy transfer from Si-nc to Nd 3+ ions also drops and leads to a decrease of the coupling efficiency at low temperature. The competition between the decrease of the coupling efficiency and the decrease of non-radiative recombination explains the saturation of the Nd-related PL.

To confirm the previous results showing the role of indirect excitation via Si-nc in the saturation of Nd-related PL at low temperature, we compared the evolution of the normalized PL intensities of the rare earth at 920 nm for direct and indirect excitations as a function of the temperature (Fig. 3). For direct excitation, the excitation line (585 nm) was resonant with the 4 G5/2 and 2 G7/2 electronic levels of neodymium ions and, for indirect excitation, the excitation line was non resonant with electronic levels of neodymium ions. For both direct and indirect excitations, PL intensities have been normalized in order to compare the evolution of the intensity as a function of the temperature. Actually, the Nd-related PL intensity obtained for non resonant excitation through

Si-nc at 325 nm is much higher than the one obtained for resonant excitation of the rare earth at 585 nm. This can be explained by the absorption cross section of Si-nc which is several orders of magnitude higher than the one of Nd. [10] As previously seen in Fig. 2 (a), the Nd-related PL saturates below 100 K for an indirect excitation thanks to Si-nc; on the contrary, for resonant excitation, the Nd-related PL linearly increases as the temperature drops from 300 to 10 K and does not saturate. This result confirms that the origin of the saturation of Nd-related PL at low temperatures is the indirect excitation of the rare earth via Si-nc.

Indirect excitation thanks to amorphous Si nanoparticles could also lead to a saturation of the Nd-related PL intensity at low temperature. Thus, we studied a Nd-doped silicon oxide thin film annealed at 800 °C where Si nanoparticles were generated by demixtion. The room-temperature PL spectrum of this sample (inset of Fig. 4) shows the Nd-related PL band around 920 nm but the PL of Si-nc generally observed around 700-800 nm is not seen, revealing that the Si nanoparticles are amorphous at 800 °C. In this sample without Si-nc, we demonstrated in a previous paper [20] that the indirect excitation is due to the existence of electronic defect states or amorphous Si clusters.

Fig. 4 presents the Nd-related PL intensity as a function of the temperature for an excitation line which is non-resonant with electronic levels of neodymium. For this sample containing no Si-nc, the indirect excitation of Nd 3+ ions leads to a linear rise of the Nd-related PL intensity as the temperature decreases from 300 to 10 K. Unlike the indirect excitation thanks to Si-nc, indirect excitation of neodymium via electronic defect states or amorphous Si clusters do not lead to saturation of Nd-related PL intensity at low temperatures. This result shows that the indirect excitation of Nd 3+ ions leads to the saturation of their PL only when it occurs thanks to Si-nc, because of the strong decrease of their radiative recombination efficiency at low temperatures.

Finally, according to the Förster model, the radiative recombination rate of the Si-nc has to be high to obtain an efficient coupling and an intense Nd-related PL. Nevertheless, if the radiative recombination rate of the donor is very high, we can wonder if Si-nc do not emit luminescence preferentially rather than transferring their energy to Nd 3+ ions. Thus, to obtain a strong Nd-related PL, the optimal configuration is certainly a compromise between the radiative processes of Si-nc and the coupling with the rare earth that compete with each other.

Conclusions

We studied the low-temperature PL properties of Nd-doped silicon oxide thin films containing Si-nc elaborated by co-evaporation of SiO and SiO2 powders. We showed that the Ndrelated PL intensity is strongly dependent on the temperature and that the temperature dependence of the PL intensity is different depending on the excitation process (direct or indirect). Above 100 K, the PL of the rare earth strongly depends on thermally activated non-radiative recombinations;

then, the Nd-related PL intensity increases as the temperature drops from 300 to 100 K. On the contrary, below 100 K, the PL intensity of neodymium saturates and is almost constant. We explained this result by the indirect excitation of the Nd 3+ ions via silicon nanocrystals whose PL intensity also saturates below 100 K. Indeed, the strong increase of the radiative decay time of Si-nc at low temperatures leads to a significant reduction of the radiative recombination rate of the nanoclusters, and, according to the Förster model, results in a decrease of the energy transfer from Si-nc to Nd 3+ ions. Silicon nanocrystals, which act as sensitizers for Nd 3+ ions, are then less efficient at temperatures below 100 K. On the contrary, in absence of Si-nc (sample annealed at 800 °C), when the indirect excitation occurs thanks to electronic defect states or amorphous Si clusters, the Nd-related PL intensity does not saturate and increases as the temperature drops to 10 K. In this case, the sensitizers do not lose their efficiency at low temperatures.

Figure 2 (

 2 Figure 2 (b) presents the PL intensity of Si-nc as a function of the temperature and shows that the

Figure 1 :

 1 Figure 1: (Color online) CW-PL spectra of Nd-doped silicon oxide thin films containing Si

Figure 2 :Figure 3 :Figure 4 :

 234 Figure 2: PL intensity and decay time of Nd ions at 920 nm (a) and Si-nc at 750 nm (b) as a

Figure 1 :

 1 Figure 1: (Color online) CW-PL spectra of Nd-doped silicon oxide thin films containing Si

Figure 2 :

 2 Figure 2: PL intensity and decay time of Nd ions at 920 nm (a) and Si-nc at 750 nm (b) as a

Figure 3 :

 3 Figure 3: Normalized Nd-related PL intensity as a function of the temperature for direct excitation

Figure 4 :

 4 Figure 4: Nd-related PL intensity as a function of the temperature for a sample without Si-nc

Highlights

• Neodymium-doped silicon oxide thin films have been prepared by evaporation.

• Silicon nanocrystals are generated in the films by annealing post-treatments.

• Under indirect excitation, neodymium ions are sensitized by nanocrystals.

• Below 100 K, the neodymium-related photoluminescence intensity saturates.

• Saturation is explained by a decrease of the coupling efficiency with nanocrystals.