Original Article
A first pilot study on the neonatal screening of primary immunodeficiencies in Spain: TRECS and KRECS identify severe T- and B-cell lymphopaenia
Primer estudio piloto en España sobre el cribado neonatal de las inmunodeficiencias primarias: TRECS y KRECS identifican linfopenias T y B graves
P. Olbricha, B. de Felipea, C. Delgado-Pecellinb, R. Roderoc, P. Rojasc, J. Aguayoc, J. Marquezd, J. Casanovasd, B. Sáncheze, J.M. Lucenae, P. Ybot-Gonzalezf, S. Borteg,h,i, O. Netha,
Corresponding author
a Sección de Infectología e Inmunodeficiencias, Unidad de Pediatría, Hospital Virgen del Rocío, Sevilla, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain
b Unidad de Metabolopatías, Hospital Universitario Virgen del Rocío, Sevilla, Spain
c Unidad de Neonatología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
d Unidad de Pediatría, Hospital Virgen del Valme, Sevilla, Spain
e Unidad de Inmunología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
f Grupo de Neurodesarrollo, Unidad de Pediatría, Hospital Virgen del Rocío, Sevilla, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain
g Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Estocolmo, Suecia
h Translational Centre for Regenerative Medicine(TRM), University of Leipzig, Leipzig, Alemania
i ImmunoDeficiencyCenter Leipzig at Hospital St Georg gGmbH Leipzig, Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Leipzig, Alemania
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"apellidos" => "Neth" "email" => array:1 [ 0 => "olafw.neth.sspa@juntadeandalucia.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor1" ] ] ] ] "afiliaciones" => array:9 [ 0 => array:3 [ "entidad" => "Sección de Infectología e Inmunodeficiencias, Unidad de Pediatría, Hospital Virgen del Rocío, Sevilla, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Metabolopatías, Hospital Universitario Virgen del Rocío, Sevilla, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unidad de Neonatología, Hospital Universitario Virgen del Rocío, Sevilla, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Unidad de Pediatría, Hospital Virgen del Valme, Sevilla, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Unidad de Inmunología, Hospital Universitario Virgen del Rocío, Sevilla, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Grupo de Neurodesarrollo, Unidad de Pediatría, Hospital Virgen del Rocío, Sevilla, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Estocolmo, Suecia" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Translational Centre for Regenerative Medicine(TRM), University of Leipzig, Leipzig, Alemania" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "ImmunoDeficiencyCenter Leipzig at Hospital St Georg gGmbH Leipzig, Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Leipzig, Alemania" "etiqueta" => "i" "identificador" => "aff0045" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Primer estudio piloto en España sobre el cribado neonatal de las inmunodeficiencias primarias: <span class="elsevierStyleItalic">TRECS</span> y <span class="elsevierStyleItalic">KRECS</span> identifican linfopenias T y B graves" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1097 "Ancho" => 1585 "Tamanyo" => 89921 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">TRECs and KRECs values obtained from heel blood samples (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1068). Circles: screened neonates; white triangles: T−B− SCID controls (CDC); black triangles: healthy controls (CDC); white squares: T−B+ and AT controls (internal); black squares: XLA controls (internal); continuous grey line: TRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>copies/μL and KRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>copies/μL; dotted grey line: TRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>8 and KRECS<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>copies/μL.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders comprising more than 240 different pathologies, with an approximate incidence of 1:500 live births. Congenital defects of the immune system, such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinaemia (XLA) are less frequent, although they still have a considerable incidence of 1:70<span class="elsevierStyleHsp" style=""></span>000 to 1:100<span class="elsevierStyleHsp" style=""></span>000 live births.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> The vast majority of neonates with severe T- and/or B-cell lymphopaenias, including those suffering from severe PIDs, have no family history of PID and are asymptomatic in the first weeks of life.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Due to these features, delayed diagnosis is frequent, and it is associated with considerable morbidity and mortality due to the development of severe clinical manifestations at a later point.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–4</span></a> There are highly efficacious treatment options for the most severe forms of PID, for instance, immune globulin replacement therapy for the agammaglobulinaemias; and curative treatments for SCIDs, such as haematopoietic stem cell transplantation or gene therapy.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a> It has been demonstrated that early diagnosis followed by implementation of preventive and therapeutic measures reduces the rate of sequelae, improves the quality of life of patients, and dramatically improves survival outcomes.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8</span></a> Likewise, early identification of patients with SCID helps prevent severe iatrogenic damage, for instance by avoiding administration of live vaccines (such as the rotavirus vaccine) currently recommended to start at 2 months of age, when most patients have yet to develop characteristic symptoms.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The methodology needed to detect PID routinely in the neonatal period has been developed in recent years. In United States, real-time PCR has been used to identify patients with SCID by quantification of T-cell receptor excision circles (TRECs) in dried blood spot (DBS) samples.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10–12</span></a> Recently, pilot studies have been conducted in Sweden and Germany to evaluate a method that allows detection of T-cell lymphopaenias (through low levels of TRECs), that are typically associated with SCID, and B-cell lymphopaenias (through low levels of kappa-deleting recombination excision circles [KRECs]) associated with other severe PIDs such as XLA or ataxia telangiectasia (AT).<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13–16</span></a> TRECs and KRECs are episomal DNA fragments that result from gene rearrangements that occur during T- and B-lymphocyte maturation. The excision circles do not replicate during mitosis and thus exhibit a dilution pattern that allows the quantitative estimation of cell replication.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,16</span></a> Thus, patients suffering from severe PIDs who have T- and/or B-cell lymphopaenias have very low levels of TRECs and KRECs, regardless of the molecular aetiology of the PID, which is very useful considering the genetic heterogeneity of these disorders.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,13,16</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In Spain, neonates are not routinely screened for potentially lethal diseases of the immune system, despite evidence that these pathologies meet the screening criteria adapted from Wilson and Jungner, which determine the appropriateness of including specific diseases in population screenings: high morbidity and mortality, an initial latent stage, availability of an accessible and relatively non-invasive screening method, evidence of benefits of early diagnosis, availability of curative or effective treatment, and finally, a favourable cost-benefit analysis.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17–19</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Due to a lack of previous studies and to shortfalls in the data of national registries, we do not know the real current prevalence of severe PIDs in Spain. The results of neonatal screening for PIDs in California changed what was known about the prevalence of SCID, showing a rate of 1:70<span class="elsevierStyleHsp" style=""></span>000 live births compared to previous estimates ranging from 1:100<span class="elsevierStyleHsp" style=""></span>000 to 1:150<span class="elsevierStyleHsp" style=""></span>000 live births.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">This paper presents the initial data of a pilot study with the purpose of: (a) finding out the magnitude of an unidentified problem and (b) providing data on the feasibility and performance of a novel methodology using samples that had been obtained previously for the established neonatal screening programme.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In a second phase of the study with a larger sample we hope to: (a) obtain reliable information on the epidemiology of T- and/or B-cell lymphopaenia in our setting; (b) learn about the aetiology of T- and/or B-cell lymphopaenia, and, lastly (c) identify neonates with lymphopaenias who could benefit from early treatment, thus improving the prognosis of patients suffering from a PID.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study design, setting, and population</span><p id="par0035" class="elsevierStylePara elsevierViewall">We conducted an observational, descriptive and longitudinal study of the levels of TREC and KREC in dry blood samples obtained from neonates born at the Hospitales Universitarios Virgen del Rocío (HUVR) and the Hospital de Especialidades Virgen del Valme during the period under study (February and May, 2014). Neonates were excluded from the study if their legal guardians had not given informed consent.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Sample and data collection</span><p id="par0040" class="elsevierStylePara elsevierViewall">Heel blood samples were dropped on Schleicher & Schuell #912 filter paper (3rd to 5th day postpartum) as part of the established routine neonatal screening process. Two 3.2<span class="elsevierStyleHsp" style=""></span>mm discs were punched for each sample, and stored at 4<span class="elsevierStyleHsp" style=""></span>°C until they were processed. We collected relevant demographic and clinical data for the mother and the neonates: sex, gestational age, birth weight, and pathology results from the routine neonatal screening.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Sample processing and multiplex real-time polymerase chain reaction (TRECs/KRECs/ACTB assay)</p><p id="par0050" class="elsevierStylePara elsevierViewall">DNA was purified (DNA Purification Solution, Qiagen, Maryland, USA) and extracted (DNA Elution Solution, Qiagen, Maryland, USA) from the samples following a previously described process.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Absolute quantification of TRECs, KRECs, and ACTB in dried blood spot samples was done following the previously described process.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The ACTB (β-actin) copy number reflects the success of DNA extraction from DBS samples.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Quality controls</span><p id="par0055" class="elsevierStylePara elsevierViewall">We included internal controls (designed by plasmid cloning) and external controls that obtained through the Newborn Screening Quality Assurance Programme of the Centres for Disease Control and Prevention (CDC) in Chamblee, USA (SCID, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2; healthy, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2). We also tested samples from patients with a confirmed diagnosis of SCID (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1), XLA (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2) and AT (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2).</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Definition and interpretation of results</span><p id="par0060" class="elsevierStylePara elsevierViewall">Based on the lower limit of detection of the assay, of 1<span class="elsevierStyleHsp" style=""></span>copy/μL for TRECs and KRECs, and on the results of previous studies, we established the following cut-off scores for an estimated 99.8% sensitivity in detecting severe T- and/or B-cell lymphopaenias: TRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>15/μL and KRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>10/μL with ACTB<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>1000/μL.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">We defined three categories based on the assay results (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The algorithm that specified the actions to be taken after obtaining abnormal, inconclusive, or normal results is presented in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">In cases of abnormal or inconclusive results, the PCR assay was repeated using a new punch from the same filter paper (retest). If the results were abnormal or inconclusive in the retest, collection of another heel blood sample was requested (recall). If the results were confirmed using the new DBS sample, the legal guardians were advised to have the infant assessed by a specialist.</p><p id="par0080" class="elsevierStylePara elsevierViewall">We also analysed the results based on cut-off points adapted to the preliminary results obtained in this study (TRECS<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>8/μL, KRECS<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>4/μL, ACTB<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>1000/μL). This adaptation is consistent with the experience of other groups that have used this assay (Borte et al., unpublished data).</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Data analysis</span><p id="par0085" class="elsevierStylePara elsevierViewall">We performed a descriptive analysis. Qualitative variables were expressed as absolute frequencies and percentages. Quantitative variables, depending on the normality of their distribution (assessed by means of the Kolmogorov–Smirnov tests or the Shapiro–Wilk test, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>50), were expressed as mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>standard deviation or as median and interquartile range (IQR), respectively, or by the minimum and maximum scores in the assay.</p><p id="par0090" class="elsevierStylePara elsevierViewall">We calculated the rates of abnormal, inconclusive, and normal results for the TRECs/KRECs/ACTB assay for a 95% confidence interval. To assess the reliability of the assay, we calculated the proportion of false positive results. We analysed the causes/variables associated with or related to the presence of T- and B-cell lymphopaenias using Pearson's chi squared test or Fisher's exact test for qualitative variables; and for quantitative variables we used Student's <span class="elsevierStyleItalic">t</span> test for independent samples or the Mann–Whitney <span class="elsevierStyleItalic">U</span> test depending on the normality of their distribution.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The statistical significance level was set at <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05. We performed the statistical analysis using the IBM software SPSS Statistics version 20.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Demographic and clinical characteristics of the sample</span><p id="par0100" class="elsevierStylePara elsevierViewall">We analysed 1068 blood samples collected from 1088 neonates born in the two participating centres. Of all samples, 20 (1.87%) could not be analysed because the filter paper did not have a large enough volume of blood. Most samples came from healthcare centres belonging to the service area of the HUVR (76%); 48% of the neonates included in the study were male; and 67.5% had been born at term. The mean gestational age was 39 weeks (IQR, 38–40 weeks), and the mean birth weight was 3238<span class="elsevierStyleHsp" style=""></span>g (IQR, 2930–3520<span class="elsevierStyleHsp" style=""></span>g). Most of the samples corresponded to newborns weighing more than 2500<span class="elsevierStyleHsp" style=""></span>g (79.1%). We received some valid samples with informed consent forms that had been filled out correctly, but which were not accompanied by information about gestational age (19.9%) or birth weight (15.5%).</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Results of the TRECs/KRECs/ACTB assay</span><p id="par0105" class="elsevierStylePara elsevierViewall">The results of the TRECs/KRECs/ACTB assay, calculated for the two subgroups of gestational age and birth weight, are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>. The mean and median for the three parameters (TRECs, KRECs and ACTB) were similar for the analysed subgroups.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Selection of different cut-off points for the TRECs and KRECs variables</span><p id="par0110" class="elsevierStylePara elsevierViewall">When we applied the TRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>15/μL and KRECS<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>10/μL cut-off points, eight samples (0.75%) gave abnormal results. Following the established algorithm, we retested those samples taking punches from the same filter paper as before, obtaining normal results in all but one of the samples. A second filter paper needed to be prepared from a newly collected blood sample in only one neonate (0.09%) after obtaining an abnormal KRECs result (2<span class="elsevierStyleHsp" style=""></span>copies/μL) in the retest. A normal result for KRECs (167<span class="elsevierStyleHsp" style=""></span>copies/μL) was obtained with the second filter paper preparation.</p><p id="par0115" class="elsevierStylePara elsevierViewall">To assess the feasibility of the assay with different cut-off points based on our sample, we used TRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>8/μL and KRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>4/μL. We found no abnormal results for this cut-off points in the general population. However, all the abnormal controls were identified reliably.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Prematurity and birth weight</span><p id="par0120" class="elsevierStylePara elsevierViewall">We found no significant differences when we compared the TRECs and KRECs values of preterm newborns (none with gestational age<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>28 weeks) with those of full-term newborns. Likewise, we did not observe any differences between neonates with a birth weight of 2500<span class="elsevierStyleHsp" style=""></span>g or lower, and neonates with birth weights greater than 2500<span class="elsevierStyleHsp" style=""></span>g (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Internal and external controls</span><p id="par0125" class="elsevierStylePara elsevierViewall">We analysed a total of nine controls (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>): one sample from a patient recently diagnosed with SCID (T−, B+ type); two samples of patients aged 3 and 17 years previously diagnosed with XLA, who were reliably identified with the assay (KRECs<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0<span class="elsevierStyleHsp" style=""></span>copies/μL); and two patients aged 1 and 17 years diagnosed with AT and severe lymphopaenia.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">We also analysed four samples sent by the CDC, two of which were classified as T−B− (one of them with a low ACTB copy number), and two of which had normal results.</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Discussion</span><p id="par0135" class="elsevierStylePara elsevierViewall">Patients with severe PIDs benefit from early diagnosis, as it enables prompt implementation of preventive, supportive, and therapeutic measures that improve their overall prognosis and, in the case of patients with SCID, improve survival rates through hematopoietic stem cell transplantation.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5–8</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Previous studies have demonstrated the reliability of the methodology based on TRECs determination in heel blood samples for identifying patients suffering from severe T-cell lymphopaenia.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,20</span></a> Considering this evidence, European experts in PID have expressed their unambiguous support for the introduction of this screening test in Europe.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Recently, Modell et al. presented cost-benefit data that greatly favoured the implementation of neonatal screening for SCID, and proposed a model to estimate its socioeconomic impact for different populations.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Their calculations, based on screening data from the United States, showed that the total healthcare cost for a patient with delayed diagnosis amounted to $6<span class="elsevierStyleHsp" style=""></span>000<span class="elsevierStyleHsp" style=""></span>000; while the cost of mass screening and the treatment and follow-up of one patient diagnosed following the screening amounted to $1<span class="elsevierStyleHsp" style=""></span>385<span class="elsevierStyleHsp" style=""></span>000.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> It is worth noting that the cost per neonate of the TRECs and KRECs screening in our study was €1.46, and therefore well below the cost of screening in the United States ($4.25/neonate) and the United Kingdom (£8.30/neonate), where the screening only includes the TRECs assay.</p><p id="par0145" class="elsevierStylePara elsevierViewall">The potential of KRECs to be a marker for disorders of B-lymphocyte development in the field of routine neonatal screening has been reported in the literature.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,22</span></a> By determining TRECs and KRECs simultaneously in a single assay, its diagnostic capacity increases. Multiplex PCR (TRECs/KRECs/ACTB assay) can identify classic congenital T-lymphocyte defects (SCID), but also other immune disorders in asymptomatic newborns, such as agammaglobulinaemias, combined immunodeficiencies, and AT.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,21</span></a> The assay can also identify patients with an atypical SCID phenotype that could go undetected in assays that only determine TREC levels.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">In our pilot study, we analysed 1088 samples from 1068 neonates born in southern Spain with the aim of knowing the levels of TRECs and KRECs in this population, identifying suitable cut-off points, and assessing the feasibility of the TRECs/KRECs/ACTB assay in our setting.</p><p id="par0155" class="elsevierStylePara elsevierViewall">Recent studies in the United Kingdom, France, and Israel, most of them retrospective, suggest that it would be beneficial to add screening for SCID to the routine neonatal screenings.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,24,25</span></a> Due to its prospective design, our study is one of the first of its kind not only in Spain, but also in Europe.</p><p id="par0160" class="elsevierStylePara elsevierViewall">The TRECs and KRECs values observed were comparable to those previously described in other populations based on the same methodology.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> At first we used conservative cut-off values of TRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>15/μL and KRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>10/μL. With these cut-offs, 0.75% of the tested samples had abnormal results in our population. Other groups have reported figures between 0.08% and 4.1%, depending on the cut-off points used.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,20,21</span></a> Population-based studies with a high number of abnormal samples would be unfeasible, because of our healthcare area (with 25<span class="elsevierStyleHsp" style=""></span>000 births/year) such a rate would entail having 188 samples retested every year. There are 3 possible reasons why the retest rate is this high: (a) low quality of the DBS samples taken before the analysis; (b) the learning curve for the methodology; and finally (c) conservative cut-off points. When the abnormal samples were retested, all but one gave results above the initial cut-off points (0.09%). This recall rate is considered adequate for this type of study.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">When we considered more restrictive cut-off points (TRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>8/μL and KRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>4/μL), we observed that all samples tested normal (not pathological). Recent data published by Gaspar et al. in the United Kingdom, and data by Borte et al. (personal communication) are similar and suggest that a specific cutoff point needs to be determined for each laboratory and population.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,26</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The ultimate goal is to reduce the retest rate. To achieve this, it is important that an effort is made to obtain quality samples and to improve their quality, and that a suitable cut-off point for the Spanish population is determined. This requires ongoing communication with the associated healthcare centres. Reducing the retest rate would prevent unnecessary costs and worry in families, and in particular cases, it would preclude the need to collect a new blood sample from the newborn (recall).</p><p id="par0175" class="elsevierStylePara elsevierViewall">Preterm neonates may get false positive results more frequently with this assay, so they need to be managed differently, as specified in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>. Our pilot study found no significant differences between the two birth weight subgroups (<2500<span class="elsevierStyleHsp" style=""></span>g vs ≥2500<span class="elsevierStyleHsp" style=""></span>g) and the two gestational age subgroups (<37 weeks vs ≥37 weeks), although we need to consider that our population did not include samples from extremely preterm neonates (birth weight <1000<span class="elsevierStyleHsp" style=""></span>g or gestational age <28 weeks). For now, given the controversy in the literature, it seems prudent to maintain a conservative approach in neonates born preterm or requiring intensive care who have received positive results.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,22,23</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Out of the four controls provided by the CDC, we correctly identified two normal samples and two abnormal samples compatible with a T−B− SCID phenotype, one of them with low ACTB copy numbers, which confirmed the diagnostic capacity of the assay.</p><p id="par0185" class="elsevierStylePara elsevierViewall">Samples of patients previously diagnosed with XLA and AT were also analysed. Abnormal results were found for both pathologies. Patients with XLA were identified through very low copy numbers of KRECs, and both patients with AT should TRECs and KRECs values be below the established cut-off points, as had been observed in previous studies.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,15</span></a> Since these samples were not collected in the neonatal period, their value to validate the cut-off point for these pathologies is limited. Nevertheless, the fact that they gave abnormal results in the screening is worth noting, as the patients with AT (ages 1 and 17 years) had significant lymphopaenia and required prophylactic treatment against <span class="elsevierStyleItalic">Pneumocystis jirovecii</span> and immune globulin replacement therapy.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Last of all, we analysed a sample obtained from a patient recently diagnosed with T−B+ SCID. It is noteworthy that all patients presented clearly abnormal levels of TRECs and/or KRECs (0–1<span class="elsevierStyleHsp" style=""></span>copy/μL) well below the cut-off points.</p><p id="par0195" class="elsevierStylePara elsevierViewall">This paper is the first to present results of a prospective pilot study that used an innovative methodology on dried blood samples from Spanish newborns to identify those with severe T- and B-cell lymphopaenias. The study provides valuable information on the feasibility and diagnostic capacity of this methodology. The prospective and continuous recruitment of neonatal samples will allow us to increase the validity of the obtained data, which will help implement neonatal screening for severe PIDs at the regional and eventually national levels. The cooperation of different groups of providers in the healthcare system (nurses, neonatologists, primary care paediatricians, paediatric specialists, immunologists, and experts in metabolic disorders) is essential for its implementation to be successful. The ultimate objective is to be able to diagnose asymptomatic newborns with severe PIDs in the first weeks of life. This will allow prompt initiation of preventive and supportive measures, and even of curative treatment, improving the quality of life of these patients and their families.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Funding</span><p id="par0200" class="elsevierStylePara elsevierViewall">1. Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos <span class="elsevierStyleSmallCaps">III</span> (PI13/01104).</p><p id="par0205" class="elsevierStylePara elsevierViewall">2. Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI, “Scott Family Funding”).</p><p id="par0210" class="elsevierStylePara elsevierViewall">3. Río Hortega grants for hiring research interns. Instituto de Salud Carlos <span class="elsevierStyleSmallCaps">III</span>.</p><p id="par0215" class="elsevierStylePara elsevierViewall">4. German Federal Ministry of Education and Research (BMBF 1315883).</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Authorship</span><p id="par0220" class="elsevierStylePara elsevierViewall">P. Olbrich and B. de Felipe contributed equally to this work.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflicts of interest</span><p id="par0225" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres381368" "titulo" => array:6 [ 0 => "Abstract" 1 => "Introduction" 2 => "Objectives" 3 => "Material and methods" 4 => "Results" 5 => "Conclusion" ] ] 1 => array:2 [ "identificador" => "xpalclavsec360147" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres381369" "titulo" => array:6 [ 0 => "Resumen" 1 => "Introducción" 2 => "Objetivo" 3 => "Materiales y métodos" 4 => "Resultados" 5 => "Conclusión" ] ] 3 => array:2 [ "identificador" => "xpalclavsec360148" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study design, setting, and population" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Sample and data collection" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Quality controls" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Definition and interpretation of results" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Data analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Demographic and clinical characteristics of the sample" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Results of the TRECs/KRECs/ACTB assay" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Selection of different cut-off points for the TRECs and KRECs variables" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Prematurity and birth weight" ] 4 => array:2 [ "identificador" => "sec0065" "titulo" => "Internal and external controls" ] ] ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Authorship" ] 10 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-06-22" "fechaAceptado" => "2014-08-06" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec360147" "palabras" => array:5 [ 0 => "Newborn screening" 1 => "Primary immunodeficiency diseases" 2 => "Severe combined immunodeficiency" 3 => "X-linked agammaglobulinaemia" 4 => "Lymphopaenia" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec360148" "palabras" => array:5 [ 0 => "Cribado neonatal" 1 => "Inmunodeficiencias primarias" 2 => "Inmunodeficiencia combinada grave" 3 => "Agammaglobulinemia ligada al cromosoma C" 4 => "Linfopenia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected infants/children. The measurement of T-cell receptor excision circles (TRECS) and kappa-deleting recombination excision circles (KRECS) can identify neonates with severe T or B-cell lymphopaenia.</p> <span class="elsevierStyleSectionTitle" id="sect0015">Objectives</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">To determine TRECS and KRECS levels from prospectively collected dried blood spot samples (DBS) and to correctly identify severe T and B-cell lymphopaenia.</p> <span class="elsevierStyleSectionTitle" id="sect0020">Material and methods</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Determination of TRECS and KRECS by multiplex PCR from neonates born in two tertiary hospitals in Seville between February 2014 and May 2014. PCR cut-off levels: TRECS<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>copies/μl, KRECS<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>copies/μl, ACTB (β-actin)<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>1000<span class="elsevierStyleHsp" style=""></span>copies/μl. Internal (XLA, ataxia telangiectasia) and external (SCID) controls were included.</p> <span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">A total of 1068 out of 1088 neonates (mean GA 39 weeks (38–40) and BW 3238<span class="elsevierStyleHsp" style=""></span>g (2930–3520) were enrolled in the study. Mean (median, min/max) copies/μl, were as follows: TRECS 145 (132, 8/503), KRECS 82 (71, 7/381), and ACTB 2838 (2763, 284/7710). Twenty samples (1.87%) were insufficient. Resampling was needed in one neonate (0.09%), subsequently giving a normal result. When using lower cut-offs (TRECS<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>8 and KRECS<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>4 copies/μl), all the samples tested were normal and the internal and external controls were correctly identified.</p> <span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">This is the first prospective pilot study in Spain using TRECS/KRECS/ACTB-assay, describing the experience and applicability of this method to identify severe lymphopaenias. The ideal cut-off remains to be established in our population. Quality of sampling, storage and preparation need to be further improved.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0040">Introducción</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El diagnóstico precoz de inmunodeficiencias primarias, como la inmunodeficiencia combinada grave (IDCG) y la agammaglobulinemia ligada al cromosoma X (ALX), mejora el pronóstico de los niños afectados. La medida de los <span class="elsevierStyleItalic">T-cell receptor excision circles</span> (TRECS) y <span class="elsevierStyleItalic">kappa-deleting recombination excision circles</span> (KRECS) puede identificar neonatos con linfopenias T y/o B graves.</p> <span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cuantificar los niveles de TRECS y de KRECS de manera prospectiva a partir de muestras de sangre seca de talón para identificar de manera correcta linfopenias T y/o B.</p> <span class="elsevierStyleSectionTitle" id="sect0050">Materiales y métodos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Determinación de TRECS y de KRECS mediante reacción en cadena de polimerasa multiplex en neonatos nacidos entre febrero y mayo del 2014. Los puntos de corte empleados fueron: TRECS < 15 copias/μl, KRECS < 10 copias/μl, ACTB (β-actina) > 1.000 copias/μl. Se incluyeron controles internos (ALX, ataxia) y externos (IDCG).</p> <span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Fueron analizadas 1.068 muestras de las 1.088 recogidas (edad gestacional media: 39 semanas [38-40]; peso al nacer medio 3.238<span class="elsevierStyleHsp" style=""></span>g [2.930-3.520]). La media (mediana, min/máx) copias/μl obtenidas fueron las siguientes; TRECS 145 (132, 8/503), KRECS 82 (71, 7/381) y ACTB 2838 (2763, 284/7710). Veinte muestras (1,87%) fueron insuficientes para el análisis. El <span class="elsevierStyleItalic">re-test</span> fue necesario en un neonato (0,09%), confirmándose resultados normales posteriormente. Empleando puntos de corte inferiores (TREC < 8 y KREC < 4 copias/μl), todas las muestras resultaron normales y se identificaron los controles internos y externos correctamente.</p> <span class="elsevierStyleSectionTitle" id="sect0060">Conclusión</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Es el primer estudio prospectivo realizado en España usando el ensayo TREC/KREC/ACTB para identificar linfopenias graves. Es necesario establecer puntos de corte adecuados para nuestra población, mejorar la toma de muestras, su almacenamiento y la preparación de las mismas.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Olbrich P, de Felipe B, Delgado-Pecellin C, Rodero R, Rojas P, Aguayo J, et al. Primer estudio piloto en España sobre el cribado neonatal de las inmunodeficiencias primarias: <span class="elsevierStyleItalic">TRECS</span> y <span class="elsevierStyleItalic">KRECS</span> identifican linfopenias T y B graves. An Pediatr (Barc). 2014;81:310–317.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1550 "Ancho" => 2537 "Tamanyo" => 243031 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Algorithm for verification of abnormal results in the TRECs/KRECs/ACTB assay.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1097 "Ancho" => 1585 "Tamanyo" => 89921 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">TRECs and KRECs values obtained from heel blood samples (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1068). Circles: screened neonates; white triangles: T−B− SCID controls (CDC); black triangles: healthy controls (CDC); white squares: T−B+ and AT controls (internal); black squares: XLA controls (internal); continuous grey line: TRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>copies/μL and KRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>copies/μL; dotted grey line: TRECs<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>8 and KRECS<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>copies/μL.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="8" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">TREC/KREC/ACTB assay</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Abnormal</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Inconclusive</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TREC, copies/μL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><15 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">KREC, copies/μL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ACTB, copies/μL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><1000 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab581230.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Definition of assay results.</p>" ] ] 3 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">GA: gestational age.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">N</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">TRECS (copies/μL)</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">KRECS (copies/μL)</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ACTB (copies/μL)</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mean \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Median \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Max \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mean \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Median \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Max \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mean \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Median \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Max \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GA<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">135 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(12.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">150 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">140 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">503 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">274 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2853 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2744 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">352 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5894 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GA<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">721 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(67.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">149 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">136 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">503 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">381 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2017 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2746 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">284 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7710 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unknown GA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">212 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(19.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">129 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">119 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">378 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">324 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2902 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">866 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6528 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1068 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">145 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">132 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">503 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">381 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2838 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2763 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">284 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7710 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="15" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weight ≤2500<span class="elsevierStyleHsp" style=""></span>g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(5.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">138 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">123 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">315 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">222 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2920 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2911 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">352 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5894 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weight >2500<span class="elsevierStyleHsp" style=""></span>g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">845 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(79.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">150 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">137 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">503 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">381 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2823 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2746 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">502 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7709 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unknown weight \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">166 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(15.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">123 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">116 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">415 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">324 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2887 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2789 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">284 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2628 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1068 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">145 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">132 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">503 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">381 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2838 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2763 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">284 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7710 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab581231.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Results of the TRECs/KRECs/ACTB assay in the general population and in relation to gestational age and birth weight.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">AT: ataxia telangiectasia; CDC: Centers for Disease Control and Prevention; SCID: severe congenital immunodeficiency; XLA: X-linked agammaglobulinaemia.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">TREC (copies/μL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">KREC (copies/μL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ACTB (copies/μL) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">XLA (patient) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3229 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">XLA (patient) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3009 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AT (patient) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 18 | 13 | 31 |
| 2024 October | 86 | 58 | 144 |
| 2024 September | 84 | 57 | 141 |
| 2024 August | 81 | 83 | 164 |
| 2024 July | 77 | 43 | 120 |
| 2024 June | 83 | 32 | 115 |
| 2024 May | 91 | 60 | 151 |
| 2024 April | 82 | 54 | 136 |
| 2024 March | 74 | 31 | 105 |
| 2024 February | 70 | 35 | 105 |
| 2024 January | 48 | 23 | 71 |
| 2023 December | 48 | 25 | 73 |
| 2023 November | 43 | 30 | 73 |
| 2023 October | 45 | 26 | 71 |
| 2023 September | 29 | 29 | 58 |
| 2023 August | 50 | 17 | 67 |
| 2023 July | 49 | 34 | 83 |
| 2023 June | 45 | 33 | 78 |
| 2023 May | 66 | 33 | 99 |
| 2023 April | 41 | 41 | 82 |
| 2023 March | 67 | 37 | 104 |
| 2023 February | 78 | 31 | 109 |
| 2023 January | 46 | 37 | 83 |
| 2022 December | 67 | 48 | 115 |
| 2022 November | 88 | 49 | 137 |
| 2022 October | 49 | 42 | 91 |
| 2022 September | 37 | 52 | 89 |
| 2022 August | 63 | 61 | 124 |
| 2022 July | 62 | 46 | 108 |
| 2022 June | 66 | 45 | 111 |
| 2022 May | 73 | 55 | 128 |
| 2022 April | 112 | 59 | 171 |
| 2022 March | 144 | 89 | 233 |
| 2022 February | 134 | 57 | 191 |
| 2022 January | 112 | 67 | 179 |
| 2021 December | 72 | 60 | 132 |
| 2021 November | 92 | 58 | 150 |
| 2021 October | 55 | 69 | 124 |
| 2021 September | 46 | 61 | 107 |
| 2021 August | 60 | 50 | 110 |
| 2021 July | 59 | 25 | 84 |
| 2021 June | 49 | 34 | 83 |
| 2021 May | 90 | 56 | 146 |
| 2021 April | 156 | 58 | 214 |
| 2021 March | 105 | 24 | 129 |
| 2021 February | 70 | 18 | 88 |
| 2021 January | 48 | 21 | 69 |
| 2020 December | 57 | 27 | 84 |
| 2020 November | 42 | 25 | 67 |
| 2020 October | 39 | 16 | 55 |
| 2020 September | 49 | 16 | 65 |
| 2020 August | 51 | 10 | 61 |
| 2020 July | 32 | 14 | 46 |
| 2020 June | 77 | 19 | 96 |
| 2020 May | 107 | 14 | 121 |
| 2020 April | 87 | 17 | 104 |
| 2020 March | 91 | 27 | 118 |
| 2020 February | 102 | 24 | 126 |
| 2020 January | 64 | 18 | 82 |
| 2019 December | 113 | 24 | 137 |
| 2019 November | 63 | 18 | 81 |
| 2019 October | 39 | 23 | 62 |
| 2019 September | 193 | 15 | 208 |
| 2019 August | 335 | 33 | 368 |
| 2019 July | 55 | 39 | 94 |
| 2019 June | 87 | 45 | 132 |
| 2019 May | 163 | 40 | 203 |
| 2019 April | 105 | 48 | 153 |
| 2019 March | 60 | 27 | 87 |
| 2019 February | 56 | 16 | 72 |
| 2019 January | 81 | 29 | 110 |
| 2018 December | 89 | 38 | 127 |
| 2018 November | 124 | 43 | 167 |
| 2018 October | 191 | 44 | 235 |
| 2018 September | 78 | 28 | 106 |
| 2018 June | 5 | 0 | 5 |
| 2018 May | 6 | 0 | 6 |
| 2018 April | 39 | 0 | 39 |
| 2018 March | 24 | 0 | 24 |
| 2018 February | 21 | 0 | 21 |
| 2018 January | 19 | 0 | 19 |
| 2017 December | 35 | 0 | 35 |
| 2017 November | 34 | 0 | 34 |
| 2017 October | 29 | 0 | 29 |
| 2017 September | 19 | 0 | 19 |
| 2017 August | 28 | 0 | 28 |
| 2017 July | 27 | 1 | 28 |
| 2017 June | 46 | 22 | 68 |
| 2017 May | 45 | 12 | 57 |
| 2017 April | 35 | 9 | 44 |
| 2017 March | 28 | 7 | 35 |
| 2017 February | 21 | 9 | 30 |
| 2017 January | 27 | 11 | 38 |
| 2016 December | 61 | 20 | 81 |
| 2016 November | 51 | 6 | 57 |
| 2016 October | 94 | 18 | 112 |
| 2016 September | 89 | 13 | 102 |
| 2016 August | 39 | 5 | 44 |
| 2016 July | 17 | 8 | 25 |
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