Genomic approach to Idiopathic Calcium Nephrolithiasis: searching for susceptibility genes in a three generation family

Idiopathic calcium nephrolithiasis (ICN) is a multifactorial disease with a pathogenesis depending upon the interplay of environmental, metabolic, anatomical and genetic factors. The importance of hereditary factors in ICN has emerged from a number of studies on families and twins affected by ICN. Computer programs predicted the best inheritance fit with a model of single gene co-dominant model/polygenic model. Most candidate gene or association studies have produced, up to date, negative or only marginal results, leaving the genetic basis of ICN still an open question. But, genetic analysis techniques are rapidly evolving and promise to improve our knowledge of the genetic basis of nephrolithiasis and allied disorders. Whole-genome scanning techniques, like Next-Generation Sequencing (NGS) and CGH (Comparative Genomic Hybridization) array, are the most recent technical approaches of molecular genetics that allow to trace out a complete draw of variation present in the human genome, namely SNPs (Single Nucleotide Polymorphisms) and heterogeneous structural variants. In the last years, indeed, several studies have recognized the critical role of structural genetic variants, mostly represented by Copy-Number Variants (CNVs), in modulating gene expression and complex diseases phenotype. Aim of this project was to identify some of the major susceptibility genes involved in idiopathic calcium nephrolithiasis applying the potential of whole-genome scanning technologies to a case study very peculiar, both for clinical manifestations both for its genetic background. The proband, since 30 years, suffers of a recurrent and severe form of ICN, with intermittent hypercalciuria and phosphaturic tubulopathy, expelling, up to date, about 300 calculi both spontaneously and by lithotripsy (33 treatments). Strikingly, he belongs to a family with consanguinity in which nephrolithiasis is present in several members and is transmitted in an apparently dominant fashion, with males being more severely affected than females. CGH arrays has been performed in the proband and in eight members of the family in order to detect the presence of CNVs in the genome. A duplication of 308 kb region of the Xq22.2 chromosome has been detected in the proband. This CNV resulted particularly interesting because it was a novel (not known) variant and it was shared by other three family members (maternal inheritance). Moreover, matching the Xq22.2 duplication over a database of 14375 individuals only 5 overlapping duplications were found, confirming its extreme rarity. Strikingly, all these 5 duplication shared a common region that corresponded to NUP62CL gene, suggesting a likely importance of this genetic trait. Furthermore, performing an expression study, we observed a significant and marked down-regulation of NUP62CL. Thus, even if we could not have a definitive proof of principle, this Xq22.2 CNV seemed to have an important role for ICN pathogenesis in our family. Nonetheless, given its presence in a member of the family that was not evidently affected and given the severity of the phenotype of some members of the paternal branch, we postulated that additional genetic determinants were also responsible of the severe phenotype encountered in the proband. In this light, we performed whole exome sequencing of the proband to identify rare single nucleotide variants that may have a role as susceptibility variants for ICN in the case-study family. By bioinformatic analyses and molecular validation, we could draw a polygenic model of heredity, with the identification of four possible susceptibility genes: XDH, ATP6V1B1, HNF1B, NUP62CL. The XDH gene, normally responsible of xanthinuria type I, was highlighted for the presence of two very rare variants with a damaging predicted effect on protein. Next, we discovered a missense homozygous variant in ATP6V1B1 gene, whose role is already known in distal tubular acidosis, that seemed to account for the ICN intermediate phenotype hypocitraturia observed in the family. In addition, we found an extremely rare heterozygous variant in HNF1B gene, a causative factor in cystic nephropathy, and the proband, indeed, recently showed pre-calyceal cysts. Strikingly, we again evidenced NUP62CL gene for the presence of two homozygous variants that operate activating criptic splicing sites, thus eventually generating an aberrant mRNA. This gene has never been associated to ICN but, having a known role in oxalate transport, could be responsible of some of the biological mechanisms that are on the basis of ICN pathogenesi

The association between prenatal atrioventricular septal defects and chromosomal abnormalities

Objective Atrioventricular septal defect is associated with a high risk of a chromosomal abnormality, particularly trisomy 21. The aim of this study is to assess the rate of trisomy 21 in fetuses diagnosed with an atrioventricular septal defect and to examine the influence of prior screening on the rate of trisomy 21. Methods Electronic ultrasound database was searched to identify fetuses diagnoses with an atrioventricular septal defect from 2002 to 2014. Rate of trisomy 21 and other aneuploidies was calculated among fetuses with normal situs. The prevalence of trisomy 21 and other aneuploidies was assessed in women with low and high first trimester risk for trisomy 21, using a cut-off value of 1:150 and 1:250. Results A total 110 fetuses with a diagnosis of atrioventricular septal defect were identified. Among the 98 fetuses with normal situs, the prevalence of trisomy 21 was 46% (95%CI: 36-56%). Using a 1:150 threshold, the rate of trisomy 21 within the low-risk group was 41% (95%CI: 27-57%) while in the high-risk group it was 70% (95% CI: 52-83%), significantly higher than in the low risk group (p = 0.028). Similar results were obtained when the 1:250 threshold was applied (66% versus 41%, p = 0.055). Conclusions The rate of trisomy 21 among fetuses identified with an atrioventricular septal defect in the second trimester is high even in those that undergo first trimester combined screening. Some fetuses with a high-risk screening result show a normal karyotype. Therefore, an offer of an invasive procedure to check fetal karyotyping is indicated. Knowledge of these rates may be helpful for parents in the decision making process

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Role of prenatal magnetic resonance imaging in fetuses with isolated mild or moderate ventriculomegaly in the era of neurosonography: international multicenter study

Objectives To assess the role of fetal magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses presenting with mild or moderate isolated ventriculomegaly (VM) undergoing multiplanar ultrasound evaluation of the fetal brain. Methods This was a multicenter, retrospective, cohort study involving 15 referral fetal medicine centers in Italy, the UK and Spain. Inclusion criteria were fetuses affected by isolated mild (ventricular atrial diameter, 10.0–11.9 mm) or moderate (ventricular atrial diameter, 12.0–14.9 mm) VM on ultrasound, defined as VM with normal karyotype and no other additional central nervous system (CNS) or extra‐CNS anomalies on ultrasound, undergoing detailed assessment of the fetal brain using a multiplanar approach as suggested by the International Society of Ultrasound in Obstetrics and Gynecology guidelines for the fetal neurosonogram, followed by fetal MRI. The primary outcome of the study was to report the incidence of additional CNS anomalies detected exclusively on prenatal MRI and missed on ultrasound, while the secondary aim was to estimate the incidence of additional anomalies detected exclusively after birth and missed on prenatal imaging (ultrasound and MRI). Subgroup analysis according to gestational age at MRI (< 24 vs ≥ 24 weeks), laterality of VM (unilateral vs bilateral) and severity of dilatation (mild vs moderate VM) were also performed. Results Five hundred and fifty‐six fetuses with a prenatal diagnosis of isolated mild or moderate VM on ultrasound were included in the analysis. Additional structural anomalies were detected on prenatal MRI and missed on ultrasound in 5.4% (95% CI, 3.8–7.6%) of cases. When considering the type of anomaly, supratentorial intracranial hemorrhage was detected on MRI in 26.7% of fetuses, while polymicrogyria and lissencephaly were detected in 20.0% and 13.3% of cases, respectively. Hypoplasia of the corpus callosum was detected on MRI in 6.7% of cases, while dysgenesis was detected in 3.3%. Fetuses with an associated anomaly detected only on MRI were more likely to have moderate than mild VM (60.0% vs 17.7%; P < 0.001), while there was no significant difference in the proportion of cases with bilateral VM between the two groups (P = 0.2). Logistic regression analysis showed that lower maternal body mass index (adjusted odds ratio (aOR), 0.85 (95% CI, 0.7–0.99); P = 0.030), the presence of moderate VM (aOR, 5.8 (95% CI, 2.6–13.4); P < 0.001) and gestational age at MRI ≥ 24 weeks (aOR, 4.1 (95% CI, 1.1–15.3); P = 0.038) were associated independently with the probability of detecting an associated anomaly on MRI. Associated anomalies were detected exclusively at birth and missed on prenatal imaging in 3.8% of cases. Conclusions The incidence of an associated fetal anomaly missed on ultrasound and detected only on fetal MRI in fetuses with isolated mild or moderate VM undergoing neurosonography is lower than that reported previously. The large majority of these anomalies are difficult to detect on ultrasound. The findings from this study support the practice of MRI assessment in every fetus with a prenatal diagnosis of VM, although parents can be reassured of the low risk of an associated anomaly when VM is isolated on neurosonography

Genomic approach to Idiopathic Calcium Nephrolithiasis: searching for susceptibility genes in a three generation family

Idiopathic calcium nephrolithiasis (ICN) is a multifactorial disease with a pathogenesis depending upon the interplay of environmental, metabolic, anatomical and genetic factors. The importance of hereditary factors in ICN has emerged from a number of studies on families and twins affected by ICN. Computer programs predicted the best inheritance fit with a model of single gene co-dominant model/polygenic model. Most candidate gene or association studies have produced, up to date, negative or only marginal results, leaving the genetic basis of ICN still an open question. But, genetic analysis techniques are rapidly evolving and promise to improve our knowledge of the genetic basis of nephrolithiasis and allied disorders. Whole-genome scanning techniques, like Next-Generation Sequencing (NGS) and CGH (Comparative Genomic Hybridization) array, are the most recent technical approaches of molecular genetics that allow to trace out a complete draw of variation present in the human genome, namely SNPs (Single Nucleotide Polymorphisms) and heterogeneous structural variants. In the last years, indeed, several studies have recognized the critical role of structural genetic variants, mostly represented by Copy-Number Variants (CNVs), in modulating gene expression and complex diseases phenotype. Aim of this project was to identify some of the major susceptibility genes involved in idiopathic calcium nephrolithiasis applying the potential of whole-genome scanning technologies to a case study very peculiar, both for clinical manifestations both for its genetic background. The proband, since 30 years, suffers of a recurrent and severe form of ICN, with intermittent hypercalciuria and phosphaturic tubulopathy, expelling, up to date, about 300 calculi both spontaneously and by lithotripsy (33 treatments). Strikingly, he belongs to a family with consanguinity in which nephrolithiasis is present in several members and is transmitted in an apparently dominant fashion, with males being more severely affected than females. CGH arrays has been performed in the proband and in eight members of the family in order to detect the presence of CNVs in the genome. A duplication of 308 kb region of the Xq22.2 chromosome has been detected in the proband. This CNV resulted particularly interesting because it was a novel (not known) variant and it was shared by other three family members (maternal inheritance). Moreover, matching the Xq22.2 duplication over a database of 14375 individuals only 5 overlapping duplications were found, confirming its extreme rarity. Strikingly, all these 5 duplication shared a common region that corresponded to NUP62CL gene, suggesting a likely importance of this genetic trait. Furthermore, performing an expression study, we observed a significant and marked down-regulation of NUP62CL. Thus, even if we could not have a definitive proof of principle, this Xq22.2 CNV seemed to have an important role for ICN pathogenesis in our family. Nonetheless, given its presence in a member of the family that was not evidently affected and given the severity of the phenotype of some members of the paternal branch, we postulated that additional genetic determinants were also responsible of the severe phenotype encountered in the proband. In this light, we performed whole exome sequencing of the proband to identify rare single nucleotide variants that may have a role as susceptibility variants for ICN in the case-study family. By bioinformatic analyses and molecular validation, we could draw a polygenic model of heredity, with the identification of four possible susceptibility genes: XDH, ATP6V1B1, HNF1B, NUP62CL. The XDH gene, normally responsible of xanthinuria type I, was highlighted for the presence of two very rare variants with a damaging predicted effect on protein. Next, we discovered a missense homozygous variant in ATP6V1B1 gene, whose role is already known in distal tubular acidosis, that seemed to account for the ICN intermediate phenotype hypocitraturia observed in the family. In addition, we found an extremely rare heterozygous variant in HNF1B gene, a causative factor in cystic nephropathy, and the proband, indeed, recently showed pre-calyceal cysts. Strikingly, we again evidenced NUP62CL gene for the presence of two homozygous variants that operate activating criptic splicing sites, thus eventually generating an aberrant mRNA. This gene has never been associated to ICN but, having a known role in oxalate transport, could be responsible of some of the biological mechanisms that are on the basis of ICN pathogenesisLa nefrolitiasi calcica idiopatica (NCI) è una malattia multifattoriale, la cui patogenesi dipende dall’interazione di fattori ambientali, metabolici, anatomici e genetici. L’importanza dei fattori ereditari è emersa da diversi studi su famiglie e gemelli affetti da NCI. Il modello di ereditarietà più probabile sembrerebbe, come predetto da programmi bioinformatica, ad eredità monogenica co-dominante o poligenica. La maggior parte degli studi a gene candidato o di associazione condotti fin ora ha prodotto risultati negativi o marginali, lasciando pertanto le basi genetiche della NCI una questione ancora aperta. Tuttavia, le nuove tecnologie di analisi genetica sono in continua evoluzione e potrebbero contribuire ad approfondire le nostre conoscenze sulla patogenesi della NCI. Le tecnologie whole-genome scanning, quali Next-Generation Sequencing (NGS) and CGH (Comparative Genomic Hybridization) array, rappresentano gli approcci di genetica molecolare più recenti, e permettono di tracciare una mappa completa della variabilità presente nel genoma umano, in particolare SNPs (Single Nucleotide Polymorphisms) e varianti strutturali. Negli ultimi anni l’importanza di queste ultime, maggiormente rappresentate dalle Copy-Number Variants (CNVs), è stata infatti dimostrata in numerosi studi che ne hanno individuato un ruolo critico per lo sviluppo di malattie genetiche complesse. Scopo di questo studio è stata la ricerca di alcune delle maggiori varianti di suscettibilità alla NCI, applicando l’enorme potenziale delle tecnologie whole genome scanning ad un caso studio molto peculiare, sia per manifestazioni cliniche che per il bagkground genetico. Il probando da circa 30 anni è affetto da una forma severa di NCI, con ipercalciuria intermittente e tubulopatia fosfaturica, espellendo fino ad oggi circa 300 calcoli, sia spontaneamente che mediante litotripsia (33 interventi). Egli appartiene ad una famiglia con consanguineità, in cui la nefrolitiasi viene trasmessa in modo apparentemente dominante, con maschi affetti più severamente e meno frequentemente rispetto alle femmine. Da un’analisi CGH array, al fine di individuare la presenza di eventuali CNV, è stato possibile identificare una duplicazione di una regione di 308 Kb del cromosoma X (Xq22.2 CNV) del probando. Questa CNV è risultata particolarmente interessante poiché fin ora mai identificata e condivisa da altri tre familiari (eredità materna). Inoltre, confrontando la duplicazione Xq22.2 con un database di 14375 individui sono state identificate solo 5 duplicazioni “ overlappanti”, confermandone pertanto l’estrema rarità. In particolare, tutte queste 5 duplicazioni mostravano una regione minima comune, corrispondente al gene NUP62CL, suggerendone una possibile significatività. In uno studio di espressione da noi effettuato si è inoltre osservata una significativa e marcata down-regolazione di NUP62CL. Pertanto, pur non avendone avuto prova definitiva, è sembrato che la CNV Xq22.2 giocasse un ruolo importante nella patogenesi della NCI nella nostra famiglia. Tuttavia, data la sua presenza anche in un membro non evidentemente affetto e considerata anche la severità del fenotipo NCI di alcuni membri del ramo paterno, è stato ipotizzato che la presenza aggiuntiva di altri determinanti genetici potesse essere responsabile del fenotipo estremo riscontrato nel probando. In quest’ottica, è stato sequenziato l’intero esoma del probando (Whole Exome Sequencing) al fine di individuare varianti puntiformi rare che potessero agire da ulteriori varianti di suscettibilità alla NCI nella famiglia caso studio. La fase di analisi bioinformatica e validazione molecolare ha portato a delineare un quadro di eredità poligenica, con l’individuazione di quattro possibili geni di suscettibilità: XDH, ATP6V1B1, HNF1B, NUP62CL. Il gene XDH, fattore causativo della xanthinuria di tipo I, è stato evidenziato per la presenza di due varianti rare con un predetto effetto dannoso sulla struttura proteica. Il gene ATP6V1B1, di cui è già noto il ruolo nell’acidosi tubulare distale, presentava una variante missenso che sembrava render conto del fenotipo intermedio ipocitraturia osservato nella famiglia. E’ stata individuata, inoltre, una variante estremamente rara nel gene HNF1B, un fattore causativo di nefropatia cistica e, concordemente, il probando recentemente aveva mostrato la presenza di cisti pre-caliceali. Infine, soprendentemente, è stato possibile evidenziare ancora una volta il gene NUP62CL per la presenza di due varianti omozigoti, che agiscono attivando dei siti criptici di splicing e quindi con un probabile effetto di produzione di un mRNA aberrante. Questo gene non è stato mai associato alla NCI ma, possedendo un ruolo noto nel trasporto dell’ossalato, potrebbe essere responsabile di alcuni dei meccanismi che sottendono alla patogenesi della NC

Microbiome and Gestational Diabetes: Interactions with Pregnancy Outcome and Long-Term Infant Health

Microbiota composition is progressively being connected to different physiologic effects, such as glucose metabolism, and also to different pathologies, such as gestational diabetes mellitus (GDM). GDM is a public health concern that affects an important percentage of pregnancies and is correlated with many adverse maternal and neonatal outcomes. An increasing number of studies are showing some connections between specific microbial composition of the gut microbiota and development of GDM and adverse outcomes in mothers and neonates. The aim of this review is to analyze the available data on microbial changes that characterize healthy pregnancies and pregnancies complicated by GDM and to understand the correlation of these changes with adverse maternal outcomes; this review will also discuss the consequences of these maternal gut microbiome alterations on neonatal microbiota composition and neonatal long-term outcomes

Mid-pregnancy fetal biometry, uterine artery Doppler indices and maternal demographic characteristics: Role in prediction of small-for-gestational-age birth

Introduction The aim of this study was to evaluate the role of mid-trimester fetal biometry, uterine artery Doppler indices and maternal demographics in prediction of small-for-gestational-age (SGA) birth. Materials and methods We conducted a retrospective cohort study in a single referral center. The study included 23 894 singleton pregnancies scanned between 19 and 24 weeks of gestation. Maternal demographics included age, body mass index and ethnicity. Fetal biometry, birthweight and uterine artery pulsatility index values were converted into centiles. Multivariable logistic regression analysis was performed and the predictive accuracy was assessed using receiver operating characteristic curve analysis. The main outcome measure was prediction of delivery of preterm and term SGA neonates defined as a birthweight in the lowest centile groups (37, <37 and <32 weeks of gestation respectively at a 10% false-positive rate; maternal factors, fetal biometry and uterine artery Doppler combined detected 40, 66 and 89% of term, preterm and very preterm SGA <5th centile at a 10% false-positive rate. Conclusions Second-trimester screening can identify the majority of pregnancies at high risk of SGA birth and showed a higher performance for earlier gestational ages at birth and lower birthweight centiles