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Background: The global prevalence of α-thalassemia necessitates effective newborn screening strategies due to its severe clinical consequences. Traditional methods such as liquid chromatography (LC), capillary electrophoresis (CE), and isoelectric focusing (IEF) face limitations, including low separation efficiency, poor sensitivity for detecting Hb Bart's, and time-intensive operations, particularly with dried blood spots (DBS). These limitations hinder timely and accurate screening. This study addresses the need for a more efficient, sensitive, and rapid method for detecting Hb Bart's in newborns., Results: We enhanced IEF separation and sensitivity by designing a microfluidic IEF (mIEF) system with shortened columns and employing a coelution sample loading technique using oil-sealed blood spots for rapid sample pretreatment. Our experiments demonstrated significant improvements: the total analysis time was reduced from 1110 min (IPG IEF) and 46 min (LC) per batch to 36 min per batch. For individual samples, the focusing time decreased from 6 min (previous mIEF) to 3 min, with the microcolumn length shortened by 50 %, from 30 mm to 15 mm. The developed method showed excellent consistency with clinical Bart's detection and PCR diagnosis, achieving 100 % sensitivity and 98 % specificity for α-thalassemia screening., Significance and Novelty: Our novel mIEF method provides an efficient, sensitive, and rapid tool for screening newborns for α-thalassemia. This advancement addresses the limitations of traditional techniques, improving early diagnosis and intervention strategies and ultimately enhancing health outcomes for at-risk newborns., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Necrotizing enterocolitis (NEC) is the leading cause of death among premature infants, and there is a lack of specific early diagnostic markers. Blood sampling is expected to better reflect pathophysiological and metabolic changes in systematic illness, but there is a risk of iatrogenic anemia, especially in premature infants. Dried blood spots technique seems to have important advantages compared to whole blood sampling as it requires only 12-15 μL as sample volume. This study aimed to investigate the special metabolomics of preterm neonates at high risk of NEC using dried blood spots., Methods: Cases and controls were strictly matched 1:1. Dried blood spots ( n  = 32, 16 cases-16 controls) from newborn screening were subjected to LC-MS/MS. Metabolomic data were analyzed by orthogonal partial least squares-discriminant analysis (OPLS-DA) and univariate/multivariate statistical analysis., Results: Compared to the control group, the NEC group had a significant reduction in seven amino acids (glycine, alanine, threonine, proline, ornithine, lysine, and asparagine)., Conclusions: The metabolic profile of neonates with NEC differs significantly from that of controls, making possible their separation with the use of targeted (LC-MS/MS) dried blood spots-based metabolomic analysis. Seven specific markers were identified for early detection and intervention.

This past year, there were many important advances for patients with cystic fibrosis (CF). Of the many publications related to CF in 2023, there was further evaluation of highly effective modulator therapy, new assessments and guidelines for clinical manifestations and therapies for CF, advances in newborn screening and diagnosis, and evaluation of outcomes for people with CF transmembrane conductance regulator-related metabolic syndrome/CF screen positive, inconclusive diagnosis. The aim of this review article is not to provide a full assessment of the wide range of articles published in 2023, but to provide a brief review of publication that may lead to changes in clinical care., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Daily serum creatinine monitoring protocols for acute kidney injury (AKI) are invasive and may lead to surveillance resistance. We aimed to understand if use of urine neutrophil gelatinase-associated lipocalin (uNGAL) could increase high-risk nephrotoxic medication (NTMx) associated AKI screening adherence in neonates., Methods: Statistical process control methods prior to and post implementation were trended. The primary outcome, screening adherence, was defined as either daily serum creatinine or uNGAL assessment through 2 days post high-risk NTMx exposure., Results: 1291 monitoring days from the pre-implementation era (4/2020-6/2021) were compared to1377 monitoring days from the post-era (6/2021-10/2022). AKI screening adherence increased (81 to 92%) following implementation of optional uNGAL screening. Urine NGAL accounted for 35% of screening obtained. Use of uNGAL resulted in a 40% reduction in blood sampling for serum creatinine., Conclusions: Incorporation of uNGAL as a complementary screening tool to serum creatinine demonstrated sustained increased AKI surveillance in our Baby NINJA monitoring program., Competing Interests: Competing interests: Cara Slagle, MD is a consultant for AM Pharma and Medtronic and has received honorariums from Medtronic, the University of Alabama, and the AKI Critical Care Foundation, all unrelated to the work above. Stuart Goldstein, MD and Cincinnati Children’s Hospital receive royalties from Vigilanz Corporation (Minneapolis, MN) for the NINJA application licensed to Vigilanz from Cincinnati Children’s Hospital Medical Center. Dr. Goldstein consults and receives research funding from BioPorto Diagnostics, Inc, which markets The ProNephroAKI NGAL Test™., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

This scoping review aimed to synthesize the analytical techniques used and methodological limitations encountered when undertaking secondary research using residual neonatal dried blood spot (DBS) samples. Studies that used residual neonatal DBS samples for secondary research (i.e. research not related to newborn screening for inherited genetic and metabolic disorders) were identified from six electronic databases: Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Medline, PubMed and Scopus. Inclusion was restricted to studies published from 1973 and written in or translated into English that reported the storage, extraction and testing of neonatal DBS samples. Sixty-seven studies were eligible for inclusion. Included studies were predominantly methodological in nature and measured various analytes, including nucleic acids, proteins, metabolites, environmental pollutants, markers of prenatal substance use and medications. Neonatal DBS samples were stored over a range of temperatures (ambient temperature, cold storage or frozen) and durations (two weeks to 40.5 years), both of which impacted the recovery of some analytes, particularly amino acids, antibodies and environmental pollutants. The size of DBS sample used and potential contamination were also cited as methodological limitations. Residual neonatal DBS samples retained by newborn screening programs are a promising resource for secondary research purposes, with many studies reporting the successful measurement of analytes even from neonatal DBS samples stored for long periods of time in suboptimal temperatures and conditions.

Newborn screening for cystic fibrosis (CF) occasionally results in an inconclusive diagnosis of this disease, and these individuals are designated as CFTR-related metabolic syndrome (CRMS) in the United States, and CF Screen Positive Inconclusive Diagnosis (CFSPID) in other countries. Some of these asymptomatic individuals will progress to symptomatic disease, but risk factors associated with disease progression are not well understood. This scoping review was conducted to comprehensively map nonbiological risk factors in the CRMS/CFSPID literature and to identify understudied topics. Six electronic databases were systematically searched, resulting in 2951 studies. Forty nine eligible works were identified as including information on nonbiological risk factors related to CRMS/CFPSID. Eligible studies were published from 2002 to 2024, most prevalently in the United States (36.7%), and as quantitative data (81.6%). Of the 49 eligible works, 23 articles contributed only intellectual conjecture, while 26 articles contained original data, which underwent full-text qualitative content analysis. Key themes identified in descending order of content coverage included Psychological Impact, Management Care, Newborn Screening and Diagnostics, Communicating Diagnosis, and Lifestyle and External Exposures. This scoping review identified that while nonbiological risk factors are being studied in the CRMS/CFSPID literature, there was nearly equal distribution of works gathering original data to those citing previously published information. These findings indicate a critical need for original data collection on these risk factors, particularly on understudied topics identified herein., (© 2024 Wiley Periodicals LLC.)

Newborn screening (NBS) programmes are highly successful, trusted, public health interventions. Genomic sequencing offers the opportunity to increase the benefits of NBS by screening infants for a greater number and variety of childhood-onset conditions. This study aimed to describe who needs to do what, when, and for whom to deliver genomic newborn screening (gNBS) and capture perceived implementation barriers and enablers. 'Key informants' (individuals involved in the delivery of NBS) were interviewed. The Actor, Action, Context, Time and Target framework guided data collection and analysis. Participants (N = 20) identified new Actions required to deliver gNBS (educating healthcare providers, longitudinal psychosocial support), NBS Actions needing modification (obtaining consent) and NBS Actions that could be adopted for gNBS (prompt referral pathways). Obtaining consent in a prenatal Context was a source of some disagreement. The Time to disclose high chance results was raised as a key consideration in gNBS programme design. Genetic counsellors were identified as key Actors in results management, but workforce limitations may be a barrier. Online decision support tools were an enabler to offering gNBS. The implementation of gNBS will require behaviour changes from HCPs delivering NBS. Findings can inform how to deliver gNBS at population-scale., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: This study was approved by the Royal Children’s Hospital Human Research Ethics Committee (HREC/90929/RCHM-2022). All participants gave informed consent to participate., (© 2024. The Author(s).)

Biotinidase deficiency (BTD) is an autosomal recessive disorder characterized by impaired recycling of the water-soluble vitamin biotin which leads to a spectrum of clinical manifestations ranging from mild to severe, including mainly neurological and cutaneous symptoms. Biotin supplementation is a cornerstone of treatment, but diagnosis often relies on measuring serum enzyme activity, which needs to be confirmed by genetic analysis. Thus, molecular methods become necessary in the differential diagnosis of BTD. Accordingly, countries with a high-incidence have implemented next-generation sequencing (NGS) techniques to newborn screening programs for BT. Nevertheless, NGS platforms, while well-established, present challenges in cost, labor, accessibility, and duration for newborn screening programs targeting BTD, therefore these limitations necessitate the exploration of alternative systems to ensure efficient and widespread screening. Here, third-generation sequencing platforms, notably Oxford Nanopore Technology (ONT), present promising solutions to the associated challenges. Hence, in the present study, we aimed to develop an ONT-based assay for the screening of BTD gene. After designing and optimizing primers for long-PCR using reference DNA, we assessed the performance of the ONT assay in BTD patients previously diagnosed by enzyme assay and confirmed using Illumina-based sequencing. The results demonstrate a strong correlation between the two methods, indicating the reliability of the ONT-based assay. Moreover, this first in-house single gene testing specifically tailored for BTD successfully detected previously known genetic variants with high sequencing depths, affirming the effectiveness of ONT-based sequencing in human genetics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Thyroglobulin (Tg) is a biomarker of iodine status. Newborn Tg is a more sensitive marker than neonatal TSH in detecting variations in iodine intake. This study aims to validate an enzyme-linked immunosorbent assay (ELISA) for Tg determination on dried blood spots (DBS) in newborns. This study also sets out to assess the stability of Tg and the influence of newborns' hematocrit on Tg determination., Methods: A commercially available ELISA Tg assay was adapted for use on DBS. DBS-Tg in cord blood was measured in 209 newborns delivered from healthy euthyroid pregnant women. Sensitivity, linearity, repeatability, and intermediate fidelity were determined using the appropriate standards and quality control materials., Results: The limit of detection of the DBS-Tg assay was 2.4 µg/L, and the limit of quantification was 5.8 µg/L. Repeatability and intermediate fidelity were 7.7-8.3% and 11.0-11.2%, respectively. The median cord plasma Tg and DBS-Tg values in newborns were not significantly different, 30.2 (21.3-44.4) µg/L and 31.6 (19.3-48.7) µg/L (P = 0.48) with the ELISA, respectively, and 76.5 (40.0-101.5) µg/L with the Elecsys assay with an R = 0.88. DBS-Tg concentrations decrease with increasing hematocrit values (P < 0.05). DBS-Tg values were stable at a concentration of 25 µg/L for 12 months at -20ºC and 4ºC., Conclusion: This DBS-Tg assay demonstrated good analytical performance over a wide range of Tg concentrations, suggesting it is well suited to detecting variations in Tg concentrations. Studies comparing populations with different prevalence of anemia should consider the effect of hematocrit on DBS-Tg determination. The availability of a DBS-Tg assay for newborns makes it possible to integrate iodine status monitoring with newborn screening for inherited metabolic diseases.

In developed countries, Newborn Screening (NBS) programs aim to detect treatable yet clinically silent disorders. The selection of disorders to be included in NBS considers severity, treatment availability, prevalence, and analysis cost. However, numerous genetic disorders remain excluded from routine testing due to high expenses and specialized equipment requirements. Here we present SCAN, a novel, non-invasive, and cost-effective decision-support tool utilizing nanopore sequencing for estimating proportions of chromosomes responsible for the most common aneuploidies. SCAN combines DNA enrichment (amplification), barcoding, nanopore sequencing, and machine learning predictive modeling. In a proof-of-concept study for Klinefelter Syndrome, SCAN achieved 100% sensitivity, specificity, and accuracy, becoming the world's first IVD-certified genetic test utilising nanopore sequencing. Further model training shows promise in expanding this assay to detect other chromosomal aneuploidies included in the protocol., Competing Interests: Declarations. Competing interests: The authors declare the following competing interests: AKS’s PhD project is financed by gMendel ApS. Remaining authors declare no competing interests., (© 2024. The Author(s).)

Newborn screening for cystic fibrosis (CF-NBS) using an IRT-DNA algorithm with a 12 CFTR-variant panel and an IRT/IRT failsafe was officially implemented in the French-speaking Community of Belgium in January 2020. This screening protocol was evaluated after 4 years according to the criteria defined by the European Cystic Fibrosis Society's working group on neonatal screening. Immunoreactive trypsinogen concentration (IRT) was measured on dried blood spots collected between the second and the fourth day of life. CFTR variants genotyping was initiated when IRT ≥ 99th percentile (P99). If at least 1 variant was identified, the child was referred to a CF center for a sweat test (ST). If IRT ≥ 99.9th percentile with no variant identified, a failsafe was provided with IRT repeated on day 21 and subsequent ST in case of persistent IRT > P99. Extensive Gene Analysis was initiated if sweat chloride level was ≥ 30 mmol/L. Over a period of 4 years, 212.979 newborns were screened. Forty-two were diagnosed with CF: 34 by CF-NBS, 3 following a meconium ileus, 3 by family history and 2 missed cases. Additionally, 112 healthy carriers and 14 CFSPID were identified. The median age at the first consultation was 23 days. The sensitivity of our CF-NBS is 95% (target ≥ 95%), the positive predictive value 18% (target ≥ 30%) and CF/CFSPID ratio 2.8., Conclusion:  Although follow-up is limited, this first evaluation demonstrates encouraging sensitivity and early management before one month of age., What Is Known: • Newborn screening for cystic fibrosis improves the prognosis of patients., What Is New: • This article presents an initial assessment of our screening after 4 years., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recent technological advances have led to the expansion of testing options for newborns with suspected rare genetic conditions, particularly in high-income healthcare settings. This article summarises the key genomic testing approaches, their indications and potential limitations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/objectives: Genetic newborn screening (NBS) has already entered the phase of common practice in many countries. In Germany, spinal muscular atrophy (SMA), severe combined immunodeficiency (SCID) and sickle cell disease (SCD) are currently a mandatory part of NBS. Here, we describe the experience of six years of genetic NBS including the prevalence of those three diseases in Germany., Methods: Samples and nucleic acids were extracted from dried blood spot cards, commonly used for NBS. A qPCR assay was used to detect disease-causing variants for SMA and SCD, and the detection of T-cell receptor excision circles (TRECs) was performed for SCID screening., Results: The results of the NBS of over 1 million newborns for SMA, approximately 770,000 for SCID and over 410,000 for SCD are discussed in detail. In these newborns, we have identified 121 cases of SMA, 15 cases of SCID and syndrome-based immunodeficiencies and 77 cases of SCD or β-thalassemia., Conclusions: The flexibility of multiplex qPCR is assessed as an effective tool for incorporating different molecular genetic markers for screening. The processing of dried blood spot (DBS) filter cards for molecular genetic assays and the assays are described in detail; turn-around times and cost estimations are included to give an insight into the processes and discuss further options for optimization. The identified cases are in the range expected for the total number of screened newborns, but present a more exact view on the actual prevalences for Germany.

Background: Methylmalonic acidemia (MMA) is one of the most common hereditary organic acid metabolism disorders that endangers the lives and health of infants and children. Early detection and intervention before the appearance of a newborn's clinical symptoms can control disease progression and prevent or mitigate its serious consequences., Methods: 42,004 newborns from two Chinese populations were included in the study. The small molecular metabolite analytes were detected from the dried blood spot (DBS) samples by MS/MS. Genetic analysis of 68 Chinese MMA cases were performed by whole-exome sequencing and Sanger sequencing. Random forest classifiers (RFC) were constructed to improve the MMA screening performance and genotype prediction in two Chinese populations. Meanwhile, other six machine learning models were trained to separate MMA patients from normal newborns. Model performance was assessed using accuracy, sensitivity, specificity, false positive rate (FPR), and positive predictive value (PPV) and the area under the receiver operating characteristic curve (AUC)., Results: In the total 42,004 newborn samples, 68 MMA cases were identified by genetic analysis, 42 cases of which were caused by variants in MMACHC, 24 cases by variants in MMUT, and two cases by variants in MMAA. Three novel variants including c.449T>G (p.I150R) of MMACHC, c.1151C>T (p.S384F) and c.1091&#95;1108delins (p.Y364Sfs*4) in MMUT were identified in the MMA patients. RFC for newborn screening of MMA performed best as compared to several other classification models based on machine learning with 100% sensitivity, low FPR, excellent PPV and AUC. In addition, the subdivision RFC for MMA genotype prediction was constructed with superior performance., Conclusions: It can be seen that RFC is extremely helpful for detection and genotype prediction in the newborn MMA screening. In addition, our findings extend the variant spectrum of genes related to MMA., Competing Interests: Declarations Ethics approval and consent to participate The study protocol was approved by the Ethics Committee of the National Research Institute for Family Planning (Beijing, China). Before newborn screening and the study, each patient’s parent or guardian provided informed consent. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Congenital hypothyroidism is the most common preventable cause of intellectual disability. Therefore, the majority of developed countries have aimed to diagnose cases early through screening programs. In these screening programs, levels of thyroid-stimulating hormone (TSH) and free thyroxine are examined in dried blood spots taken between days 3 and 5 of life. While many countries accept TSH threshold value of 8 mU/L, there is still no consensus on the ideal TSH threshold value. As no twin studies on the TSH threshold value have been conducted previously, this study was planned. Eight pairs of twins were included in the study, with one of the twins having plasma TSH value ≥8 mU/L and the other <8 mU/L, measured between days 3 and 5 of life. The study aimed to investigate whether determining threshold TSH value of 8 mU/L would be beneficial by comparing somatic growth, mental development, and neuromotor development between twins. The age, gender, gestational weeks, birth weights, height, weight, and initial TSH values taken between days 3 and 5 of all cases were recorded. The patients' plasma Vitamin B12, folate, 25-OH Vitamin D, ferritin, and hemoglobin levels were measured. After that, they were evaluated by a child and adolescent psychiatry. Finally, the Denver Developmental Test was applied to the cases. There was no significant impairment in somatic growth, mental development, and neuromotor development in the long-term outcomes of cases with plasma TSH ≥ 8 mU/L compared to those with plasma TSH < 8 mU/L among the twins participating in our study., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Sickle cell disease (SCD) is a prevalent inherited blood disorder. Globally, approximately 515 000 babies are born with SCD annually, with 75% of these births occurring in Africa. Integrating newborn screening (NBS) for SCD into primary healthcare structures, such as immunisation programmes, holds significant promise, with dried blood spots (DBS)-point-of-care technologies (POCT) like HaemoTypeSC offering cost-effective screening solutions. However, scaling up DBS-POCT for NBS of SCD in Africa remains challenging., Objective: This study aims to explore individual, organisational and external factors that may influence the reliability, feasibility, acceptability, adoption and sustainability of using DBS-POCT with HaemoTypeSC for NBS of SCD at primary healthcare centres in African countries., Method: This qualitative study will be conducted in seven African countries that are part of the SickleInAfrica consortium sites. The study design is informed by the Consolidated Framework for Implementation Research (CFIR) and the Implementation Outcome Model. Participants will be mothers whose babies have been diagnosed with SCD, healthcare professionals and policy-makers. In-depth interviews and focus group discussions will be used for data collection. Data analysis will be through thematic analysis., Ethics and Dissemination: Research ethics approvals have been obtained from the seven countries. Written informed consent will be obtained from all participants. The study results will be disseminated in peer-reviewed scientific journals, scientific conferences, reports to national ministries of public health and webinars., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Deficiency of cofactors for various enzymes can lead to inborn errors of metabolism. These conditions frequently occur as seizures, which lead to permanent brain damage. Newborn screening for biomarkers associated with these disorders can help in early detection and treatment. Our objective was to establish a liquid chromatography mass spectrometry technique for quantifying biomarkers in dried urine spots to detect specific vitamin-responsive inborn errors metabolism. Biomarkers were extracted from dried urine spots using a methanol:0.1% v/v formic acid solution (75:25) containing an internal standard mixture. Separation was achieved using a Luna PFP column (150 mm × 4.6 mm, 3 µm) under gradient elution conditions. The LC-MS technique was validated as per ICH M10 guidelines. Urine samples from healthy newborns in Udupi district, South India, were analyzed to establish reference values for these biomarkers. The method demonstrated excellent linearity (R 2  > 0.99) with low limits of quantification: 0.1 µg/mL for leucine, isoleucine, valine, proline, hydroxyproline, methylmalonic acid, and 3-hydroxyisovaleric acid; 0.01 µg/mL for pipecolic acid and α-aminoadipic semialdehyde; and 0.03 µg/mL for piperideine-6-carboxylate. Interconvertibility between urine and dried urine spot assays was observed from the results of the regression and Bland-Altman analyses. Reference intervals for these biomarkers in the Udupi neonatal population were established using the validated dried urine spot method., (© 2024 The Author(s). Journal of Separation Science published by Wiley‐VCH GmbH.)

Background: Newborn screening (NBS) for isovaleric acidemia (IVA) is implemented via tandem mass spectrometry (MS/MS), but false-positive results are still common. In addition, NBS for IVA is limited by a lack of suitable biomarkers, especially after the use of pivaloylester-containing antibiotics., Methods: We conducted a retrospective cohort study to explore the clinical correlation between antibiotic administration and false-positive results for isovalerylcarnitine (C5)., Results: A total of 509,313 newborns were recruited from the initial NBS study, only one of whom underwent genetic confirmation, conducted between 2015 and 2020. Significant associations between false-positive C5-carnitine screening results and treatment with pivalate-generating antibiotics were identified with retrospective analysis., Conclusions: The current results highlight the detrimental effects of false-positive C5-carnitine screening results. Unless the licensing of pivalate-generating antibiotics for use during the neonatal period is reconsidered, a second-tier test for C5 determination will be necessary., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Perfusion index is a dependable indicator for assessing the perfusion status of newborns. A low perfusion index indicates compromised hemodynamic function. The study aims to investigate perfusion index in asymptomatic newborns aged 35 to 41 weeks who did not require medical support., Methods: Healthy neonates born in four major maternity hospitals of Tehran University from 2019 to 2021 were selected. To ensure consistency and reliability in data collection, a detailed manual was developed and distributed, along with comprehensive training sessions for all personnel involved., Results: A total of 994 newborns entered the study. Among them, echocardiography was adversely affected in 218 neonates due to abnormal screening pulse oximetry. Of these 218 neonates, 53 were found to have abnormal echocardiography results. The median perfusion index value in healthy neonates was 1.6%, and the median oxygen saturation was 97%. A percentile perfusion index curve was developed for healthy neonates to establish a normal reference range., Conclusion: Developing a percentile perfusion index curve specific to healthy neonates provides a useful reference range for healthcare providers to assess perfusion status in this population, but further research is needed to confirm its accuracy., (© 2024 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Importance: The incidence of retinopathy of prematurity (ROP) has been increasing in the US since 2003. Understanding the progression of and racial disparities in ROP incidence in California can provide a contrasting perspective that may guide future research and practice in the management and prevention of ROP., Objective: To describe how the screening and incidence of ROP among very preterm infants in California changed from January 1, 2012, to December 31, 2021., Design, Setting, and Participants: This study used a cohort of very preterm infants (defined as infants born prior to 32 weeks' gestational age or weighing less than 1500 g) admitted to 60 neonatal intensive care units across California from January 1, 2012, to December 31, 2021. Among this cohort, several factors were examined, including (1) the clinical and sociodemographic covariates of the population with and without ROP, (2) trends in screening for ROP, and (3) the incidence of ROP in total and by race and ethnicity. Data analysis was performed in April 2024., Exposures: Race and ethnicity and other birthing parental and infant descriptive characteristics., Main Outcomes and Measures: Incidence rates of ROP and severe ROP. The primary measures were rates of ROP screening and incidence rates of ROP and severe ROP. Time trends in the risk of ROP and severe ROP were estimated using robust Poisson regression models., Results: In this cohort of 39 269 very preterm infants (<32 weeks' gestational age) eligible for ROP screening, the mean (SD) infant gestational age was 28.6 (2.6) weeks. The mean (SD) birth weight was 1075 (274) g, and 48.6% of infants were female. The birthing parents of the population were 12.6% Asian, 13.3% Black, 44.9% Hispanic White or Hispanic other race, 0.7% Native American/Alaskan, 24.7% non-Hispanic White, and 1.0% Pacific Islander. From January 1, 2012, to December 31, 2021, in California, ROP screening rates remained steady at 95% or greater for eligible infants less than 30 weeks of gestational age for all race and ethnic subgroups. In this study cohort among all very preterm infants (<32 weeks' gestational age), the incidence of ROP decreased from 31% in 2012 to 29% in 2021. Incidence rates of ROP among Asian and Hispanic individuals decreased the most quickly compared to other racial and ethnic groups, narrowing disparities., Conclusions and Relevance: In this cohort study, in contrast to increasing national trends, the total incidence of and racial and ethnic disparities in ROP incidence remained steady or decreased from 2012 to 2021 in California.

Newborn screening is a public health measure to diagnose rare diseases at birth, thereby minimising negative effects of late treatment. Genomic technologies promise an unprecedented expansion of screened diseases at low cost and with transformative potential for newborn screening programmes. However, barriers to the public funding of genomic newborn screening are poorly understood, particularly in light of the heterogenous European newborn screening landscape. This study therefore aims to understand whether international newborn screening experts share a common understanding of the barriers to fund genomic newborn screening. For this purpose, we convened 21 European newborn screening experts across a range of professions and national backgrounds in a Delphi study. Stable consensus, determined via the Wilcoxon matched-pairs signed-ranks test, was found via three consecutive survey rounds for all presented barriers. Experts generally judged the scenario of genomic newborn screening being available to every newborn in seven years to be unlikely, identifying treatability and the absence of counselling and a skilled workforce as the most significant barriers to public funding. We identify value re-definition for rare disease treatments, centralisation of genomic expertise, and international research consortia as avenues for pan-European actions which build on the consensus achieved by our Delphi panel., Competing Interests: Declaration of competing interest Anne-Sophie Chalandon and Alicia Granados are employed by Sanofi S.A. The views presented here are those of the authors and not necessarily those of Sanofi S.A., its directors, officers, or staff. Julian Nam is employed by F. Hoffmann-La Roche Ltd. The views presented here are those of the authors and not necessarily those of F. Hoffmann-La Roche Ltd., its directors, officers, or staff. Andreas Clemens is employed by Novartis AG. The views presented here are those of the authors and not necessarily those of Novartis AG, its directors, officers, or staff. All other authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Newborn screening for Phenylketonuria (PKU) began in 1963, and since then knowledge and treatment recommendations have evolved. In the decades following newborn screening for PKU, individual and family experiences varied widely. We present narratives by people living with PKU during these years, including individuals actively following in PKU clinic and those who have been out of PKU clinic for many years. These stories describe different individual experiences, including diet discontinuation in childhood, changing treatment guidelines, and new treatments that have become available., (© 2024 The Author(s). American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

The purpose of the study was to investigate correlation and concordance between total serum bilirubin (TSB) and transcutaneous bilirubin measured at covered (TcBC) and uncovered (TcBU) skin during and after discontinuation of phototherapy. A cross-sectional study included ≥ 34 weeks gestation infants requiring phototherapy for neonatal hyperbilirubinemia. In-house, photo-opaque patches were placed on infants' sternums before phototherapy initiation. Simultaneous blood sampling for TSB, TcBC, and TcBU measurements were performed. Among 103 infants included in the final analysis, 70% were full-term. Covering skin during phototherapy resulted in strong TcBC-TSB correlation (r = 0.91, 95% CI 0.87-0.94, P < 0.001) compared to TcBU (r = 0.53, 95% CI 0.37-0.65, P < 0.001), persisting post-phototherapy (r = 0.88, 95% CI 0.82-0.91, P < 0.001). Bland-Altman analysis showed a higher mean difference and wider 95% limits of agreement for TcBU-TSB during phototherapy (-6.3 mg/dL and -11.1 to -1.6) vs TcBC-TSB (0.9 mg/dL and -1.2 to 2.9). Passing-Bablok regression analysis confirmed good agreement between TcBC and TSB., Conclusions: The application of in-house, photo-opaque patches enhanced the correlation and agreement between TcBC and TSB during and after discontinuation of phototherapy. This may prove particularly useful in resource-limited settings where commercial devices are unavailable., What Is Known: • Transcutaneous bilirubin measurement has been widely used as a screening method for neonatal hyperbilirubinemia. • The accuracy of transcutaneous bilirubin measurements during and after phototherapy in infants with hyperbilirubinemia has been debated., What Is New: • Our study demonstrated that utilizing carefully designed photo-opaque patches enhanced the accuracy of transcutaneous bilirubin measurement during and after phototherapy. • Effective in-house alternatives are crucial in resource-limited settings where commercial opaque patches are not always accessible or affordable., (© 2024. The Author(s).)

Importance: Sudden infant death syndrome (SIDS) is a major cause of infant death in the US. Previous research suggests that inborn errors of metabolism may contribute to SIDS, yet the relationship between SIDS and biomarkers of metabolism remains unclear., Objective: To evaluate and model the association between routinely measured newborn metabolic markers and SIDS in combination with established risk factors for SIDS., Design, Setting, and Participants: This was a case-control study nested within a retrospective cohort using data from the California Office of Statewide Health Planning and Development and the California Department of Public Health. The study population included infants born in California between 2005 and 2011 with full metabolic data collected as part of routine newborn screening (NBS). SIDS cases were matched to controls at a ratio of 1:4 by gestational age and birth weight z score. Matched data were split into training (2/3) and testing (1/3) subsets. Data were analyzed from January 2005 to December 2011., Exposures: Metabolites measured by NBS and established risk factors for SIDS., Main Outcomes and Measures: The primary outcome was SIDS. Logistic regression was used to evaluate the association between metabolic markers combined with known risk factors and SIDS., Results: Of 2 276 578 eligible infants, 354 SIDS (0.016%) cases (mean [SD] gestational age, 38.3 [2.3] weeks; 220 male [62.1%]) and 1416 controls (mean [SD] gestational age, 38.3 [2.3] weeks; 723 male [51.1%]) were identified. In multivariable analysis, 14 NBS metabolites were significantly associated with SIDS in a univariate analysis: 17-hydroxyprogesterone, alanine, methionine, proline, tyrosine, valine, free carnitine, acetyl-L-carnitine, malonyl carnitine, glutarylcarnitine, lauroyl-L-carnitine, dodecenoylcarnitine, 3-hydroxytetradecanoylcarnitine, and linoleoylcarnitine. The area under the receiver operating characteristic curve for a 14-marker SIDS model, which included 8 metabolites, was 0.75 (95% CI, 0.72-0.79) in the training set and was 0.70 (95% CI, 0.65-0.76) in the test set. Of 32 infants in the test set with model-predicted probability greater than 0.5, a total of 20 (62.5%) had SIDS. These infants had 14.4 times the odds (95% CI, 6.0-34.5) of having SIDS compared with those with a model-predicted probability less than 0.1., Conclusions and Relevance: Results from this case-control study showed an association between aberrant metabolic analytes at birth and SIDS. These findings suggest that we may be able to identify infants at increased risk for SIDS soon after birth, which could inform further mechanistic research and clinical efforts focused on monitoring and prevention.

Diagnostic delay remains a barrier to improving biliary atresia (BA) outcomes. We tested the implementation feasibility of a two stage BA newborn screening program in an integrated healthcare system., Methods: Under a waiver of consent, we measured direct bilirubin (DB) levels in well newborns undergoing standard of care hyperbilirubinemia screening at four hospitals. Initial DB was measured by modifying nursery admission electronic medical record order sets. Second-stage DB was obtained at ~2 weeks of age under parental permission/informed consent (PP/IC). Implementation measures included the proportions of (1) eligible newborns that were screened before nursery discharge, (2) newborns undergoing second stage screening at ~2 weeks of age, and (3) newborns that underwent clinical evaluation for persistently elevated DB., Results: A total of 12,276 newborns met eligibility criteria for screening, of which 12,055 (98.2%) underwent first-stage screening in the newborn nursery. Ninety-four (0.78%) had elevated positive initial screens. Ninety newborns (95.7%) underwent second-stage screening (n = 20) or contact was made with the primary care provider to recommend second-stage screening (n = 70). Among all screened newborns, 15 (0.12%) had abnormal second screens. All had follow-up clinical evaluation for potential cholestatic liver disease. No BA cases were identified through screening, though two infants who met exclusion criteria (admission to the newborn intensive care unit) were subsequently diagnosed with BA during the screening period., Conclusions: BA newborn screening is feasible in an integrated health network. Low consent rates have implications for future studies. Program infrastructure is required for implementation success and sustainability., (© 2024 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: New York (NY) State implemented a new cystic fibrosis (CF) newborn screen (NBS) algorithm in December 2017 with improvement in positive predictive value and unanticipated increased identification of infants with cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS). Repeat sweat testing is recommended in infants with CRMS. During the COVID-19 pandemic infants with CRMS were lost to follow up. With this quality improvement (QI) initiative, we aimed to perform repeat sweat testing in 25% of infants lost to follow up. We also describe consensus recommendations for CRMS from the NY CF NBS Consortium., Methods: Our QI team identified the primary drivers contributing to absent follow up, outreached to families, and created a questionnaire to evaluate parental understanding of CRMS using QI-based strategies., Results: Of 350 infants diagnosed with CRMS during the study period, 179 (51.1%) infants were lost to follow up. A total of 31 (17.3%) were scheduled for repeat sweat tests and followed up at CF Centers. Families reported high satisfaction with the CRMS knowledge questionnaire., Conclusions: With this QI-based approach, we effectively recaptured infants with CRMS previously lost to follow up during the COVID-19 pandemic. Ongoing concerns about infection risk and lack of understanding on the part of families and pediatricians likely contributed to patients with CRMS lost to follow up. Consensus recommendations for CRMS include annual visits with repeat sweat testing until 2-6 years of age and education for adolescents about clinical and reproductive implications of CRMS., (© 2024 Wiley Periodicals LLC.)

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder (LSD) caused by reduced activity of the acid sphingomyelinase (ASM) enzyme, which leads to progressive storage of sphingomyelin and related lipids in the body. ASMD is caused by biallelic variants in the SMPD1 gene, which encodes for the ASM enzyme. Current estimates of disease incidence range from 0.4 to 0.6 in 100 000 livebirths, although this is likely an underestimation of the true frequency of the disorder. While there is no cure for ASMD, comprehensive care guidelines and enzyme replacement therapy are available, making an early diagnosis crucial. Newborn screening (NBS) for ASMD is possible through measurement of ASM activity in dried blood spots and offers the opportunity for early diagnosis. In 2015, Illinois (IL) became the first to initiate statewide implementation of NBS for ASMD. This study describes the outcomes of screen-positive patients referred to Ann & Robert H. Lurie Children's Hospital (Lurie). Ten infants were referred for diagnostic evaluation at Lurie, and all 10 infants were classified as confirmed ASMD or at risk for ASMD through a combination of molecular and biochemical testing. Disease incidence was calculated using data from this statewide implementation program and was ~0.79 in 100 000 livebirths. This study demonstrates successful implementation of NBS for ASMD in IL, with high screen specificity and a notable absence of false positive screens., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Aim: One third of Australian children diagnosed with type 1 diabetes present with life-threatening diabetic ketoacidosis (DKA) at diagnosis. Screening for early-stage, presymptomatic type 1 diabetes, with ongoing follow-up, can substantially reduce this risk (<5% risk). Several screening models are being trialled internationally, without consensus on the optimal approach. This pilot study aims to assess three models for a routine, population-wide screening programme in Australia., Methods: An implementation science-guided pilot study to evaluate the feasibility, acceptability and costs of three screening models in children will be conducted between July 2022 and June 2024. These models are as follows: (1) Genetic risk-stratified screening using newborn heel prick dried bloodspots, followed by autoantibody testing from 11 months of age; (2) genetic risk-stratified screening of infant (6-12 months) saliva followed by autoantibody testing from 10 months of age; and (3) autoantibody screening using capillary dried bloodspots collected from children aged 2, 6 or 10 years. Cohorts for each model will be recruited from targeted geographic areas across Australia involving ≥2 states per cohort, with a recruitment target of up to 3000 children per cohort (total up to 9000 children). The primary outcome is screening uptake for each cohort. Secondary outcomes include programme feasibility, costs, parental anxiety, risk perception, satisfaction, well-being and quality of life, and health professional attitudes and satisfaction., Conclusions: This pilot is the first direct comparison of three screening implementation models for general population screening. Findings will provide evidence to inform a potential national screening programme for Australian children., Trial Registration: ACTRN12622000381785., (© 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Newborn screening (NBS) for cystic fibrosis (CF) is universal in the United States. Protocols vary but include an immunoreactive trypsinogen (IRT) level and CFTR variant panel. California CF NBS has a 3-step screening: IRT level, variant panel, and CFTR sequencing if only one variant identified on panel., Methods: This was a cohort study of infants with CF born in California (2007-2021) to examine racial and ethnic differences in having a false-negative NBS result for CF and at which step the false-negative occurred. We examined how different CFTR variant panels would improve detection of variants by race and ethnicity: original 39-variant panel, current 75-variant panel, and all 402 disease-causing CFTR variants in the CFTR2 database., Results: Of the 912 infants born in California with CF, 84 had a false-negative result: 38 due to low IRT level and 46 with a high IRT value (but incomplete variant detection). Asian (OR 6.3) and Black infants (OR 2.5) were more likely to have a false-negative screening result than non-Hispanic white infants. The majority of false-negative screening (but CF diagnosis) cases among American Indian/Native Alaskan and non-Hispanic White infants were due to low IRT levels. The majority of Asian and Hispanic infants with false-negative screening had no variants detected. Detection of two CFTR variants was improved with the 75-variant panel in Black, Hispanic, and non-Hispanic White infants and with the 402-variant panel in Black, Hispanic, non-Hispanic White, and other race infants., Conclusions: Larger CFTR panels in NBS improved the detection of CF in all races and ethnicities., (© 2024 Wiley Periodicals LLC.)

Developmental dysplasia of the hip (DDH) is the most common musculoskeletal anomaly of childhood. This study analyses paediatrician's concordance performing hip ultrasound according to Graf's method. An analytical cross-sectional study is designed. Patients' hips are evaluated by Graf's ultrasound method at 4-6 and 12-16 weeks of age. Demographic characteristics, pregnancy history, factors related to DDH, hip type, and α and β angles are collected. To assess the agreement degree of hip diagnosis and hip types Kappa index (I. kappa) is used. Intraclass correlation coefficient (ICC) evaluates the concordance of α and β angles. A p value < 0.05 is considered statistically significant. All results are represented with their 95% confidence interval (95% CI). Four hundred sixty-seven neonates are recruited and meet the inclusion criteria. A total of 3182 images were analysed. Agreement between paediatricians according to hip diagnosis and different types ranges from moderate to almost perfect I. kappa 0.6-1.0 (95% CI 0.5-0.7; 95% CI 1.0-1.0). α angle ICC for paediatricians is between 0.75 and 0.88 (95% CI 0.61-0.86; 95% CI 0.80-0.92). β angle value agreement degree among paediatricians at both visits is moderate. The Graf method is the most popular ultrasound technique for hip assessment. In our setting, paediatricians carry out children follow-up; therefore, they should perform universal screening. In this study agreement degree between paediatricians varies between substantial and almost perfect. Conclusion: The Graf ultrasound procedure performed by paediatricians is a reliable test and can be used for DDH screening. What is Known • Developmental dysplasia of the hip (DDH) is the most common congenital musculoskeletal anomaly of childhood. Early diagnosis and treatment improve DDH prognosis. Lack of detection can cause complications such as lameness, early osteoarthritis and need for hip replacement at an early age. What is New • Today, the best screening method is still subject of debate. But it seems that with selective screening many pathological hips go unnoticed. Universal screening implementation may be a challenge in some countries. But the question is if this could be carried out by paediatricians as part of healthy child follow-up., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Citrin deficiency is an autosomal recessive disorder caused by a defect of citrin resulting from mutations in the SLC25A13 gene. Intrahepatic cholestasis and various metabolic abnormalities, including hypoglycemia, galactosemia, citrullinemia, and hyperammonemia may be present in neonates or infants in the "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD) form of the disease. Because at present, newborn screening (NBS) for citrin deficiency using citrulline levels in dried blood spots (DBS) can only detect some of the patients, we tried to develop a new evaluation system to more reliably detect newborns with citrin deficiency utilizing parameters already in place in present NBS methods. To achieve this goal, we re-analyzed NBS profiles of amino acids and acylcarnitines in 96 NICCD patients, who were diagnosed through selective screening or positive family history. Hereby, we identified the combined evaluation of arginine (Arg), citrulline (Cit), isoleucine+leucine (Ile + Leu), tyrosine (Tyr), free carnitine (C0) / glutarylcarnitine (C5-DC) ratio in DBS as potentially sensitive to diagnose citrin deficiency in pre-symptomatic newborns. In particular, a scoring system using threshold levels for Arg (≥9 μmol/L), Cit (≥ 39 μmol/L), Ile + Leu (≥ 99 μmol/L), Tyr (≥ 96 μmol/L) and C0/C5-DC ratio (≥327) was significantly effective to detect newborns who later developed NICCD, and could thus be implemented in existing NBS programs at no extra analytical costs whenever citrin deficiency is considered to become a novel target disease., (© 2023 SSIEM.)

This study aimed to describe the femoral groove morphology using ultrasound in children under 6 months, estimate the incidence of trochlear dysplasia, and evaluate associated risk factors. A prospective study included 298 patients who underwent universal ultrasound screening for hip dysplasia [developmental dysplasia of the hip (DDH)] and knee ultrasound. Measurements of sulcus angle (SA), trochlear depth (TD), and trochlear facet asymmetry (TFA) were analyzed. Trochlear dysplasia was considered present if the ASO was ≥159°. Reproducibility was assessed using the intraclass correlation coefficient (ICC) in 60 knees. Logistic regression adjusted for confounders, presenting odds ratios (OR) and 95% confidence intervals (CI). Significance was set at P  < 0.05. Analysis included 596 knees (298 patients). Females accounted for 51% of patients, with 7% having breech presentation, 4.4% DDH, 6.4% family history of DDH, and 5% family history of patellofemoral instability. ICC showed excellent agreement for SA and TD, but poor for TFA. Trochlear dysplasia incidence was 3% (9/298; 67% bilateral). Median (IQR) values were 147.5 (144.0-150.5) for SA, 2.4 (2.2-2.8) for TD, and 1.1 (1.0, 1.1) for TFA. Breech presentation (OR, 9.68; 95% CI 1.92-48.71, P  = 0.006) and concomitant DDH (OR 6.29, 95% CI 1.04-37.78, P  = 0.044) were associated with trochlear dysplasia. Ultrasound effectively evaluates femoral groove morphology and diagnoses trochlear dysplasia in newborns. Trochlear dysplasia incidence was 3%, with a 10-fold higher risk in breech presentation and 6-fold higher risk in concomitant DDH. Standardized screening and timely treatment protocols should be further investigated. Level of evidence: Diagnostic Level II., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hemoglobinopathies are the commonest genetic defect worldwide (7% of the world's population has at least one hemoglobin mutation). Although prenatal screening for hemoglobinopathies is not obligatory during pregnancy in Italy, it is offered to women by the Italian National Health Service in the pre-conception phase. The screening of newborns is a valid alternative, and has been adopted in various European countries, albeit in a piecemeal fashion. Neonatal screening has the advantage of providing early diagnosis of a hemoglobinopathy. Here we report the findings from the experience with neonatal screening in Friuli-Venezia Giulia since 2010., Materials and Methods: The hemoglobinopathy screening project in Friuli-Venezia Giulia, a Region in north Italy, began in November 2010. High-performance liquid chromatography was performed on dried blood spot samples collected by obstetric nurses from neonates within 5-8 days after birth., Results: From 2010 to 2019, 11,956 newborns were screened, and abnormal hemoglobin was found in 519 of them (4.34%): the variants identified included HbS, HbC, HbD, HbE and HbX. More specifically, the HbS variant was observed in 347 (2.9%) newborns and the homozygous pattern was identified in 24 (0.2%) cases. The screening also detected two cases of β-thalassemia major., Discussion: We report our experience of 10 years of screening newborns for hemoglobinopathies in the Region of Friuli-Venezia Giulia, in which 7.7% of people come from malaria-endemic areas. Increased mobility and migratory flows bringing in hemoglobinopathy carriers from endemic areas have led to an increase in mutations in non-malarial countries, with a current incidence of around 4% in the newborns we tested. This means that hemoglobinopathies can be described as a rare condition. Our data show that incidence rates are comparable to those of other inherited disorders such as phenylketonuria, thereby justifying the inclusion of the test for hemoglobinopathies into screening programs for rare diseases.

Purpose: Newborn screening using dried blood spot (DBS) samples for the targeted measurement of metabolites and nucleic acids has made a substantial contribution to public healthcare by facilitating the detection of neonates with genetic disorders. Here, we investigated the applicability of non-targeted quantitative proteomics analysis to newborn screening for inborn errors of immunity (IEIs)., Methods: DBS samples from 40 healthy newborns and eight healthy adults were subjected to non-targeted proteomics analysis using liquid chromatography-mass spectrometry after removal of the hydrophilic fraction. Subsequently, DBS samples from 43 IEI patients were analyzed to determine whether patients can be identified by reduced expression of disease-associated proteins., Results: DBS protein profiling allowed monitoring of levels of proteins encoded by 2912 genes, including 1110 listed in the Online Mendelian Inheritance in Man database, in healthy newborn samples, and was useful in identifying patients with IEIs by detecting reduced levels of disease causative proteins and their interacting proteins, as well as cell-phenotypical alterations., Conclusion: Our results indicate that non-targeted quantitative protein profiling of DBS samples can be used to identify patients with IEIs and develop a novel newborn screening platform for genetic disorders., (© 2024. The Author(s).)

Background and Aims: Newborn screening (NBS) for glucose-6-phosphate dehydrogenase (G6PD) deficiency by biochemical tests is being used worldwide, however, the outcomes arising from combined genetic and biochemical tests have not been evaluated. This research aimed to evaluate the outcomes of application of combined genetic and biochemical NBS for G6PD deficiency and to investigate the molecular epidemiological characteristics, variant spectrum, and genotype-phenotype correlation of G6PD deficiency in China., Methods: A population-based cohort of 29,601 newborns were prospectively recruited from eight NBS centers in China between February 21 and December 30, 2021. Biochemical and genetic NBS was conducted simultaneously., Results: The overall prevalence of G6PD deficiency was 1.12% (1.86% for male, and 0.33% for female; 1.94% for South China and 0.08% for North China). Genetic NBS identified 10 male patients undetected by biochemical NBS. The overall positive predictive values (PPVs) of biochemical and genetic NBS were 79.95% and 47.57%, respectively. A total of 15 variants were identified, with the six most common variants being c.1388G > A, c.1376G > T, c.95A > G, c.871G > A, c.1024C > T and c.392G > T (94.2%). The activity of G6PD was correlated with the type and WHO classification of variants., Conclusion: This study highlighted that combined screening could enhance the efficiency of current NBS for diagnosing G6PD deficiency. The prevalence, variant spectrum and allele frequency of G6PD deficiency vary across different regions. Our data provide valuable references for clinical practice and optimization of future screening strategies for G6PD deficiency., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: There is insufficient evidence to determine if non-invasive transcutaneous bilirubin (TcB) measurement can replace serum bilirubin (SBR) in assessing rebound hyperbilirubinaemia after phototherapy., Objective: To investigate if TcB can safely guide management of neonates after phototherapy., Subjects: 100 well neonates ≥35 weeks' gestation who had received inpatient phototherapy., Method: Measurement of both helix (manufacturer's recommendation) and earlobe TcB coincidentally with routine SBR 12 hours after cessation of phototherapy. All mothers gave written informed consent., Results: Gestation ranged from 35 +0 to 41 +5 (median 37 +6 ) weeks; birth weight 2018-4566 (median 3230) g; age 55-222 (median 109) hours at testing. 86% neonates were Caucasian. Outcomes determined by SBR included restarting phototherapy (n=0), repeat SBR next day (n=29), no further routine follow-up (n=71).TcB and SBR measurements were unpredictably inconsistent. Helix TcB tended to underestimate SBR (mean difference 50.1 (95% CI 113.9 to -13.7) μmols/L); for earlobe TcB mean difference was -13.4 (95% CI 46.3 to -73.2) μmols/L (overestimate), but bias was greater over the range of mean differences. No demographic factor predicted consistency between TcB and SBR. TcB was 25% (helix) and 76% (earlobe) sensitive in predicting repeat phototherapy and/or repeat SBR; specificities were 92% and 58%, respectively. Adding a safety margin of 120 μmols/L to helix TcB value could have safely avoided invasive SBR measurement in 50/98 (51%) babies., Conclusions: Consistency between TcB and rebound SBR is unpredictable in well neonates > 35 weeks' gestation but adopting a wide safety margin has potential to reduce blood sampling. Recommencement of phototherapy is uncommon in this population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The effective implementation of whole-exome sequencing- and whole-genome sequencing-based diagnostics in the management of children affected with genetic diseases and the rapid decrease in the cost of next-generation sequencing (NGS) enables the expansion of this method to newborn genetic screening programs. Such NGS-based screening greatly increases the number of diseases that can be detected compared to conventional newborn screening, as the latter is aimed at early detection of a limited number of inborn diseases. Moreover, genetic testing provides new possibilities for family members of the proband, as many variants responsible for adult-onset conditions are inherited from the parents. However, the idea of NGS-based screening in healthy children raises issues of medical and ethical integrity as well as technical questions, including interpretation of the observed variants. Pilot studies have shown that both parents and medical professionals have moved forward and are enthused about these new possibilities. However, either the number of participants or the number of genes studied in previous investigations thus far has been limited to a few hundred, restricting the scope of potential findings. Our current study (NCT05325749) includes 7,000 apparently healthy infants born at our center between February 2021 and May 2023, who were screened for pathogenic variants in 2,350 genes. Clinically significant variants associated with early-onset diseases that can be treated, prevented, or where symptoms can be alleviated with timely introduced symptomatic therapy, were observed in 0.9% of phenotypically normal infants, 2.1% of the screened newborns were found to carry variants associated with reduced penetrance or monogenic diseases of adult-onset and/or variable expressivity, and 0.3% had chromosomal abnormalities. Here, we report our results and address questions regarding the interpretation of variants in newborns who were presumed to be healthy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background:  Hyperbilirubinaemia is a contributing condition to the prevalence of neonatal hearing loss. Because of its pathophysiology, the use of Otoacoustic Emissions (OAE) and Automated Auditory Brainstem Response (AABR) testing is essential in diagnosing hearing loss. Two-tier screening models are typically used in developing world contexts; however, a combined approach to testing (using both tests) should be used for early detection. Blood serum levels should also be monitored to determine how they impact audiological test results., Objectives:  To determine the outcomes of using a combined testing approach of both OAE and Auditory Brainstem Response (ABR) for both screening and diagnostic testing of neonates with hyperbilirubinaemia and studying the relationship between the test results and the serum bilirubin levels., Method:  A cross-sectional, comparative design was utilised. Forty neonates were tested (80 ears). Neonates underwent hearing screening and diagnostic testing (ABR and/or AABR and DPOAE tests). The study was conducted at a hospital in South Africa., Results:  One-third (32.5%) of the neonates had comorbidities. Screening results indicated that the AABR test could identify more cases of abnormalities than DPOAEs (p = 0.001). Participants with a serum level greater than 10 mg/dL presented with abnormal diagnostic ABR test results while passing the DPOAE test (p  0.001)., Conclusion:  Combined use of ABR and DPOAE testing yielded a greater identification of auditory pathology than using either test alone. Serum bilirubin levels can be used as an indicator for combination testing.Contribution: Combined use of ABR and DPOAE testing leads to greater identification of auditory pathology.

Introduction: Biliary atresia (BA) is a rare progressive neonatal cholangiopathy with unknown pathophysiology and time of onset. Newborn Screening (NBS) in Germany is routinely performed in the first days of life to identify rare congenital diseases utilizing dried blood spot (DBS) card analyses. Infants with biliary atresia (BA) are known to have altered amino acid profiles (AAP) at the time point of diagnosis, but it is unclear whether these alterations are present at the time point of NBS., Objectives: We aimed to analyze amino acid profiles in NBS-DBS of infants with Biliary Atresia., Methods: Original NBS-DBS cards of 41 infants who were later on diagnosed with BA were retrospectively obtained. NBS-DBS cards from healthy newborns (n = 40) served as controls. In some BA infants (n = 14) a second DBS card was obtained at time of Kasai surgery. AAP in DBS cards were analyzed by targeted metabolomics., Results: DBS metabolomics in the NBS of at that time point seemingly healthy infants later diagnosed with BA revealed significantly higher levels of Methionine (14.6 ± 8.6 μmol/l), Histidine (23.5 ± 50.3 μmol/l), Threonine (123.9 ± 72.8 μmol/l) and Arginine (14.1 ± 11.8 μmol/l) compared to healthy controls (Met: 8.1 ± 2.6 μmol/l, His: 18.6 ± 10.1 μmol/l, Thr: 98.1 ± 34.3 μmol/l, Arg: 9.3 ± 6.6 μmol/l). Methionine, Arginine and Histidine showed a further increase at time point of Kasai procedure. No correlation between amino acid levels and clinical course was observed., Conclusion: Our data demonstrate that BA patients exhibit an altered AAP within 72 h after birth, long before the infants become symptomatic. This supports the theory of a prenatal onset of the disease and, thus, the possibility of developing a sensitive and specific NBS. Methionine might be particularly relevant due to its involvement in glutathione metabolism. Further investigation of AAP in BA may help in understanding the underlying pathophysiology., (© 2024. The Author(s).)

G6PD deficiency (G6PDd) is the most common X-linked genetic disease worldwide and the most common cause of severe neonatal hyperbilirubinemia (NH) in Nigeria. Screening for G6PDd has been recommended for over thirty years but is still not routinely done in Nigeria. We sought to investigate a low-cost rapid diagnostic test to determine G6PDd in Nigerian neonates. Enrolled neonates were screened using the CareStartTM G6PD point-of-care rapid diagnostic test; and mothers/caregivers of neonates with G6PDd were asked about their cord care product(s); transcutaneous bilirubin levels were done on neonates with G6PDd using the JM 103 meter. One hundred and forty neonates were enrolled between 15 January and 1 July 2022. Eighteen (12.8%) of all neonates enrolled and 13.9% of enrolled males (0% of females) were G6PDd. Seventeen of the mothers/caregivers of the G6PDd neonates were asked about cord care. The majority of mothers/caregivers (15/17, 88%%) reported including methylated spirits in their neonate's cord care; seven of these used chlorohexidine plus methylated spirits (41.2%) while only one mother/caregiver used chlorohexidine alone. One mother/caregiver used mentholatum alone and another used mentholatum, chlorhexidine gel, and methylated spirits. Maximum bilirubin levels for those infants with G6PDd ranged from 3.2 to 18.8 mg/dl with 16/17 (94.1%) of bilirubin levels exceeding 5.5 mg/dl. This study again highlights the need for large-scale G6PDd screening. Additionally, it highlights the need to correlate the type of cord care with the risk of NH in future studies., (© The Author(s) [2024]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The measurement of T-cell receptor excision circle (TREC) is used for newborn screening (NBS) in dried blood spot (DBS) samples from Guthrie card for severe combined immunodeficiency (SCID). Here, we report the results of first newborn screening pilot program for SCID conducted in Türkiye., Methods: The study was carried out together with Ankara University School of Medicine and The Ministry of Health, Public Health General Directorate, Pediatric and Adolescent Health Department. TREC measurements were performed in randomly selected Guthrie card samples obtained from 20253 babies born between October 2018 and October 2020. The TREC analyses were performed together with beta Actin (β-Actin) via RT-PCR (Real Time Polymerase Chain Reaction)., Results: TRECs found to be normal (≥15 copies/µl) in 98,6% of the newborns (n: 19975) but low (<15 copies/µl) in 1.4% (n:278) at the initial analyses. TRECs were retested in 278 suspected infants and found to be normal in 160 (0.8%) while low in 118 (0.58%). New DBS were obtained from the babies with low TRECs (new sample test). TRECs were normal in 108 (0.53%) of the new sample tests and low in 10 (0.049%). Two among 10 babies who had abnormal (undetectable) TRECs were diagnosed as SCID; ADA (P1) and RAG1 (P2) defects were confirmed respectively. They both received curative treatments [gene therapy (P1) and HSCT (P2)]. The remaining 6 of 8 newborns with abnormal TRECs were found normal after clinical and laboratory immune work-up, while medical records of other two revealed early postnatal death due to extreme prematurity., Conclusion: In the light of this study the incidence of SCID was detected at least 1/10000 live births in Türkiye. This study shows the feasibility and usefulness of initiating SCID screening in Türkiye., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Haskologlu, Kocak, Tufan, Aksoy, Bastug, Oner, Islamoglu, Baskin, Esenboga, Acican, Ceylaner, Guner, Keles, Cagdas, Reisli, Tezel, Dogu, Tezcan and Ikinciogullari.)

Introduction: Early diagnosis of Severe Combined Immunodeficiency (SCID) increases survival outcomes and quality of life while significantly minimizing healthcare burden and costs. Despite growing evidence supporting the benefits and cost-effectiveness of SCID detection through newborn screening (NBS), it has yet to be implemented in Malaysia. This study aims to explore experts' opinions on the current status, challenges, and crucial strategies needed for the successful implementation of SCID NBS., Methodology: A guided, structured interview was employed to explore opinions on the current status, barriers, and strategies for implementing SCID NBS in Malaysia. All 13 invited experts participated in this study, indicating complete participation from the entire Malaysian immunology fraternity (consisting of eight clinical immunologists and five immunopathologists)., Key Findings: Several initiatives are ongoing to establish SCID NBS in Malaysia. Hindrances such as low immunologist-to-patient ratio, unequal placements of immunologists throughout Malaysia, society's low disease awareness, national health prioritization, lack of stakeholder engagement, and inadequacy of local study/data were highlighted. Pilot research on SCID NBS, advocacy workshops, and promotion materials are among the ongoing activities outlined in the blueprint, paving the way for this nationwide NBS program to be achievable in the near future., Conclusion: This article provides recommendations to policymakers in mandating SCID NBS. Strategies by key stakeholders are underway, particularly in advocacy programs and efforts to increase awareness among clinicians and the public., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chang, Mohd Noh, Abdul Latiff, Woo, Ismail, Abd Hamid, Siniah, Zainal Abidin, Sham, Mat Ripen, Baharin, Abdul Wahab, Zainudeen, Hashim, Wong, Ahmad Shawaludin and Ali.)

The diagnosis of retinopathy of prematurity (ROP) is primarily image-based and suitable for implementation of artificial intelligence (AI) systems. Increasing incidence of ROP, especially in low and middle-income countries, has also put tremendous stress on health care systems. Barriers to the implementation of AI include infrastructure, regulatory, legal, cost, sustainability, and scalability. This review describes currently available AI and imaging systems, how a stable telemedicine infrastructure is crucial to AI implementation, and how successful ROP programs have been run in both low and middle-income countries and high-income countries. More work is needed in terms of validating AI systems with different populations with various low-cost imaging devices that have recently been developed. A sustainable and cost-effective ROP screening program is crucial in the prevention of childhood blindness., Competing Interests: National Institute of Health (R01 HD107494, R01 EY019474, P30 EY010572); Research to Prevent Blindness (Career Advancement Award, Career Development Award, Unrestricted departmental funding grant); J.P.C. and R.V.P.C. have a financial interest in Siloam Vision, a company that may have a commercial interest in the results of this research and technology. OHSU and UIC have reviewed and managed this potential conflict of interest. A.C. is a consultant to Siloam Vision. The sponsor or funding organization had no role in the design or conduct of this research. The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Spinal muscular atrophy (SMA) is a genetic neuromuscular progressive disorder that is currently treatable. The sooner the disease-modifying therapies are started, the better the prognosis. Newborn screening for SMA, which is already performed in many countries, has been scheduled to begin in the near future. The development of a well-organized program is paramount to achieve favorable outcomes for the child who is born with the disease and for the costs involved in health care. We herein present a review paper hoping to point out that SMA neonatal screening is urgent and will not increase the cost of its care., Competing Interests: MMB: has received grants for clinical trials from Biogen; and honoraria for advisory board or lectures from: Genzyme-Sanofi, PTC Therapeutics, Roche, Sarepta, Pfizer, Novartis, and Biogen. FN: has received grants for clinical trials from PTC Therapeutics, and Roche; and honoraria for advisory board or lectures from: PTC Therapeutics, Roche, Novartis, and Biogen. TD: has given lectures sponsored by Biogen, Novartis, and Roche. LS: has received personal compensation from Biogen, Novartis, Roche, Scholar Rock, BioHaven, Illulina, and Zentech. APQCA: has received grants for clinical trials from GSK, PTC Therapeutics, Roche, and Sarepta; and honoraria for advisory board or lectures from: Genzyme-Sanofi, PTC Therapeutics, Roche, Sarepta, Pfizer, Novartis, and Biogen. And JGG: has received grants for clinical trials from Biogen; and honoraria for advisory board or lectures from: PTC Therapeutics, Roche, Sarepta, Pfizer, Novartis, Biogen, Genzyme-Sanofi, and Astellas., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Since January 2020, neonatal screening for cystic fibrosis (CF-NBS) has been implemented in the Wallonia-Brussels Federation. It's based on the immunoreactive trypsin (IRT1) assay between day 2 and day 4, associated with a 12 CFTR pathogenic variants analysis and with an IRT control on day 21. The aim of this study is to evaluate the performance of our CF-NBS in Liège according to the quality criteria defined by the European Cystic Fibrosis Society's working group on neonatal screening. After four years, 58.762 newborns have been screened. Nineteen children with cystic fibrosis were diagnosed : 14 by NBS, 3 following a meconium ileus, 1 by family history and 1 false negative diagnosed on clinical basis. Furthermore, 39 healthy carriers and 2 uncertain diagnosis (CFSPID) were identified. The sensitivity of CF NBS is 93,3 % (target ≥ 95 %), the positive predictive value (PPV) 17,7 % (target ≥ 30 %). Increasing the TIR1 threshold by 0,1 in 0,1 from P99 to P99,5, would be associated with a lower sensitivity and a non-significant improvement of PPV. A national assessment of CF NBS needs to be carried out.

Background: Complications of prematurity are the leading cause of under-5 mortality globally and 80% of newborn deaths are of low birth weight (LBW) babies. Early identification of LBW and preterm infants is crucial to initiate timely interventions., Objective: To evaluate the feasibility and diagnostic accuracy of alternative neonatal anthropometric measurements in identifying LBW and preterm infants in Africa., Methods: In this systematic review and meta-analysis, we evaluated the diagnostic performance of infant foot length, mid-upper arm circumference (MUAC), head and chest circumferences against birth weight and gestational age. Pooled correlation between the index and the reference methods was estimated. Multiple anthropometric thresholds were considered in estimating the pooled sensitivity, specificity and area under receiver operating characteristic curve (AUC)., Results: 21 studies from 8 African countries met the inclusion criteria. Correlation coefficients with birth weight were 0.79 (95% CI 0.70 to 0.85) for chest circumference, 0.71 (95% CI 0.62 to 0.78) for MUAC and 0.66 (95% CI 0.59 to 0.73) for foot length. Foot length measured by rigid ruler showed a higher correlation than tape measurement. Chest circumference with 28.8 cm cut-off detects LBW babies with AUC value of 0.92 (95% CI 0.71 to 0.97). Foot length identified preterm infants, with 82% sensitivity, 89% specificity and AUC of 0.91 (95% CI 0.69 to 0.98) at a 7.2 cm optimal cut-off point. MUAC had an AUC of 0.83 (95% CI 0.47 to 0.95) for preterm detection. In identifying LBW babies, foot length and MUAC have AUC values of 0.89 (95% CI 0.70 to 0.96) and 0.91 (95% CI 0.73 to 0.97) at 7.3 cm and 9.8 cm optimal cut-off points, respectively. Foot length and MUAC are relatively simple and minimise the risk of exposing infants to cold., Conclusion: Newborn foot length, MUAC, head and chest circumferences have comparable diagnostic accuracy in identifying LBW and preterm babies. Using foot length and MUAC in low-resource settings are the most feasible proxy measures for screening where weighing scales are not available., Prospero Registration Number: CRD42023454497., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)