Catastrophic antiphospholipid syndrome: challenging case and importance of multidisciplinary evaluation and management.

Our case depicts a challenging diagnosis of catastrophic antiphospholipid syndrome in a young patient with a heterogenous presentation with extensive clinical course, a wide range of investigations, including multimodality imaging, and multidisciplinary expertise, to initiate prompt treatment addressing multiorgan thrombotic injury.

Functionality of pea protein isolate solutions is affected by reconstitution conditions.

Pea protein isolate (PPI), a high-concentration protein ingredient derived from peas, is increasingly utilized in food applications, including beverages, meat or dairy alternatives, and baked goods. The protein extraction process typically used to manufacture PPI renders the protein highly denatured, which can have a negative impact on its functionality. Therefore, it is critical to understand how to prepare and utilize PPI to maximize its functionality. The current study evaluates the effect of select reconstitution conditions on the structure and functionality of PPI, across a range of protein concentrations (4%-10%) relevant to a variety of food applications. Temperature during reconstitution with water and hydration time impacted both protein hydration and its functionality. Increasing reconstitution temperature from 20 to 60°C and increasing hydration time from 10 to 40 min decreased PPI particle size in solution and increased PPI solubility. Viscosity of PPI solutions also increased with mild heating and longer hydration time, whereas their flow behavior was highly dependent on protein concentration. Experimental data demonstrates that reconstitution conditions have a significant impact on PPI functionality. These findings can help food formulators develop high-quality food products that utilize PPI as a functional ingredient. PRACTICAL APPLICATION: Protein in commercially available pea protein isolates (PPIs) is usually highly denatured, and thus, it is important to find ways to maximize its functionality in practical applications. The findings of this study inform food scientists how to leverage PPI at various protein concentrations with optimal reconstitution conditions to develop high-quality products. Generally, mild heating and longer hydration times improve PPI functional performance.

Evidence of coupled autotrophy and heterotrophy on plastic biofilms and its influence on surrounding seawater.

We measured phytoplankton primary production and heterotrophic bacterial activities on microplastics and seawater in the Northwestern Mediterranean Sea during two 3-month spring periods over 2 consecutive years. Microorganisms growing on a 5 mm diameter low density polyethylene films (LDPE; 200 µm thick) faced two contrasting conditions depending on the year. Spring 2018 was characterized by consistent nutrient inputs and bloom development. In spring 2019, nutrient inputs and bloom were low. For the first time, we observed a clear coupling between primary production and heterotrophic prokaryote production on microplastics during both years, but with different intensity between years that reflected the crucial role of the trophic environmental conditions (nutrient supply) in shaping microbial activities on plastics. We found that high primary production on plastics could support the whole (net autotrophy) or the majority of the bacterial carbon demand needed for heterotrophic activities, supplemented by other carbon sources if surrounding waters are highly productive. We propose that microbial activity on plastics influences the microbial community in the surrounding seawater, especially when the environmental conditions are less favorable. An illustrative image of the role of plastics in the environment could be that of an inverter in an electrical circuit that mitigates both positive and negative variations. Our results highlight the potential role of the plastisphere in shaping biogeochemical cycles in the context of increasing amounts of plastic particles in the marine environment.

Investigating the illicit market in veterinary medicines: An exploratory online study with pet owners in the United Kingdom.

The illicit market in veterinary medicines is an overlooked issue despite threatening the health of non-human and human animals. It is thought to be increasing within the major markets of the global North due to the growth of e-commerce and social media sites. This paper examines the online market in illicit veterinary medicines through an exploratory study of the public's online experiences as pet owners in the UK. To this end, we collected data through literature-based research and an online survey. Drawing on Passas' criminogenic asymmetries framework, the research found that the confluence of legal, political, cultural, economic and knowledge asymmetries likely facilitate the market in illicit veterinary medicines in the UK. Our research concludes that, while previous reports suggest the illicit market is dominated by medicines to treat pets, it increasingly consists of medicines for farmed animals. This brings its own set of challenges and risks, and a pressing need for further research on the market's dynamics.

Determination of pediatric reference limits for 10 commonly measured autoantibodies.

OBJECTIVES: The objective of this study was to establish pediatric reference limits for autoimmune disease markers in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort of healthy children and adolescents to support their interpretation and clinical decision making. The CALIPER is a national study of healthy children aiming to close gaps in pediatric laboratory medicine by establishing a robust database of pediatric reference intervals for pediatric disease biomarkers (caliperdatabase.org). METHODS: Healthy children and adolescents (n=123, aged 1-19) were recruited to CALIPER with informed consent. Serum autoantibody testing conducted on the BIO-FLASH analyzer (Werfen, Barcelona, Spain) included anti-dsDNA IgG, anti-Sm IgG, anti-RNP IgG, anti-SSB/La IgG, anti-Ro60 IgG, anti-Ro52 IgG, anti-cardiolipin IgG, anti-MPO IgG, anti-PR3 IgG, and anti-tTG IgA. Pediatric reference limits representing 95th, 97.5th, and 99th percentiles were calculated using the non-parametric rank method according to Clinical Laboratory Standards Institute C28-A3 guidelines. RESULTS: The proportion of samples with results above the lower limit of the analytical measuring range were: anti-cardiolipin IgG 90%, anti-dsDNA 22%, anti-Sm 13%, anti-RNP 0.8%, anti-SSB/La 0%, anti-Ro60 0%, anti-Ro52 0%, anti-MPO 25%, anti-PR3 9%, and anti-tTG IgA 28%. Pediatric reference limits and associated 90% confidence intervals were established for all 10 markers. All autoantibodies could be described by one age range except for anti-cardiolipin IgG and anti-MPO. A sex-specific difference was identified for anti-tTG IgA. CONCLUSIONS: Robust pediatric reference limits for 10 commonly clinically utilized autoimmune markers established herein will allow for improved laboratory assessment and clinical decision making in pediatric patients using the BIO-FLASH assay platform worldwide.

Hypotension on cardiopulmonary stress test predicts 90 day mortality after LVAD implantation in INTERMACS 3-6 patients.

AIMS: Cardiopulmonary stress test (CPX) is routinely performed when evaluating patient candidacy for left ventricular assist device (LVAD) implantation. The predictive value of hypotensive systolic blood pressure (SBP) response during CPX on clinical outcomes is unknown. This study aims to determine the effect of hypotensive SBP response during to clinical outcomes among patients who underwent LVAD implantation. METHODS AND RESULTS: This was a retrospective single center study enrolling consecutive patients implanted with a continuous flow LVAD between 2011 and 2022. Hypotensive SBP response was defined as peak exercise SBP below the resting value. Multivariable Cox-regression analysis was performed to evaluate the relationship between hypotensive SBP response and all-cause mortality within 30 and 90 days of LVAD implantation. A subgroup analysis was performed for patients implanted with a HeartMate III (HM III) device. Four hundred thirty-two patients underwent LVAD implantation during the pre-defined period and 156 with INTERMACS profiles 3-6 met our inclusion criteria. The median age was 63 years (IQR 54-69), and 52% had ischaemic cardiomyopathy. Hypotensive SBP response was present in 35% of patients and was associated with increased 90 day all-cause mortality (unadjusted HR 9.16, 95% CI 1.98-42; P = 0.0046). Hazard ratio remained significant after adjusting for age, INTERMACS profile, serum creatinine, and total bilirubin. Findings were similar in the HM III subgroup. CONCLUSIONS: Hypotensive SBP response on pre-LVAD CPX is associated with increased perioperative and 90 day mortality after LVAD implantation. Additional studies are needed to determine the mechanism of increased mortality observed.

Pediatric Reference Intervals for Point-of-Care Random Glucose in Healthy Children and Adolescents.

BACKGROUND: Glucose testing at the point-of-care (POC) is routinely used in the diagnosis, prognosis, and monitoring of diabetic states and other clinical conditions. Accurate reference intervals (RIs) are essential in appropriate clinical decision-making. In this study, RIs were established for random glucose (whole blood) in the Canadian Laboratory Initiative on Pediatric Reference (CALIPER) cohort using 2 POC instruments: the Nova Biomedical StatStrip (handheld glucometer) and Radiometer ABL90 FLEX Plus (benchtop instrument). An analytical comparison was also completed between the 2 POC systems and a laboratory-based analyzer (Ortho Vitros 5600). METHODS: Approximately 400 healthy children and adolescents (birth to 18 years) were recruited with informed consent from community schools or clinics providing care to metabolically stable/healthy children. Random venous samples were collected and run sequentially on the Nova Biomedical StatStrip (whole blood), Radiometer ABL90 FLEX Plus (whole blood), and Ortho Vitros 5600 (serum). RIs and method comparisons between analytical platforms were completed according to CLSI guidelines. RESULTS: Significantly different glucose concentrations were observed in infancy, requiring age-specific partitioning (0-<1 month, 1-<6 months, 6 months-<19 years) on all platforms. Excellent concordance was observed between POC platforms (Pearson r > 0.90), with a small negative bias. Good comparability was observed between POC and laboratory-based platforms (Pearson r > 0.80). CONCLUSION: This study established comprehensive pediatric RIs for random glucose (whole blood) on modern POC systems in the CALIPER cohort for the first time. Results demonstrate excellent concordance in glucose values between POC systems and good comparability with a laboratory-based analyzer. These data will assist in more accurate clinical decision-making in pediatric healthcare institutions.

Comparative effects of high pressure processing and heat treatment on in vitro digestibility of pea protein and starch.

The effects of high-pressure processing (HPP) and heat treatment on the digestibility of protein and starch in pea protein concentrate (PPC) were investigated. Samples of PPC with 5% (5 P) and 15% (15 P) protein were treated by HPP (600 MPa/5 °C/4 min) or heat (95 °C/15 min) and their in vitro static and dynamic digestibility were compared to untreated controls. HPP-treated PPC underwent a greater degree of proteolysis and showed different peptide patterns after static gastric digestion compared to untreated and heat-treated PPC. Differences in protein digestibility among treatments during dynamic digestion were only significant (p < 0.05) during the first 20 min of jejunal, ileal, and total digestion for 5 P, and during the first 60 min of ileal digestion for 15 P. Neither static nor dynamic starch digestibility were dependent on treatment. HPP did not reduce trypsin inhibitor activity, whereas heat treatment reduced it by ~70%. HPP-induced structural modifications of proteins and starch did not affect their overall in vitro digestibility but enhanced gastric proteolysis.

Invasive hemodynamics are equivocal for functional outcomes after MitraClip.

OBJECTIVES: To evaluate invasive hemodynamics in assessing MC therapy success as well as evaluate its effectiveness as a predictor of functional outcomes. BACKGROUND: Mitral regurgitation grade is a poor predictor of functional outcomes after a MitraClip. There is a paucity of data on invasive hemodynamics as a predictor of outcomes. METHODS: Sixty-nine patients underwent MC between 2015 and 2018 at the University of Minnesota Medical Center and were retrospectively analyzed. Invasive hemodynamics were performed before and after device deployment with transesophageal echocardiographic guidance. Statistical analysis was performed using STATA version 16. Student's t test was used for continuous variables and Pearson's chi-squared test for categorical variables. Mann-Whitney test was performed for continuous variables where data were not normally distributed. Logistic and linear regression were used to investigate relationships between variables and outcomes. RESULTS: A total of 69 patients were included in the study. The mean age was 83 (75-87) years and 38 (55%) were male. Eighty-one percentage had >/= NYHA III symptoms. Eighty-seven percentage had severe MR. Pulmonary capillary wedge pressure was 20 (15-24). Overall, there was significant improvement in left atrial pressure including mean left atrial pressure index, MR, and NYHA class after MC (<.001). There was no significant association between invasive hemodynamics (including left atrial mean pressure index or its reduction rate) and functional outcomes (p = NS). MR grade was also not predictive of functional outcomes. CONCLUSION: Left atrial pressure may not be a significant predictor of functional outcomes, and, in isolation, may not be an improvement over MR grade.

Pediatric reference intervals for 32 routine biochemical markers using the siemens healthineers atellica® CH assays in healthy children and adolescents.

BACKGROUND: Pediatric reference intervals are essential for test interpretation. With development of newer analytical systems, de novo reference interval establishment is of necessary importance. In the current study, pediatric reference intervals were determined for 32 analytes using Siemens Healthineers Atellica® CH assays in the CALIPER cohort of healthy children and adolescents. METHODS: Approximately 600 healthy children and adolescents were recruited with informed consent and collected serum samples were analyzed on the Siemens Healthineers Atellica® CH platform. Assays studied included enzymes, proteins, lipids, electrolytes, and additional markers Reference intervals were established according to Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: Of the 32 parameters, 26 required age partitioning and 18 required sex partitioning. Reference value distributions included consistent increases, decreases, and dynamic variation across the age continuum. Chloride, LDL cholesterol, glucose, lipase, sodium, and triglyceride demonstrated no age or sex-specific differences. CONCLUSION: The current study expands the clinical utility of the CALIPER database to include 32 Siemens Atellica® chemistry assays. Reference value distributions for Siemens assays mirrored those observed on other comparable assays/systems with few exceptions (e.g. lipase, direct and total bilirubin). These finding support the robustness of previously derived reference intervals in the CALIPER cohort and other global cohorts.

Complex biological patterns of soluble cytokines and CD163 in childhood necessitating age-specific reference intervals for evidence-based clinical interpretation.

BACKGROUND: Cytokine measurements to support clinical laboratory and research investigations have become increasingly common in pediatrics. However, there is a paucity of accurate pediatric reference intervals (RIs) essential to the interpretation of cytokine results. To address this gap, here, we establish age- and sex-specific pediatric reference values for clinically relevant inflammatory markers including CD163, and the cytokines IL-1ß, IL-6, IL-10, IL-18, TNF-α, IFN-γ, and CXCL-9. METHODS: Healthy children and adolescents (n = 311, 1-19 years) were recruited as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) study. Multi-analyte measurements in plasma and analytical performance verification were conducted on the ProteinSimple® Ella™ automated immunoassay platform (Bio-Techne, MN, USA). Age- and sex-specific RIs were calculated based on Clinical and Laboratory Standards Institute guidelines. Additionally, 75th and 95th percentile cut-offs were determined. RESULTS: Three types of reference value distributions were observed: (a) consistent levels throughout age and sex: IL-6, and IFN-γ, (b) gradual decline in concentration with age: CD163, TNF-α, CXCL-9, and IL-10, (c) significantly higher concentrations during ages 4-14 years than earlier and later ages: IL-1ß and IL-18. Reference values for CXCL-9, IL-10, and TNF-α under 8 years of age differed significantly from older children. CD163, IL-18 and IL-1ß required three age partitions. CD163 demonstrated significant sex differences in ages 8-13 years. CONCLUSION: The circulating profile of cytokines in children is complex and can vary by age and sex. This necessitates careful interpretation of test results based on age and/or sex specific RIs facilitating more accurate clinical decision making.

Continuous reference curves for common hematology markers in the CALIPER cohort of healthy children and adolescents on the Sysmex XN-3000 system.

INTRODUCTION: Clinicians and healthcare professionals rely heavily on health-associated standards, such as reference intervals (RIs), for appropriate laboratory test result interpretation. RIs are commonly partitioned into discrete age/sex bins based on statistical and/or clinical significance. In pediatric hematology, such partitioning does not adequately represent complex variation in analyte concentrations throughout maturation. The objective of this study was to establish continuous RIs for common hematological parameters in the healthy pediatric Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort. METHODS: Data from healthy CALIPER children and adolescents (6 months-<19 years) were used to generate continuous RIs (ie, 2.5th and 97.5th quantiles) for 19 hematological parameters. Continuous curves were statistically established with nonparametric quantile regressions. Flagging rate analysis was completed for the established continuous upper and lower reference limits and subsequently compared to previously published discrete CALIPER reference intervals for all parameters. RESULTS: Continuous RIs were established for 19 hematology parameters, where seven required sex-specific reference curves. Based on flagging rate assessment, continuous RIs appear to more accurately estimate hematological reference limits over the pediatric age range, especially for analytes with complex age- and sex-specific reference value patterns. CONCLUSIONS: This is the first study to generate continuous RIs for a breadth of hematological markers in a healthy pediatric Canadian population. The increased power of continuous reference intervals to accurately estimate the complex relationship between hematological analyte concentration and age during a time of extensive growth and development is expected to improve laboratory test result interpretation and, subsequently, pediatric clinical decision-making.

Cardiac Biomarkers in Pediatrics: An Undervalued Resource.

BACKGROUND: The clinical use of common cardiac biomarkers, such as brain natriuretic peptides and troponins, has traditionally been limited to adult populations in the assessment of heart failure and acute coronary syndrome, respectively. While many have discounted the value of these markers in pediatric populations, emerging evidence suggests they may be useful in the diagnosis and prognostication of many cardiac and noncardiac pathologies in neonates, children, and adolescents, and an increasing number of pediatric hospitals are routinely measuring cardiac markers in their clinical practice. CONTENT: This review summarizes and critically evaluates the current literature regarding the application of cardiac biomarkers for clinical decision-making in the pediatric population. Main potential clinical indications discussed herein include primary cardiac disease, immune-related conditions, and noncardiac disease. Important diagnostic and interpretative challenges are also described in relation to each potential indication. SUMMARY: Despite a general lack of clinical awareness regarding the value of cardiac biomarkers in pediatrics, there is increasing literature to support their application in various contexts. Cardiac biomarkers should be considered an undervalued resource in the pediatric population with potential value in the diagnosis and prognosis of myocarditis, congenital heart disease, and heart failure, as well as in the assessment of severity and cardiac involvement in immune-related and other systemic conditions. While interpretation remains challenging in pediatrics due to the age- and sex-specific dynamics occurring throughout growth and development, this should not prevent their application. Future research should focus on defining evidence-based cut-offs for specific indications using the most up-to-date assays.

Pediatric reference interval verification for endocrine and fertility hormone assays on the Abbott Alinity system.

OBJECTIVES: The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) has developed an extensive database of reference intervals (RIs) for several biomarkers on various analytical systems. In this study, pediatric RIs were verified for key immunoassays on the Abbott Alinity system based on the analysis of healthy children samples and comparison to comprehensive RIs previously established for Abbott ARCHITECT assays. METHODS: Analytical performance of Alinity immunoassays was first assessed. Subsequently, 100 serum samples from healthy children recruited with informed consent were analyzed for 16 Alinity immunoassays. The percentage of test results falling within published CALIPER ARCHITECT reference and confidence limits was determined. If ≥ 90% of test results fell within the confidence limits, they were considered verified based on CLSI guidelines. If <90% of test results fell within the confidence limits, additional samples were analyzed and new Alinity RIs were established. RESULTS: Of the 16 immunoassays assessed, 13 met the criteria for verification with test results from ≥ 90% of healthy serum samples falling within the published ARCHITECT confidence limits. New CALIPER RIs were established for free thyroxine and prolactin on the Alinity system. Estradiol required special considerations in early life. CONCLUSIONS: Our data demonstrate excellent concordance between ARCHITECT and Alinity immunoassays, as well as the robustness of previously established CALIPER RIs for most immunoassays, eliminating the need for de novo RI studies for most parameters. Availability of pediatric RIs for immunoassays on the Alinity system will assist clinical laboratories using this new platform and contribute to improved clinical decision-making.

Pediatric reference intervals for endocrine markers and fertility hormones in healthy children and adolescents on the Siemens Healthineers Atellica immunoassay system.

OBJECTIVES: Rapid development in childhood and adolescence combined with lack of immunoassay standardization necessitates the establishment of age-, sex-, and assay-specific reference intervals for immunochemical markers. This study established reference intervals for 11 immunoassays on the new Siemens Healthineers Atellica® IM Analyzer in the healthy CALIPER cohort. METHODS: A total of 600 healthy participants (birth to 18 years) were recruited from the community, and serum samples were collected with informed consent. After sample analysis, age- and sex-specific differences were assessed, and outliers were removed. Reference intervals were established using the robust method (40-<120 participants) or nonparametric method (≥120 participants). RESULTS: Of the 11 immunoassays studied, nine required age partitioning (i.e., dehydroepiandrosterone-sulfate, estradiol, ferritin, folate, follicle-stimulating hormone, luteinizing hormone, progesterone, testosterone, vitamin B12), and seven required sex partitioning. Free thyroxine and thyroid-stimulating hormone demonstrated no significant age- and/or sex-specific differences. CONCLUSIONS: Overall, the age- and sex-specific trends observed closely mirrored those previously reported by CALIPER on other platforms as well as other internationally recognized studies. However, established lower and upper limits demonstrated some discrepancies between published values from healthy cohorts on alternate analytical systems, highlighting differences between manufacturers and the need for platform-specific reference intervals for informed pediatric clinical decision-making.

Pediatric Reference Intervals for Critical Point-of-Care Whole Blood Assays in the CALIPER Cohort of Healthy Children and Adolescents.

OBJECTIVES: Point-of-care testing (POCT) is being increasingly adopted to support clinical care. Data for critical care parameters in healthy children on POCT instruments are lacking. We established comprehensive reference standards for several whole blood parameters on the Radiometer ABL90 FLEX PLUS blood gas analyzer in the Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) cohort. METHODS: Approximately 300 healthy children and adolescents (age range, birth to <19 years; sex, boys and girls) were recruited with informed consent. Venous whole blood was collected (using heparinized syringes) and rapidly analyzed at the point of collection for pH, Pco2, Po2, carboxyhemoglobin, methemoglobin, lactate, and electrolytes on the ABL90 FLEX PLUS instrument. Reference intervals were established according to Clinical and Laboratory Standards Institute guidelines. RESULTS: Of the parameters assessed, 6 required age partitioning; none required sex partitioning. Reference value distributions were consistent across the pediatric age range, demonstrating higher variation in the early neonatal period. CONCLUSIONS: This study established reference standards for 10 critical care analytes in the CALIPER cohort for the first time. These data contribute to our understanding of normative pediatric values for venous electrolytes, metabolites, and blood gases on a modern POCT instrument, facilitating test interpretation in clinical settings that use these assays.

Pediatric reference interval verification for common biochemical assays on the Abbott Alinity system.

OBJECTIVES: The quality of clinical laboratory service depends on quality laboratory operations and accurate test result interpretation based on reference intervals (RIs). As new analytical systems continue to be developed and improved, previously established RIs must be verified. The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) has established comprehensive RIs for many biomarkers on several analytical systems. Here, published CALIPER RIs for 28 chemistry assays on the Abbott ARCHITECT were assessed for verification on the newer Alinity system. METHODS: An analytical validation was first completed to assess assay performance. CALIPER serum samples (100) were analyzed for 28 chemistry assays on the Alinity system. The percentage of results falling within published pediatric ARCHITECT reference and confidence limits was determined for each analyte. Based on Clinical and Laboratory Standards Institute (CLSI) guidelines, if ≥90% of test results fell within confidence limits of ARCHITECT assay RIs, they were considered verified. RESULTS: Of the 28 assays assessed, 26 met the criteria for verification. Reference values for calcium and magnesium did not meet the criteria for verification with 87% and 35% falling within previously established ARCHITECT confidence limits, respectively. However, both assays could be verified using pediatric RIs provided in the Abbott Alinity package insert. CONCLUSIONS: In this study, CALIPER ARCHITECT RIs were verified on the Alinity system for several chemistry assays. These data demonstrate excellent concordance for most assays between the Abbott ARCHITECT and Alinity systems and will assist in the implementation of the Alinity system in pediatric healthcare institutions.

Continuous reference intervals for 19 endocrine, fertility, and immunochemical markers in the CALIPER cohort of healthy children and adolescents.

BACKGROUND: Reference intervals are traditionally partitioned into discrete ranges by major covariates such as age and sex. However, discrete reference intervals often oversimplify the complex relationship between analyte concentration and age. Continuous reference intervals have been suggested to more accurately represent this complex relationship, particularly in pediatrics. The objective of this study was to establish continuous reference intervals for endocrine, fertility, and additional immunochemical parameters in the CALIPER cohort of healthy children and adolescents. METHODS: Continuous reference intervals from 1 to 18.5 years of age were established using retrospective CALIPER data collected from healthy Canadian children and adolescents. Continuous reference intervals (2.5th and 97.5th percentiles) were determined for 19 parameters by nonparametric quantile regression. Total and yearly flagging rates were calculated for the upper and lower continuous reference limits and compared to previously published partitioned reference limits. RESULTS: Continuous reference intervals were established for 19 endocrine, fertility, and additional immunochemical parameters, with 11 requiring sex-specific reference curves. Continuous reference intervals assessed both visually and by flagging rate analysis more accurately represented the relationship between analyte concentration and age, particularly for parameters with complex reference value patterns. CONCLUSION: This is the first comprehensive report to establish continuous reference intervals for several immunochemical parameters including endocrine and fertility markers in a healthy paediatric Canadian cohort. The ability of continuous reference intervals to provide a better estimate of age-related changes in reference values suggest their potential to improve paediatric laboratory test result interpretation and clinical decision-making.

Early language screening and intervention can be delivered successfully at scale: evidence from a cluster randomized controlled trial.

BACKGROUND: It is well established that oral language skills provide a critical foundation for formal education. This study evaluated the effectiveness of the Nuffield Early Language Intervention (NELI) programme in ameliorating language difficulties in the first year of school when delivered at scale. METHODS: We conducted a cluster randomized controlled trial (RCT) in 193 primary schools (containing 238 Reception classrooms). Schools were randomly allocated to either a 20-week oral language intervention or a business-as-usual control group. All classes (N = 5,879 children) in participating schools were screened by school staff using an automated App to assess children's oral language skills. Screening identified 1,173 children as eligible for language intervention: schools containing 571 of these children were allocated to the control group and 569 to the intervention group. RESULTS: Children receiving the NELI programme made significantly larger gains than the business-as-usual control group on a latent variable reflecting standardized measures of language ability (d = .26) and on the school-administered automated assessment of receptive and expressive language skills (d = .32). The effects of intervention did not vary as a function of home language background or gender. CONCLUSIONS: This study provides strong evidence for the effectiveness of a school-based language intervention programme (NELI) delivered at scale. These findings demonstrate that language difficulties can be identified by school-based testing and ameliorated by a TA delivered intervention; this has important implications for educational and social policy.