Validity and Reliability of the V-Cut Dribbling Test in Young Basketball Players.

PURPOSE: Change of direction while dribbling appears to be of interest for on-court performance in basketball. The study aim was to assess the validity and reliability of the V-cut dribbling test (VcutBk) in young basketball players. METHODS: Ninety-two young basketball players from 8 to 21 years old (74% male) were classified in relation to peak height velocity (PHV) offset. To examine validity and test-retest reliability, VcutBk was performed in 2 identical sessions separated by 1 week. Participants also performed the V-cut test and linear sprint test with and without dribbling to analyze correlations between tests in different somatic maturity stages. RESULTS: The relationships of the VcutBk with the other tests and skill-time-related deficits were interpreted from large (r > .51) to very large (r > .71). The comparisons between pre-PHV and post-PHV groups of basketball players showed significant and large effect in the VcutBk (d = 2.04; mean difference = 2.59; 95% CI, 1.86 to 3.32). Also, significant main effects when comparing PHV groups were reported in all skill-time-related deficits (P < .001, ηp2=.13-.28, moderate to large effect size). Test-retest reliability and signal-to-noise ratio analysis did not show substantial between-trials differences in VcutBk. Reliability scores showed high intraclass correlation coefficient (.95) and low coefficient of variation (0.23%). CONCLUSIONS: The VcutBk seems to be a valid and reliable test to assess change of direction while dribbling. VcutBk performance and skill-time-related deficits seem to be sensitive to somatic maturity. Basketball coaches should consider the VcutBk to assess young basketball players.

A simple method modification to increase separation of 2- and 3-hydroxyglutaric acid by GC-MS for clinical urine organic acids analysis.

Urine organic acids profiling by gas chromatography-mass spectrometry (GC-MS) is routinely performed in hospital biochemical genetics laboratories for the investigation of inborn errors of metabolism. In particular, accurate identification of urinary levels of 3-hydroxyglutaric acid (3-OHGA) is important for diagnosing glutaric aciduria type 1 (GA1), but can be challenging by routine GC-MS profiling analysis due to co-elution and spectral similarity with the isomer 2-hydroxyglutaric acid (2-OHGA). To improve analytical specificity, unique ions were selected and a simple second-tier reinjection method was developed to enhance the chromatographic separation of the 2- and 3-OHGA isomers and potential unknown interferences. Specimens flagging on the routine analysis were simply reinjected on the same GC column using a modified temperature gradient containing an isothermal hold. Correlation between the reinjection and initial methods was higher for 2-OHGA (R = 0.9612) compared to 3-OHGA (R = 0.7242). Mean differences between the reinjection and initial methods for 2-OHGA and 3-OHGA were -8.5% and -61.1% respectively. The large decrease in 3-OHGA concentration for many specimens using the reinjection method was primarily attributable to separation from unknown variable interference(s) that were falsely elevating 3-OHGA in the initial analysis despite the use of a more unique quantifier ion. Overall, the reinjection approach increased analytical specificity in evaluating for the presence of increased urinary 3-OHGA. This second-tier approach, using a GC isothermal hold, could easily be implemented or adapted by other clinical laboratories experiencing related diagnostic challenges.

Performance of Immunoglobulin G Serology on Finger Prick Capillary Dried Blood Spot Samples to Detect a SARS-CoV-2 Antibody Response.

We investigate the diagnostic accuracy and predictive value of finger prick capillary dried blood spot (DBS) samples tested by a quantitative multiplex anti-immunoglobulin G (IgG) assay to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies after infection or vaccination. This cross-sectional study involved participants (n = 6,841) from several serological surveys conducted in nonhospitalized children and adults throughout 2020 and 2021 in British Columbia (BC), Canada. Analysis used paired DBS and serum samples from a subset of participants (n = 642) prior to vaccination to establish signal thresholds and calculate diagnostic accuracy by logistic regression. Discrimination of the logistic regression model was assessed by receiver operator curve (ROC) analysis in an n = 2,000 bootstrap of the paired sample (n = 642). The model was cross-validated in a subset of vaccinated persons (n = 90). Unpaired DBS samples (n = 6,723) were used to evaluate anti-IgG signal distributions. In comparison to paired serum, DBS samples from an unvaccinated population possessed a sensitivity of 79% (95% confidence interval [95% CI]: 58 to 91%) and specificity of 97% (95% CI: 95 to 98%). ROC analysis found that DBS samples accurately classify SARS-CoV-2 seroconversion at an 88% percent rate (area under the curve [AUC] = 88% [95% CI: 80 to 95%]). In coronavirus disease 2019 (COVID-19) vaccine dose one or two recipients, the sensitivity of DBS testing increased to 97% (95% CI: 83 to 99%) and 100% (95% CI: 88 to 100%). Modeling found that DBS testing possesses a high positive predictive value (98% [95% CI: 97 to 98%]) in a population with 75% seroprevalence. We demonstrate that DBS testing should be considered to reliably detect SARS-CoV-2 seropositivity from natural infection or vaccination. IMPORTANCE Dried blood spot samples have comparable diagnostic accuracy to serum collected by venipuncture when tested by an electrochemiluminescent assay for antibodies and should be considered to reliably detect seropositivity following SARS-CoV-2 infection and/or vaccination.

Interference of ketone bodies on laboratory creatinine measurement in children with DKA: a call for change in testing practices.

BACKGROUND: The presence of ketone bodies (KBs) can interfere with creatinine (Cr) measurement in both enzymatic and Jaffe methods. Since a high proportion of children hospitalized for diabetic ketoacidosis (DKA) develop acute kidney injury (AKI), here we investigate whether KB interferences affect the accuracy of pediatric Cr measurement. METHODS: Residual patient plasma samples were pooled to make three Cr levels (~ 50, 100, and 250 µM). KBs (acetone, acetoacetate, and ß-hydroxybutyrate) were used to spike the pooled samples. All samples were measured for Cr by two enzymatic methods (E1 and E2), two Jaffe methods (J1 and J2), and LC-MS/MS. LC-MS/MS was considered the gold standard, and the % difference in Cr concentration was calculated for each method. RESULTS: E1 and E2 were unaffected by the presence of all three KBs. J1 and J2 were unaffected by the presence of ß-hydroxybutyrate. The presence of acetone resulted in dose-dependent positive interference in both Jaffe methods, whereas the presence of acetoacetate resulted in dose-dependent positive and negative interference in J1 and J2, respectively. CONCLUSIONS: Compared to the enzymatic methods, the Jaffe methods were much more susceptible to interference by acetone and acetoacetate, especially at lower Cr values which are commonly seen in pediatrics. Interpretation of changes in Cr concentration between different hospitals when transferring patients can become ambiguous and true kidney function unclear if different methods are used without awareness of method-specific biases. To improve DKA patient care, we recommend standardizing all of the Cr methods to an enzymatic method. A higher resolution version of the Graphical abstract is available as Supplementary information.

Analysis of 2-methylcitric acid, methylmalonic acid, and total homocysteine in dried blood spots by LC-MS/MS for application in the newborn screening laboratory: A dual derivatization approach.

Inborn errors of propionate, cobalamin and methionine metabolism are targets for Newborn Screening (NBS) in most programs world-wide, and are primarily screened by analyzing for propionyl carnitine (C3) and methionine in dried blood spot (DBS) cards using tandem mass spectrometry (MS/MS). Single-tier NBS approaches using C3 and methionine alone lack specificity, which can lead to an increased false-positive rate if conservative cut-offs are applied to minimize the risk of missing cases. Implementation of liquid chromatography tandem mass spectrometry (LC-MS/MS) second-tier testing for 2-methylcitric acid (MCA), methylmalonic acid (MMA), and homocysteine (HCY) from the same DBS card can improve disease screening performance by reducing the false-positive rate and eliminating the need for repeat specimen collection. However, DBS analysis of MCA, MMA, and HCY by LC-MS/MS is challenging due to limited specimen size and analyte characteristics leading to a combination of low MS/MS sensitivity and poor reverse-phase chromatographic retention. Sufficient MS response and analytical performance can be achieved for MCA by amidation using DAABD-AE and by butylation for MMA and HCY. Herein we describe the validation of a second-tier dual derivatization LC-MS/MS approach to detect elevated MCA, MMA, and HCY in DBS cards for NBS. Clinical utility was demonstrated by retrospective analysis of specimens, an interlaboratory method comparison, and assessment of external proficiency samples. Imprecision was <10.8% CV, with analyte recoveries between 90.2 and 109.4%. Workflows and analytical performance characteristics of this second-tier LC-MS/MS approach are amenable to implementation in the NBS laboratory.

Diagnostic yield from routine metabolic screening tests in evaluation of global developmental delay and intellectual disability.

Global developmental delay and intellectual disability (GDD/ID) affect 3% of the paediatric population. Although inborn errors of metabolism (IEM) are not a common cause of GDD/ID, early therapeutic intervention can improve neurodevelopmental manifestations. In 2012, a first-tier test panel, including specialized metabolic and routine chemistry tests, was piloted to community-based paediatricians in British Columbia with aims to achieve earlier diagnosis of treatable IEM. OBJECTIVE: The aim of this retrospective review was to evaluate the diagnostic yield from these first-tier tests in the 7 years before (2006 to 2012) and after (2013 to 2019) implementation at the community paediatrician level. RESULTS: Prior and postimplementation diagnostic yield of an IEM from first-tier metabolic testing was 9 out of 986 (0.91%) and 11 out of 4,345 children (0.25%), respectively. Disorders of creatine metabolism and organic acidurias were the most frequently established diagnoses in both time periods. No diagnoses were established through acylcarnitine copper/ceruloplasmin, lactate, or ammonia testing. Twenty out of 24 patients had specific neurological or other red flag signs in addition to GDD/ID. Four boys diagnosed with an x-linked creatine transporter defect (CTD) had speech-language delay as the most prominent finding. CONCLUSIONS: The expansion of first-tier metabolic testing to community-based paediatricians in BC did not yield an increase in IEM diagnoses. A modified first-tier test panel should be offered to patients with GDD/ID, neurologic, and/or red flag signs. Urine creatine testing in boys with speech-language delay warrants consideration to detect CTD.

Maternal vitamin B12 status in early pregnancy and its association with birth outcomes in Canadian mother-newborn Dyads.

Vitamin B12 (B12) is a co-enzyme essential for fetal growth and development. Lower maternal B12 status has been associated with preterm birth (<37 gestational weeks) and low birth weight (<2500 g), which are linked to morbidity and mortality across the lifespan. In Canada, 17-25 % of women in early pregnancy had a serum total B12 concentration <148 pmol/l and maternal total B12 concentration decreased throughout pregnancy. This study aimed to determine the association between maternal B12 status and birth outcomes in Canadian mother-newborn dyads. A secondary analysis of 709 mother-newborn dyads in British Columbia (BC), Canada, was conducted. Bio-banked first- (n 656) and second-trimester (n 709) maternal serum samples of apparently healthy South Asian (50 %) and European (50 %) women from the BC Prenatal Genetic Screening Program were quantified for B12 biomarkers (total B12, holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy)). Obstetric history and birth outcome data were obtained from the BC Perinatal Data Registry. All associations were determined using multiple linear regression. Maternal serum total B12, holoTC, MMA and tHcy had a mean weekly decrease of 3·64 pmol/l, 1·04 pmol/l, 1·44 nmol/l and 0·104 µmol/l, respectively (P < 0·001). Despite a total B12 concentration <148 pmol/l among 20-25 % of the women, maternal B12 biomarker concentrations were not associated with birth weight z-score, head circumference z-score and gestational age at birth (P > 0·05). Additional research in women at high risk of adverse birth outcomes and the association between maternal B12 status and functional, for example, cognitive, outcomes is needed.

Investigating oxythiamine levels in children undergoing kidney transplantation and the risk of immediate post-operative metabolic and hemodynamic decompensation.

BACKGROUND: Oxythiamine is a uremic toxin that acts as an antimetabolite to thiamine and has been associated with cases of Shoshin beriberi syndrome in adults. We sought to identify whether surgical stress and ischemia/reperfusion injury may precipitate functional thiamine deficiency in children peritransplant. METHODS: We retrospectively analyzed a cohort of pediatric kidney transplant recipients. Oxythiamine levels were measured in pre-transplant serum samples by mass spectrometry and tested for association with severity of lactic acidosis in the first 24 h post-transplant. Secondary outcomes included association with hyperglycemia and indicators of dialysis adequacy (DA). RESULTS: Forty-seven patients were included in the analysis. Median oxythiamine levels differed by modality, measuring 0.67 nM (IQR 0.31, 0.74), 0.34 nM (IQR 0.28, 0.56), and 0.25 nM (IQR 0.17, 0.38) for peritoneal dialysis (PD), hemodialysis (HD), and no dialysis, respectively (p = 0.05). Oxythiamine was associated with 24-h lactate levels (r = 0.38, p = 0.02) and negatively associated with DA (r = - 0.44, p = 0.02). Median oxythiamine levels were higher in patients with poor DA (0.92 nM (IQR 0.51, 1.01) vs. 0.40 nM (IQR 0.24, 0.51), p < 0.01). Sensitivity analysis showed absence of residual association of oxythiamine with 24-h lactate or dialysis modality, but remained significant for DA (p = 0.03). One patient manifested Shoshin beriberi syndrome (oxythiamine 2.03 nM). CONCLUSIONS: Oxythiamine levels are associated with DA at transplant. Patients on PD with no residual kidney function and low DA manifest the highest oxythiamine levels and may be at an increased risk for developing acute Shoshin beriberi syndrome in the early post-transplant period.

Performance of a Three-Tier (IRT-DNA-IRT) Cystic Fibrosis Screening Algorithm in British Columbia.

Newborn screening for Cystic Fibrosis has been implemented in most programs worldwide, but the approach used varies, including combinations of immunoreactive trypsinogen (IRT) and CFTR mutation analysis on one or more specimens. The British Columbia (BC) newborn screening program tests ~45,000 infants per year in BC and the Yukon Territory, covering almost 1.5 million km2 in western Canada. CF screening was initiated using an IRT-DNA-IRT approach with a second bloodspot card at 21 days of age for all CFTR mutation heterozygotes and any non-carriers in the top 0.1% for IRT. This second IRT was implemented to avoid sweat testing of infants without persistent hypertrypsinemia, reducing the burden of travel for families. Over nine years (2010-2018), 401,977 infants were screened and CF was confirmed in 76, and a further 28 were deemed CF screen positive inconclusive diagnosis (CFSPID). Day 21 IRT was normal in 880 CFTR mutation carriers who were quoted a very low CF risk and offered optional sweat testing. Only 13% of families opted for sweat testing and a total of 1036 sweat tests were avoided. There were six false negative CF cases (and three CFSPID) due to a low initial IRT or no CFTR mutations. Although one CFSPID case had a normal repeat IRT result, the addition of the day 21 IRT did not contribute to any CF false negatives.

A Pedagogical Approach to Integrative Neuromuscular Training to Improve Motor Competence in Children: A Randomized Controlled Trail.

Font-Lladó, R, López-Ros, V, Montalvo, AM, Sinclair, G, Prats Puig, A, and Fort-Vanmeerhaeghe, A. A pedagogical approach to integrative neuromuscular training to improve motor competence in children: a RCT. J Strength Cond Res 34(11): 3078-3085, 2020-To assess the effectiveness of a pedagogical approach to an integrative neuromuscular training (INT) program as a warm-up in physical education (PE) lessons in healthy children: (a) to improve the level of motor competence (MC) and (b) to master fundamental motor skills (FMS) patterns, considering the baseline MC level and the time spent when performing different motor tasks. One hundred ninety students (7.43 ± 0.32 years; 52% girls) were included in this randomized controlled trail and grouped up according to MC basal levels (L1-L4). Motor competence and FMS patterns (CAMSA protocol) were assessed before and after the intervention in a group-based INT warm-up (n = 97) and a group-based conventional warm-up (n = 93). The INT program improved MC (p < 0.001; d = 0.71) and FMS (p < 0.001, d = 0.52). The independent predictors of MC change were: baseline MC level (ß = -196; p < 0.012), time spent to perform the task (ß = -0.235 p < 0.003), and participation in the INT program (ß = 0.201; p < 0.005), explaining 71% of its variability. The INT warm-up shows correlations between improvements in MC in relation to time reduction (L1 p = 0.016, d, L2 p = 0.001, and L4 = 0.001) and FMS patterns (L1 p < 0.001, L2 p < 0.003, L3 p < 0.005, and L4 < 0.001) Moreover, only L3, it showed correlation between changes in time and FMS mastery (p = 0.001). Our results showed that a pedagogical approach to an INT program developed as a warm-up in primary school PE lessons can improve MC and FMS patterns in all subjects, independent of the initial MC level. More interestingly, only in L3, the improvement in MC can be explained by the balance in time required to perform the task and the level of improvement in FMS patterns.

Clinical Impact and Cost Efficacy of Newborn Screening for Congenital Adrenal Hyperplasia.

OBJECTIVES: To evaluate the clinical impact of a congenital adrenal hyperplasia (CAH) newborn screening program and incremental costs relative to benefits in screened vs unscreened infants. We hypothesized that screening would lead to clinical benefits and would be cost effective. STUDY DESIGN: This was an ambispective cohort study at British Columbia Children's Hospital, including infants diagnosed with CAH from 1988-2008 and 2010-2018. Data were collected retrospectively (unscreened cohort) and prospectively (screened cohort). Outcome measures included hospitalization, medical transport, and resuscitation requirements. The economic analysis was performed using a public payer perspective. RESULTS: Forty unscreened and 17 screened infants were diagnosed with CAH (47% vs 53% male). Median days to positive screen was 6 and age at diagnosis was 5 days (range, 0-30 days) and 6 days (range, 0-13 days) in unscreened and screened populations, respectively. In unscreened newborns, 55% required transport to a tertiary care hospital, 85% required hospitalization, and 35% required a fluid bolus compared with 29%, 29%, and 12% in screened infants, respectively. The cost of care was $33 770 per case in unscreened vs $17 726 in screened newborns. In the screened cohort, the incremental cost-effectiveness ratio was $290 in the best case analysis and $4786 in the base case analysis, per hospital day avoided. CONCLUSIONS: Compared with unscreened newborns, those screened for CAH were less likely to require medical transport and had shorter hospital stays. Screening led to a decrease in hospitalization costs. Although screening did not result in cost savings, it was assessed to be cost effective considering the clinical benefits and incremental cost-effectiveness ratio.

Serum Betaine and Dimethylglycine Are Higher in South Asian Compared with European Pregnant Women in Canada, with Betaine and Total Homocysteine Inversely Associated in Early and Midpregnancy, Independent of Ethnicity.

BACKGROUND: As a methyl donor required in the folate-vitamin B-12 independent remethylation of total homocysteine (tHcy) to methionine, betaine is critical for fetal development. Pregnant South Asian women living in Canada had a higher reported prevalence of low vitamin B-12 status compared with Europeans; betaine concentrations in this population are unknown. OBJECTIVES: We aimed to compare serum betaine concentrations between South Asian and European pregnant women, and to determine the relation between betaine and tHcy concentrations in early pregnancy. METHODS: A retrospective cohort study was conducted using biobanked serum samples of 723 apparently healthy pregnant women of South Asian (50%) and European ethnicity residing in British Columbia, Canada. Betaine, dimethylglycine (DMG), tHcy, and related metabolites were quantified in samples collected in the first (8-13 weeks of gestation) and second (14-20 weeks of gestation) trimesters. The relation between betaine and tHcy concentrations was assessed using a generalized regression model adjusted for weeks of gestation, ethnicity, prepregnancy BMI, maternal age, neonatal sex, parity, total vitamin B-12, folate, pyridoxal 5'-phosphate, and methionine concentrations. RESULTS: Median serum concentrations of betaine and its metabolite DMG were higher in South Asian women in the first (19.8 [IQR: 16.3-25.0] and 1.55 [IQR: 1.30-1.96] $\mu {\rm mol/L} $, respectively) and second trimesters (16.1 [IQR: 12.9-19.8] and 1.42 [IQR: 1.14-1.81] $\mu {\rm mol/L} $, respectively) compared with European women (17.6 [IQR: 13.7-22.6] and 1.38 [IQR: 1.12-1.77] $\mu {\rm mol/L} $, respectively) and (12.9 [IQR: 10.6-16.7] and 1.19 [IQR: 0.97-1.52] $\mu {\rm mol/L} $, respectively; all P values < 0.0001). Betaine was inversely associated with tHcy concentration (ß = -0.0208; 95% CI: -0.0341, -0.00742; P = 0.002). Additionally, total vitamin B-12 was associated with tHcy concentration (ß = -0.0312; 95% CI: -0.0401, -0.0224), after adjusting for confounding factors. CONCLUSIONS: Pregnant South Asian women residing in Canada had higher betaine and DMG concentrations, compared with women of European ethnicity, while betaine and total vitamin B-12 predicted tHcy independent of ethnicity. Our results emphasize the role of betaine, as methyl donor, in the remethylation of tHcy in a folate-replete population.

Acute Shoshin beriberi syndrome immediately post-kidney transplant with rapid recovery after thiamine administration.

Pediatric kidney transplant surgery is usually well tolerated, despite suboptimal physical conditioning that may result from uremia and nutritional deficiencies that accompany end-stage kidney failure. Nutritional supplementation is used to overcome such deficiencies, especially for children needing dialysis. Thiamine, a water-soluble vitamin also known as vitamin B1, is a critical cofactor in energy metabolism and may be competitively inhibited by the antimetabolite oxythiamine, a uremic toxin that accumulates in kidney failure. We report a case of a thiamine deficiency syndrome leading to overwhelming cardiac dysfunction, metabolic instability, and hemodynamic compromise, after otherwise uneventful kidney transplant surgery. Prior to transplant, this 14-year-old boy was treated with peritoneal dialysis and received thiamine supplementation. Post-transplant, the patient first developed hyperglycemia, then lactic acidosis, and subsequently hemodynamic instability despite escalating treatment with volume resuscitation and inotropic medication. He made a rapid and complete recovery after administration of IV thiamine. This is the first reported case of Shoshin beriberi syndrome in a pediatric kidney transplant recipient. Inadequate dialysis may have been a key factor, with toxin accumulation and thiamine transporter downregulation contributing to his status. Functional thiamine deficiency should be considered as a potential treatable cause of early post-transplant hemodynamic instability.

Reference intervals for serum total vitamin B12 and holotranscobalamin concentrations and their change points with methylmalonic acid concentration to assess vitamin B12 status during early and mid-pregnancy.

Background Maternal vitamin B12 (B-12) adequacy is important for maternal health and optimal fetal growth. However, pregnancy-specific cut-offs for B-12 biomarkers are lacking. Methods Reference intervals for serum total B-12, holotranscobalamin (holoTC) and methylmalonic acid (MMA) concentrations were calculated following CLSI EP28-A3c guidelines in 723 pregnant women of European (50%) and South Asian (50%) ethnicity, residing in British Columbia, Canada, at median (range) 11.4 (8.3-13.9) and 16.1 (14.9-20.9) weeks of gestation. Change point analyses described relationships between log serum MMA concentration with serum total B-12 and holoTC concentrations, assuming linear-linear relationships. Results The central 95% reference interval limits indicated that serum total B-12 <89.9 and <84.0 pmol/L, holoTC <29.5 and <26.0 pmol/L and MMA >371 and >374 nmol/L, in the first and second trimesters, respectively, may indicate B-12 deficiency in pregnant women. The lower limits of total B-12 and holoTC and the upper limits of MMA significantly differed by ethnicity in both trimesters. According to the change point analysis, total B-12 <186 and <180 pmol/L and holoTC <62.2 and <67.5 pmol/L in the first and second trimesters, respectively, suggested an increased probability of impaired intracellular B-12 status, with no difference between ethnicities. Conclusions We present novel reference limits and change points for B-12 biomarkers, which may be employed to identify possible B-12 deficiency in women during early and mid-pregnancy. Future research is needed to validate these cut-offs and determine the predictors and functional outcomes associated with impaired B-12 status in ethnically diverse populations.

The p.P479L variant in CPT1A is associated with infectious disease in a BC First Nation.

BACKGROUND: The hepatic carnitine palmitoyltransferase I (CPT1A) p.P479L variant is common in Aboriginal populations across coastal British Columbia, Alaska, the Canadian North, and Greenland. While the high frequency of this variant suggests positive selection, other studies have shown an association with sudden unexpected death in infancy and infection. We utilized administrative health data to evaluate hospitalizations for a single year cohort of children of First Nations descent genotyped for the variant and, matched for location of birth. Seven years of data were reviewed for 150 children split evenly between CPT1A genotypes (homozyous, heterozygous, and noncarrier of the p.P479L variant). RESULTS: Children homozygous for the p.P479L allele had a higher rate of hospital admissions at 2.6 per individual as compared to noncarriers at 0.86. Heterozygous children also showed a significant increase at 1.9 per person. Length of stay per admission was increased for both p.P479L homozygotes and heterozygotes. The odds ratio (OR) for at least one hospitalization for any reason was increased for p.P479L homozygotes relative to noncarriers (OR=10.2, confidence interval [CI] 3.5 to 30.0) as were admissions for dental caries (OR=3.4, CI 1.5 to 7.8), acute lower respiratory tract infections (OR=6.0, CI 1.6 to 22.4), and otitis media (OR=13.5, CI 1.7 to 109.4). CONCLUSIONS: The CPT1A p.P479L variant is associated with an increased rate of hospitalization for those homozygous, primarily for infectious disease causes. Heterozygotes also showed a small but significant increase in hospitalization rates suggesting some dosage effect. Functional studies will be required to identify the underlying pathological mechanism.

Atypical cerebral palsy: genomics analysis enables precision medicine.

PURPOSE: The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP). METHODS: Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy. Previous assessment by a neurologist and/or clinical geneticist, including biochemical testing, neuroimaging, and chromosomal microarray, did not yield an etiologic diagnosis. RESULTS: A precise molecular diagnosis was established in 65% of the 50 patients. We also identified candidate disease genes without a current OMIM disease designation. Targeted intervention was enabled in eight families (~15%). CONCLUSION: NGS enabled a molecular diagnosis in ACP cases, ending the diagnostic odyssey, improving genetic counseling and personalized management, all in all enhancing precision medicine practices.

Pyruvate Carboxylase Deficiency Type C: A Rare Cause of Acute Transient Flaccid Paralysis with Ketoacidosis.

Pyruvate carboxylase (PC) is a biotin-containing enzyme that is responsible for the adenosine triphosphate-dependent carboxylation of pyruvate to oxaloacetate, a key intermediate in the tricarboxylic acid cycle. PC deficiency (OMIM 266150) is a rare autosomal recessive metabolic disease, causing elevation of pyruvate, lactate, and alanine. Three types of PC deficiency have been described in the literature; A, B, and C. Type A PC deficiency, also called infantile or North American type, is characterized by infantile onset acidosis, failure to thrive, and developmental delay. The second subtype or type B, the neonatal or French form, presents usually in the neonatal period, mostly in the first 72 hours of life with severe lactic acidosis, truncal hypotonia, and seizures. The third type is called type C, is extremely rare with few cases published in the literature. In this case report, we present an 11-month-old girl who presented with acute flaccid paralysis, lethargy, and constipation with elevated ketones and lactate. She was confirmed genetically and biochemically to have PC deficiency type C. The patient's unusual presentation expands the clinical phenotype of this extremely rare disease.

Pregnant women of South Asian ethnicity in Canada have substantially lower vitamin B12 status compared with pregnant women of European ethnicity.

Maternal vitamin B12 (B12) status has been inversely associated with adverse pregnancy outcomes and positively with fetal growth and infant development. South Asians, Canada's largest ethnic minority, are prone to B12 deficiency. Yet, data are lacking on B12 status in South Asian pregnant women in North America. We sought to determine B12 status, using multiple biomarkers, in 1st and 2nd trimester pregnant women of South Asian and, for comparison, European ethnicity living in Vancouver, Canada. In this retrospective cohort study, total B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), and total homocysteine concentrations were quantified in two routinely collected (mean gestational week: 11·5 (range 8·3-13·9) and 16·5 (range 14·9-20·9)), banked serum samples of 748 healthy pregnant South Asian (n 371) and European (n 377) women. South Asian pregnant women had significantly lower B12 status than European pregnant women at both time points, as indicated by lower serum total B12 and holoTC concentrations, and higher MMA concentrations (all P≤0·001). The largest difference, which was substantial (Cohen's d≥0·5), was observed in mean serum total B12 concentrations (1st trimester: 189 (95 % CI 180, 199) v. 246 (95 % CI 236, 257) pmol/l; 2nd trimester: 176 (95 % CI 168, 185) v. 226 (95 % CI 216, 236) pmol/l). Further, South Asian ethnicity was a significant negative predictor of B12 status during pregnancy. South Asian women living in Vancouver have substantially lower B12 status during early pregnancy. Future research identifying predictors and health consequences of this observed difference is needed to allow for targeted interventions.