Personalized Metabolic Profile by Synergic Use of NMR and HRMS.

A new strategy that takes advantage of the synergism between NMR and UHPLC-HRMS yields accurate concentrations of a high number of compounds in biofluids to delineate a personalized metabolic profile (SYNHMET). Metabolite identification and quantification by this method result in a higher accuracy compared to the use of the two techniques separately, even in urine, one of the most challenging biofluids to characterize due to its complexity and variability. We quantified a total of 165 metabolites in the urine of healthy subjects, patients with chronic cystitis, and patients with bladder cancer, with a minimum number of missing values. This result was achieved without the use of analytical standards and calibration curves. A patient's personalized profile can be mapped out from the final dataset's concentrations by comparing them with known normal ranges. This detailed picture has potential applications in clinical practice to monitor a patient's health status and disease progression.

The Influence of Age and Sex on the Electrocardiogram.

The electrocardiogram (ECG) remains the most commonly used test in medical practice and as such requires to be interpreted with due care and attention to detail. The ECG changes rapidly from birth through childhood with age differences clearly related to increasing QRS voltages and a widening QRS complex. The only sex difference at this age is a slightly longer QRS duration in boys than girls.In adulthood, sex differences in QRS voltage are maximum in the under 40 age group and tend to minimise with advancing age. QRS duration is longer in males than in females, but little difference is made of this in diagnostic criteria. In a similar vein, ST amplitudes are higher in young males compared to young females with the difference diminishing as age increases. Corrected QT interval is longer in females than males.In summary, age and gender differences in the ECG are important and have been incorporated into a variety of criteria for ECG interpretation. Physicians should be aware of the main sex differences in the ECG.

Is Pulse Oximetry Useful for Screening Neonates for Critical Congenital Heart Disease at High Altitudes?

Now that pulse oximetry is used widely to screen for critical congenital heart disease, it is time to consider whether this screening method is applicable to those who live at high altitudes. Consideration of basic physical principles and reports from the literature indicate that not only is the 95 % cutoff point for arterial oxygen saturation incorrect at high altitudes, but the lower saturations are accompanied by greater variability and therefore there is the possibility of a greater percentage of false-positive screening tests at high altitudes. Because of ethnic differences in response to high altitudes, normative data will have to be collected separately in different countries and perhaps for different ethnic groups.

Normal ranges and variability of novel urinary renal biomarkers in Sprague-Dawley Rats: comparison of constitutive values between males and females and across assay platforms.

Differences were examined between male and female Sprague-Dawley rats in basal levels of a wide range of urinary biomarkers, including 7 recently qualified biomarkers. The data were generated from urine samples collected on 3 occasions from untreated rats included in a study of the effect of gentamicin nephrotoxicity on urinary renal biomarkers, reported in a companion article in this journal (Gautier et al. 2014). The performance of multiple assays (9 singleplex assays and 2 multiplex platforms from Rules Based Medicine [RBM] and Meso Scale Discovery [MSD]) was evaluated, and normal ranges and variability estimates were derived. While variability was generally greater on the RBM platform than other assays, the more striking difference in the results from different assays was in magnitude. Where differences were observed between assays for an individual biomarker, they were seen in both sexes and consistent across samples collected at different time points. Differences of up to 15-fold were observed for some biomarker values between assays indicating that results generated using different assays should not be compared. For 8 biomarkers, there was compelling evidence for a sex difference. Baseline values in males were significantly higher than in females for total protein, ß2-microglobulin, clusterin, cystatin-C, glutathione-S-transferase (GST-α), tissue inhibitor of metalloproteinases (TIMP-1), and vascular endothelial growth factor (VEGF); female values were significantly higher than that of males for albumin. The largest sex differences (male greater than female by 2- to 11-fold) were seen with ß2-microglobulin, GST-α, and TIMP-1. These data add substantially to the limited body of knowledge in this area and provide a useful framework for evaluation of the potential relevance of sex differences in the diagnostic performance of these biomarkers.

Normal Ranges of Global Left Ventricular Myocardial Work Indices in Adults: A Meta-Analysis.

BACKGROUND: Recent studies have demonstrated that left ventricular myocardial work (MW) is incremental in diagnosis and prognostication compared with left ventricular ejection fraction and myocardial strain. The authors performed a meta-analysis of normal ranges of noninvasive MW indices including global work index, global constructive work, global wasted work, and global work efficiency and determined confounders that may contribute to variance in reported values. METHODS: Four databases (PubMed, Scopus, Embase, and the Cochrane Library) were searched through January 2021 using the key terms "myocardial work," "global constructive work," "global wasted work," "global work index," and "global work efficiency." Studies were included if the articles reported LV MW using two-dimensional transthoracic echocardiography in healthy normal subjects, either in a control group or comprising the entire study cohort. The weighted mean was estimated by using the random-effect model with a 95% CI. Heterogeneity across included studies was assessed using the I2 test. Funnel plots and the Egger regression test were used to assess potential publication bias. RESULTS: The search yielded 476 articles. After abstract and full-text screening, we included 13 data sets with 1,665 patients for the meta-analysis. The reported normal mean values of global work index and global constructive work among the studies were 2,010 mm Hg% (95% CI, 1,907-2,113 mm Hg%) and 2,278 mm Hg% (95% CI, 2,186-2,369 mm Hg%), respectively. Mean global wasted work was 80 mm Hg% (95% CI, 73-87 mm Hg%), and mean global work efficiency was 96.0% (95% CI, 96%-96%). Furthermore, gender significantly contributed to variations in normal values of global work index, global wasted work, and global work efficiency. No evidence of significant publication bias was observed. CONCLUSIONS: In this meta-analysis, the authors provide echocardiographic reference ranges for noninvasive indices of MW. These normal values could serve as a reference for clinical and research use.

Urinary netrin-1 concentration in healthy full-term newborns.

INTRODUCTION: Monitoring of renal function in acute kidney injury in the pediatric population is complicated by the lack of age-related reference values of new biomarkers. Urinary netrin-1 is a new marker to demonstrate early kidney damage. Netrin-1 has a molecular mass of 72 kDa. It is therefore unlikely that it is filtered by the glomerulus under normal conditions. However, netrin-1 is highly induced after acute and chronic kidney injury and excreted in urine in humans. The aim of the study was to determine the normal concentrations of urinary netrin-1 in healthy full-term newborns. MATERIAL AND METHODS: The study included 88 healthy full-term neonates (51 boys and 37 girls) born from normal, uncomplicated pregnancies. The concentration of netrin-1 was determined in urine obtained on the first or second day of life with a commercially available ELISA kit. RESULTS: The urinary concentration of netrin-1 in newborns was independent of gender and time of urine collection. We found a negative correlation between both the urinary netrin-1 concentration and urinary netrin-1 concentration after normalization for urinary creatinine and the birth weight. CONCLUSIONS: This is the first study showing the urinary netrin-1 concentration in healthy full-term newborns. Future investigation is needed to confirm its potential role as a marker of kidney function in this age group.

Impact of age, sex and ethnicity on intra-cardiac flow components and left ventricular kinetic energy derived from 4D flow CMR.

BACKGROUND: Four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) allows quantification of left ventricular (LV) blood flow. We aimed to 1) establish reference ranges for 4D flow CMR-derived LV relative flow components and kinetic energy parameters indexed to end-diastolic volume (KEiEDV) among healthy Asian subjects, 2) assess effects of age and sex on these parameters, and 3) compare these parameters between Asian and Caucasian subjects. METHODS: 74 healthy Asian subjects underwent cine and 4D flow CMR. Relative flow components (direct flow, retained inflow, delayed ejection flow, residual volume) and multiple phasic KEiEDV (LV global, peak systolic, systolic, diastolic, peak E-wave, peak A-wave) were analyzed. Sex- and age-specific reference ranges were reported. RESULTS: Relative flow components and systolic phase KEiEDV did not vary with age. Women had higher retained inflow and peak E-wave KEiEDV, lower residual volume, peak systolic and systolic KEiEDV than men. Peak A-wave KEiEDV increased significantly (r = 0.474) whereas peak E-wave KEiEDV (r = -0.458) and E-wave/A-wave ratio (r = -0.528) decreased with age. A sub-population (n = 44) was compared with 44 sex- and age-matched Caucasian subjects: no significant group differences were observed for all 4D flow CMR parameters. CONCLUSION: Asian sex- and age-specific 4D flow CMR reference ranges were established. Sex differences in retained inflow, residual volume, peak systolic, systolic KEiEDV and peak E-wave KEiEDV were observed. Ageing influenced diastolic KEiEDV but not systolic phase KEiEDV or relative flow components. All studied parameters were similar between sex- and age-matched Asian and Caucasian subjects, implying generalizability of the ranges.

Turkish reference ranges for the left fetal modified myocardial performance index.

BACKGROUND: This study aimed to assess fetal cardiac left ventricular function in healthy pregnant women by calculating the modified myocardial performance index (Mod-MPI) and to construct reference ranges for the Turkish population. METHODS: One-hundred-two randomly selected healthy singleton pregnant women ranging between 25 and 39 gestational weeks were included in the study. Left fetal Mod-MPI was measured for each pregnant woman. Women with chronic systemic diseases or fetuses with chromosomal or structural abnormalities were excluded from the study. Mitral valve (MV) and aortic valve (AoV) clicks were used as landmarks to define the following time periods that were used to calculate the Mod-MPI: isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT), and ejection time (ET). RESULTS: The mean Mod-MPI was 0.42±0.10. The mean IRT, ICT, and ET were 43.5±10.2, 27.27±8.1, and 170.5±16.9, respectively. A significant correlation was found between Mod-MPI and gestational age, umbilical artery systolic/diastolic (UA S/D) ratio and the middle cerebral artery pulsatility index (MCA PI) values (r=0.199, p=0.047, r=-0.328, p=0.001, and r=-0.0349, p=0.001, respectively) Conclusions. The current study`s results will be a reference for future studies, especially studies investigating pathological conditions that impact fetal cardiac function.

Normal Ranges of Upper Extremity Length, Circumference, and Rate of Growth in the Pediatric Population.

Background: Upper extremity length and circumference abnormalities are present in a number of conditions in the pediatric population. In most cases, upper limb hypoplasia and hypertrophy are diagnosed when one limb appears substantially different from the other during physical examination. However, occasionally when this discrepancy exists, it can be difficult to determine which limb is the abnormal one. The purpose of this study was to establish normal values for upper extremity length, circumference, and rate of growth in children aged 0 to 17 years. Methods: In all, 377 participants had 4 measurements taken of each upper extremity: upper arm length, upper arm circumference, forearm length, and forearm circumference. Statistical analysis was performed to identify differences and rates of growth. Results: Mean values for arm and forearm length and circumference for each age, 0 to 17 years, were established. The determination of a child's expected arm length is dependent on his or her height, age, and sex, while the calculation of a child's expected forearm length depends on his or her weight, age, and sex. Male and female arms and forearms have similar growth rates of lengths and circumferences. No significant differences were found between right and left extremities for each of the 4 measurements taken. Conclusions: Contralateral limbs can be used for comparison of length and circumference of the arm and forearm in cases of unilateral upper extremity abnormality. The establishment of normal values for upper extremity length, circumference, and growth rate will be a useful diagnostic tool for upper extremity hypoplasia and hypertrophy.

Reference Intervals of Factor H and Factor H-Related Proteins in Healthy Children.

Complement is activated as part of the innate immune defense against invading pathogens. Also, it helps to remove apoptotic debris and immune complexes from the circulation. Impaired complement function due to aberrant plasma levels of complement proteins may be indicative for complement-mediated diseases or can be involved in susceptibility for infections. To determine whether plasma levels are abnormal, reference intervals (RIs) are used from adult healthy donors. Since many complement-mediated diseases have an onset during childhood, it is important to know whether these RIs can be extrapolated to children. RIs of Factor H (FH), the crucial fluid-phase regulator, and the FH-related proteins (FHRs), its homologous counterparts, are unknown in healthy children. While FH is measured to diagnose and monitor therapy of patients with atypical hemolytic uremic syndrome, recent studies also implicated increased plasma levels of FHRs in disease. Here, we investigated the levels of FH and FHRs in healthy children using recently developed specific ELISAs. We found that levels of FH, FHR-2, and FHR-3 were equal to those found in healthy adults. Levels of FHR-4A and FHR-5 were lower in children than in adults. However, only the FHR-5 levels associated with age. The RIs of these FH family proteins now serve to support the interpretation of plasma levels in prospective and retrospective studies that can be used for routine diagnostic and monitoring purposes including pediatric patient samples.

Evaluation of Normal Ranges of Wrist Radiologic Indexes in Mashhad Population.

Hand and wrist radiographic indexes such as radial inclination, ulnar variance, carpal height ratio, and radial tilt play an important role in the diagnosis and management of medical disorders, so they should be modified regarding the population and race difference. This study aims to compare the normal radiologic wrist indexes in Mashhad population with other existing databases and define some of the factors that may influence the normal radiographic indexes. A total of 100 healthy participants were enrolled in this prospective cross-sectional study. After performing PA and lateral wrist radiographs, all radiological indexes including the wrist height; 1st and 3rd metacarpal length; ulnar variance; radial tilt and radial inclination; radiolunate, capitolunate, and scapholunate angle; capitate and scaphoid length; lunate and wrist width; and lunate diameter were measured. Significant differences were found between the two genders in the 1st and 3rd metacarpal length (P<0.001 and P<0.001 respectively), wrist height (P<0.001), radial tilt (P=0.027), radiolunate angle (P=0.001), capitate and scaphoid length (P<0.001 and P<0.001 respectively), lunate and wrist width (P<0.001 and P<0.001 respectively), lunate length (P=0.003), and lunate diameter (P<0.001). A significant linear correlation was found between ulnar variance (P=0.003), scapholunate angle (P=0.016), and wrist ratio (P=0.011) with age. According to our findings, using population specific wrist and hand indexes is recommended to diagnose and follow up upper extremities conditions.

The normal ranges of cardiovascular parameters measured using the ultrasonic cardiac output monitor.

The ultrasonic cardiac output monitor (USCOM) is a noninvasive transcutaneous continuous wave Doppler method for assessing hemodynamics. There are no published reference ranges for normal values in adults (aged 18-60 years) for this device. This study aimed to (1) measure cardiovascular indices using USCOM in healthy adults aged 18-60 years; (2) combine these data with those for healthy children (aged 0-12), adolescents (aged 12-18), and the elderly (aged over 60) from our previously published studies in order to present normal ranges for all ages, and (3) establish normal ranges of USCOM-derived variables according to both weight and age. This was a population-based cross-sectional observational study of healthy Chinese subjects aged 0.5-89 years in Hong Kong. USCOM scans were performed on all subjects, to produce measurements including stroke volume, cardiac output, and systemic vascular resistance. Data from previously published studies (children, adolescents, and the elderly) were included. Normal ranges were defined as lying between the 2.5th and 97.5th percentiles. A total of 2218 subjects were studied (mean age = 16.4, range = 0.5-89; 52% male). From previous studies, 1197 children (aged 0-12, 55% male), 590 adolescents (aged 12-18, 49% male), and 77 elderly (aged 60-89, 55% male) were included. New data were collected from 354 adults aged 18-60 (47% male). Normal ranges are presented according to age and weight. We present comprehensive normal ranges for hemodynamic parameters obtained with USCOM in healthy subjects of all ages from infancy to the elderly.

Sex- and Site-Specific Normative Data Curves for HR-pQCT.

The purpose of this study was to develop age-, site-, and sex-specific centile curves for common high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite-element (FE) parameters for males and females older than 16 years. Participants (n = 866) from the Calgary cohort of the Canadian Multicentre Osteoporosis Study (CaMos) between the ages of 16 and 98 years were included in this study. Participants' nondominant radius and left tibia were scanned using HR-pQCT. Standard and automated segmentation methods were performed and FE analysis estimated apparent bone strength. Centile curves were generated for males and females at the tibia and radius using the generalized additive models for location, scale, and shape (GAMLSS) package in R. After GAMLSS analysis, age-, sex-, and site-specific centiles (10th, 25th, 50th, 75th, 90th) for total bone mineral density and trabecular number as well as failure load have been calculated. Clinicians and researchers can use these reference curves as a tool to assess bone health and changes in bone quality. © 2016 American Society for Bone and Mineral Research.