Healthy Reference Population Research Articles

Levels of high-sensitive troponin T and mid-regional pro-adrenomedullin after COVID-19 vaccination in vulnerable groups: monitoring cardiovascular safety of COVID-19 vaccination.

COVID-19 vaccines are well tolerated and effective but may have adverse effects on the cardiovascular system. Vaccine-associated myocardial injury was analysed by measuring high-sensitive troponin T (hsTnT); mid-regional pro-adrenomedullin (MR-proADM) levels were evaluated to assess endothelial dysfunction. This was a prospective study with a vulnerable population of healthcare workers (HCWs) and elderly patients (>70 years) who were vaccinated with either one dose of ChAdOx1 nCov-19 adenoviral vector vaccine (AZ) followed by one dose of the BNT162b2 messenger RNA vaccine (BNT), or with two doses of BNT (12th of January - 30th of November 2021). HsTnT and MR-proADM were measured in blood samples at three visits (V1: 1st immediately before vaccination; V2, 3: 3-4 weeks after 1st and 2nd vaccination). HsTnT of HCWs was compared to a healthy reference population. N = 162 volunteers were included (V1 = 161; V2, V3 = 162 each). N = 74 (45.7%) received AZ/BNT and n = 88 (54.3%) received BNT/BNT [elderly: n = 20 (12.3%), HCWs: n = 68 (42.0%)]. Median hsTnT levels were 4 ng/L, 5 ng/L and 4 ng/L (V1-V3) for AZ/BNT and at 5 ng/L, 6 ng/L and 6 ng/L (V1-V3) for BNT/BNT. Compared to the reference population (n = 300), hsTnT was significantly higher at all visits for both vaccination groups (p < 0.01), without differences between the AZ/BNT and BNT/BNT cohort. Median MR-proADM values were 0.43 nmol/L, 0.45 nmol/L, 0.44 nmol/L (V1-V3) in the AZ/BNT cohort and 0.49 nmol/L, 0.44 nmol/L, 0.47 nmol/L for BNT/BNT, respectively. Change of median hsTnT and MR-proADM between visits did not show significant increases. One HCW experienced a permanent and three a transient hsTnT increase ≥14 ng/L. No overall subtle, persistent cardiovascular involvement was observed after the 2nd COVID-19 vaccination. Elevated cardiovascular biomarkers in clinically asymptomatic individuals need further investigations.

A-126 The Role of Lysozyme and Other Inflammatory Markers in Understanding GI Microbiome Changes

Abstract Background The role of GI microbiome in gut health, intestinal permeability, and the development of inflammation has been well-established however, few clinical studies assess microbiome (i.e. PCR) and biochemical markers from the same stool collection. Doctor’s Data Inc. (DDI) has been performing a GI microbiome test in conjunction with other stool biochemical markers for the past 3 years, with over 7000 patient samples analyzed. The aim of this study was to analyze GA-map® Probe results for possible correlations with elevated values for fecal calprotectin, lactoferrin, and lysozyme. Methods Microbiome characterization The microbiome analysis test used in this study identifies 48 targeted analytes across six phyla using the GA-map® Dysbiosis test (Genetic Analysis AS, Oslo). The test algorithm has been trained and validated using 48 bacterial markers signal intensity obtained from 668 adults, including healthy subjects, patients with IBS and IBD. GA-map® Dysbiosis Analyzer software calculates the degree of dysbiosis (DI) of a given sample, assigning a DI ranging from 1 to 5. DI greater than 2 indicates that the microbiota is deviant from a healthy reference population (“dysbiotic”), while a score of 2 or lower is reported as “normobiotic”. Biochemical marker characterization Each stool sample was analyzed for a suite of biochemical markers - in particular calprotectin, lactoferrin and lysozyme - with the concentration determined using commercially available ELISA kits (ALPCO, Techlab). Results Using clinical cut-offs of 100.0 ug/g (calprotectin) and 7.3 ug/g (lactoferrin) the patient data was sorted into cohorts indicating disease state of “Normal”, “Intermediate” and “IBD Likely”, and further differentiated using the lysozyme result. The biochemical marker results were correlated against DI score for each stool sample (Figure 1). Conclusions DI score increases as biochemical inflammatory markers increase, with lysozyme as the key differentiating factor between patient cohorts.

Long-Term Results and Quality of Life after Surgery for Acute Aortic Dissection Type A: Contemporary Single-Centre Experience.

Background: Aortic dissection is still afflicted with significant morbidity and mortality. This research seeks to assess long-term outcomes and quality of life after emergency surgery for acute aortic dissection type A. Methods: A total of 413 patients were analysed, who had been operated upon between 2000 and 2016 at our centre. We compared our results of the early (2000-2007) versus late (2008-2016) period with regards to 30-day and follow-up mortality and need for reoperation, including risk factor analysis. Quality of life was assessed via the SF-36 survey. Results: Calculated perioperative risk by EuroSCORE increased significantly from early, 24.9%, to late, 38.0%, p < 0.001. Thirty-day rates of mortality decreased significantly from 26.7% to 17.4%, p = 0.03. Survival at 1-, 5-, and 10-years was 92.3% vs. 91.8% (p = 0.91), 75.2% vs. 81.0% (p = 0.29), and 53.4% vs. 69.7% (p = 0.04). Freedom from reoperation was comparable between groups at follow-up: 74.0% vs. 85.7%, p = 0.28. Quality of life was impaired. Conclusions: Despite more complex severity of disease and operative procedures, the results of surgery for type A aortic dissection improved significantly over time at 30-day and 10-year follow-up. Quality of life was significantly impaired compared to a healthy reference population.

Sex-Related Differences in Life Expectancy Compared to General Population after Surgery for Ascending Aortic Aneurysm.

Background/Objectives: Understanding sex-based differences in cardiovascular outcomes is paramount to improving clinical outcomes. Surgery is an aggressive but effective therapy for ascending aortic aneurysm. We sought to determine if being a woman is a risk factor for long-term mortality after this surgery. We compared their life expectancy with a general population of the same age, sex, year, and region. Methods: We compared men and women undergoing AAA surgery at our institution from 2000 to 2019. After balancing the population with propensity score (PS) matching, we compared long-term mortality control with a Cox regression. We determined the RS using the Ederer II method and compared it to a healthy reference population of the same age, sex, and region. Results: From 2000 to 2019, 232 women and 506 men underwent ascending aortic aneurysm surgery. After a mean follow-up of 51.5 ± 34.5 months, sex was not an independent risk factor for long-term mortality in the multivariable analysis [HR: 0.68 (95% CI 0.43-1.07, p = 0.23)]. Matching by baseline characteristics, 196 pairs were analyzed with no differences regarding mortality in the Cox regression [HR: 1.11 (95% CI 0.65-1.9, p = 0.23)]. Men and women who survived the postoperative period presented a relative survival of 100.3% (95% CI 97.4-101%) and 100.3% (95% CI 98.9-101.1%), respectively, similar to the reference population without the disease. Conclusions: For patients undergoing AAA surgery, sex was not an independent predictor of mortality. Men and women who survived the postoperative period presented a similar life expectancy to that of the reference population (people free from the disease of the same age, sex, year, and region).

DANSPOT: A Multicenter Stepped-Wedge Cluster-Randomized Trial of the Reclassification of Acute Myocardial Infarction: Rationale and Study Design.

Cardiac troponins are the preferred biomarkers for the diagnosis of acute myocardial infarction. Although sex-specific 99th percentile thresholds of troponins are recommended in international guidelines, the clinical effect of their use is poorly investigated. The DANSPOT Study (The Danish Study of Sex- and Population-Specific 99th percentile upper reference limits of Troponin) aims to evaluate the clinical effect of a prospective implementation of population- and sex-specific diagnostic thresholds of troponins into clinical practice. This study is a nationwide, multicenter, stepped-wedge cluster-randomized trial of the implementation of population- and sex-specific thresholds of troponins in 22 of 23 clinical centers in Denmark. We established sex-specific thresholds for 5 different troponin assays based on troponin levels in a healthy Danish reference population. Centers will sequentially cross over from current uniform manufacturer-derived thresholds to the new population- and sex-specific thresholds. The primary cohort is defined as patients with symptoms suggestive of acute coronary syndrome having at least 1 troponin measurement performed within 24 hours of arrival with a peak troponin value between the current uniform threshold and the new sex-specific female and male thresholds. The study will compare the occurrence of the primary outcome, defined as a composite of nonfatal myocardial infarction, unplanned revascularization, and all-cause mortality within 1 year, separately for men and women before and after the implementation of the new sex-specific thresholds. The DANSPOT Study is expected to show the clinical effects on diagnostics, treatment, and clinical outcomes in patients with myocardial infarction of implementing sex-specific diagnostic thresholds for troponin based on a national Danish reference population. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05336435.

Reference Intervals (RIs) in veterinary medicine

Reference Intervals (RIs) are necessary in veterinary clinical pathology to provide a data base in order to compare results obtained from healthy versus diseased animals. Data are obtained from laboratory tests and, depending on whether they have a Gaussian or non-Gaussian distribution, are processed through statistical tests to define the RIs. This process begins with a healthy reference population made up of individuals who have been initially chosen based on inclusion or exclusion criteria. It is frequently challenging to have a large number of healthy individuals on which to establish de novo RIs, especially in wild and exotic animals. However, the use of reference intervals in daily clinical practice remains a fundamental instrument for therapeutic and diagnostic decisions, but it must always be accompanied by clinical findings that can confirm the hypothesis.

Using reference equations to standardise incremental shuttle walk test performance in children and young people with chronic conditions and facilitate the evaluation of exercise capacity and disease severity

AimsThe aim was to evaluate whether standardised exercise performance during the incremental shuttle walk test (ISWT) can be used to assess disease severity in children and young people (CYP) with...

Longitudinal impact of intracerebral low-grade glioma disease on health-related quality of life.

The aim of this study was to assess health-related quality of life (HRQOL) before and after treatment for intracerebral low-grade glioma. Patients with low-grade glioma who underwent surgical tumor removal between 2012 and 2018 were eligible for this study. All individuals and their closest relatives received thorough preoperative (<seven days before surgery) and posttreatment (12 months after surgery) neuropsychological testing investigating quality of life. The assessment consisted of the Aachen Life Quality Inventory (ALQI) and the Short Form 36 (SF36) questionnaire. Calculated SF36 values were compared with reference values from population-based studies. A set of clinical features were investigated for their association with longitudinal HRQOL deterioration. A total of 25 patients were referred for further analysis, after adjustment to the 2021 WHO classification for central nervous system tumors. Compared to the values of a healthy reference population, the patients expressed significant limitations in several SF36 items, both before and after treatment. Under treatment, there were no significant changes in the SF36 items, but the ALQI questionnaire indicated decreasing HRQOL over time. Data derived from relatives revealed a high degree of concordance with the rating results of the patients. Univariate analysis identified neurological deterioration and ongoing epileptic seizures as predictors for unfavorable HRQOL after one year. Low-grade glioma disease has a significant impact on HRQOL and treatment might contribute to further deterioration. New-onset neurological deficits and ongoing epileptic seizures are predictors of limitations in quality of life. Since the results are based on a small cohort with limited follow-up time, the generalizability of these statements is limited and further studies are required.

Haematologic and plasma biochemical reference intervals for flatback turtles Natator depressus

Blood reference intervals (RIs) provide an indication of systemic health and are central to any baseline health survey. RIs are available for all sea turtle species, except for the flatback turtle Natator depressus. We developed the first nesting and foraging flatback turtle RIs from a healthy reference population of 211 individuals. We found flatback turtle RIs were generally similar to other published sea turtle RIs. For flatback turtles, we detected significant differences in blood reference values (RVs) by life stage (nesting vs. foraging), sex, and location, as well as by measurement technique (laboratory vs. field). Clinically significant differences justified the establishment of separate RIs for nesting and foraging flatback turtles and for laboratory and field techniques. Clinical application of these blood RIs for individuals in rehabilitation includes disease diagnosis, health monitoring, and the development of prognostic indicators. As sea turtles are regarded as sentinels of environmental health, flatback turtle baseline health data will also be useful for population health monitoring and as a reference for future studies where changes in RIs may indicate an environment in decline.

Use of Race and Ethnicity in Sickle Cell Disease Research

Introduction Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia, devastating ischemic pain crises and chronic organ damage, resulting in shortened lifespan. Ethnicity and race are often mentioned in SCD research. Possibly, since SCD is particularly prevalent amongst people who originate from sub-Saharan Africa. In research studies, ethno racial categories (ERCs) are frequently considered confounding variables. However, these ERCs are often large aggregate categories and include individuals with a diversity in phenotype, exposures and genetic make-up. Recent journal submission guidelines urge researchers, when applicable, to declare the relevance of the use of ERCs to the study as well as the modality through which an ERC is determined (e.g. self-identification, country of birth, visual identification by the observer). Providing such detailed information is important because true confounders with a specific feature might distort study results. However, when operationalizing ERCs in SCD research, there exists a risk of reification of already marginalized populations as both a social and a biological group. Therefore, contextualization is essential when deciding to use ERCs in SCD research. This study aims to provide an overview of how ethnicity and race are applied in SCD research. Methods We systematically searched the literature to explore the current practice of ERCs in SCD research across world regions. Embase and Medline were systematically searched in November 2022 for all published articles on SCD published from 2011 onwards. Studies were considered eligible when cases defined as individuals with SCD and controls individuals without SCD. A total of 1,105 articles in SCD research were included. Of these articles, 1,085 were domestic studies and 20 international studies. Statistical tests and models implemented in R included chi-square tests and univariate linear regression. Results In 27% (298/1,085) of all studies, ERC confounder adjustment occurred. This methodological practice was dependent on geographical region the research subjects were sourced from (p&amp;lt;0.05), as made visible in Figure 1. In 175/302 (57%) of studies with a North American study population ERC confounder adjustment took place, as well as in 45% [58/129]) of the studies reporting on a European study population. In contrast, in 6% (14/239) of sub-Saharan African study populations, ERC confounder adjustment was performed (Table 1). Of the twenty international studies, six operationalized ERCs as confounders. In five publications, the control group was sourced from the same country as the SCD cases. One study used a healthy Congolese reference population as a control cohort whilst the SCD patients were from France. ERC confounder adjustment also varied with the biomedical discipline in which the article was published. Compared to Hematological journals, articles published in journals with categories “Medicine, General &amp; Internal medicine” (OR=0.30, 95% CI -1.76 - -0.67, p&amp;lt;0.0001), were less likely to adjust for ERCs as confounders whereas articles in Ophthalmological journals (OR= 3.36, 95% CI 0.27 - 2.23, p=0.01) were more likely to do so. Of the studies that used ERC confounder adjustment, 80% (239/298) did not explain why this was relevant. Furthermore, in 70% (209/298) of these ERC-adjusted studies, it was unclear through which modality ERCs were determined. In the papers that described modalities, 49% (44/89) used ERCs from pre-existing databases, 18%(16/89) used sibling/relative recruitment, 30% (27/89) used self-reporting ERCs and 2% (2/89) used multiple ways to classify ethnicity or race. Moreover, in 28% (83/298) of the ERC-adjusted studies, it was not clear which specific categories were used. Conclusion ERC confounder adjustment is a common occurrence in SCD case-control studies in the United States and Europe. Furthermore, contrary to current author guideline recommendations, reporting on ethnicity and race in SCD studies is frequently inconsistent and incomplete. This confuses the possible relevance of ERCs to the study and inadvertently reinforces reification of these constructs. Moving forward, we recommend the promotion of global guidelines around the use of ERCs in case-control studies to stimulate further research into uncovering specific relevant mechanisms that create differences in health outcomes.

A randomized clinical trial of sex and population-specific troponin cutoffs for ruling out acute MI - the danish study of sex and population-specific cutoffs of troponin (DANSPOT)

Abstract Background Measurements of high-sensitivity cardiac troponin (cTn) T/I are used as the gold standard and are the preferred biomarkers to diagnose acute myocardial infarction (MI) in conjugation with symptoms and changes in the ECG. The URL is based on the 99th percentile of troponin concentrations in a healthy reference population. Currently, a sex-uniform manufacturer provided 99th percentile URL of troponin is utilized at Danish hospitals as a diagnostic cutoff for acute MI for both men and women. Reportedly, healthy men have twofold the troponin level compared to healthy women, suggesting that the use of a uniform URL for troponins may lead to the under-diagnostication of acute MI in women and potentially over-diagnostication in men. Purpose The purpose of the DANSPOT study is to evaluate the clinical effect on diagnosis, treatment and outcomes in men and women presenting with acute MI of implementing international guidelines recommended sex-specific 99th percentile URLs for troponin into clinical practice. Methods First, to determine the sex-specific 99th percentile URLs of troponins (table) based on a healthy Danish reference population, blood samples from Danish blood donors, were analyzed using five high-sensitivity (hs) cTn assays (Siemens Atellica and Vista hs-cTnI, Roche hs-cTnT, Abbott Alinity hs-cTnI and Orthos VITROS hs-cTnI). Second, the DANSPOT study is a nationwide cluster-randomized trial with "stepped-wedge" design (figure) with participation of 22 Danish hospital center. With one-month intervals, each of the 22 centers have been randomized to shift from the presently applied sex-uniform 99th percentile URL of troponin to the population and sex-specific 99th percentiles URLs. First center started implementing the new 99th percentiles URLs on April 1, 2022, and the last center is planned to enroll on January 1, 2024. Patients are followed up in Danish registries for 12 months after index admission. The primary endpoint is a composite of myocardial infarction, unplanned revascularization (after index admission) and all-cause mortality and is calculated for the cohort of women and men with ≥2 measurements of troponin within the first 24 hours of admission with maximal troponin level between the new sex-specific 99th percentile URLs and the old sex-uniform 99th percentile URL. Perspective The clinical significance of sex-specific 99th percentile URLs of troponin is poorly investigated and for the same reason not yet implemented in Denmark or many other countries. With the implementation of population and sex-specific 99th URLs of troponin, we expect to detect significantly more women with acute MI, theoretically resulting in a more accurate diagnosis and treatment of women and men with acute MI. This would be guideline-defining for implementing sex-specific cutoffs for troponin in Denmark as well as internationally as recommended in guidelines by professional cardiological societies.Schematic presentation of study designTable of the new 99th percentiles of cTn

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis

The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Paediatric reference intervals and curves for haemoglobin and ferritin: protocol for a systematic review and meta-analysis

IntroductionReference intervals and reference curves provide clinicians with a point of reference when evaluating patients’ laboratory test results. In practical applications, the 2.5th and 97.5th percentiles of healthy reference population...

819 ELLIPSE: Electrical Impedance Analysis in Patients Undergoing Emergency Abdominal Surgery

Abstract Introduction An ageing population represents greater operative risk; therefore, preoperative risk stratification is required to allow patients to make an informed decision. One method of risk stratification is bioelectrical impedance analysis (BIA) which can provide information such as muscle and fat mass, providing a proxy for patient metabolic health. Aim Metabolic health is intrinsically linked to outcomes following surgery. We hypothesised that BIA is a feasible method of assessing patients undergoing emergency abdominal surgery and predicting postoperative outcomes. Method A BIA analyser was used to measure patients body composition. All adult patients who met the National Emergency Laparotomy Audit (NELA) inclusion criteria were prospectively recruited and followed up until 30 days postoperatively. These patients had serial BIA measurements and compared with a healthy population. The phase angle (PA) is a raw variable which can be standardised to a healthy reference population and matched for age and gender. In summary, a higher phase angle is associated with improved outcomes. Results 31 patients were recruited and BIA analysis in patients undergoing emergency abdominal surgery was feasible. Patients with a phase angle lower than the reference population had a greater incidence of complications (p = 0.03) and had more severe complications (p = 0.023). Furthermore, the same patients also had a significantly higher NELA morbidity percentage (p = 0.022). Conclusions Our study shows that conducting BIA analysis in patients undergoing emergency abdominal surgery is feasible. The presence and severity of complications correlates with the phase angle. This represents a successful proof of concept study of BIA to predict postoperative outcomes.

Quality of life in men with Klinefelter syndrome: a multicentre study.

Klinefelter syndrome (KS) is associated with an increased risk of lower socioeconomic status and a higher risk for morbidity and mortality, which may have a significant impact on quality of life (QOL). The objective of this study is to investigate QOL in a large European cohort of men with KS. Cross-sectional multicentre study. Two-hundred-eighteen men with KS were recruited from 14 clinical study centres in 6 European countries which participated in the European dsd-LIFE study. Male normative data from a healthy and a psychiatric reference population were used for comparison. The validated World Health Organization (WHO) QOL (WHOQOL)-BREF questionnaire was used to investigate five main domains of quality of life (WHOQOL): global, physical, psychological, environment, and social. The QOL physical domain score was lower for men with KS compared to the healthy reference population (KS: 66.9; s.d. 19.4, n = 193; healthy reference population: 76.5; s.d. 16.2, n = 1324, P < 0.001) but higher compared to the psychiatric reference population (54.6; s.d. 20.6; n = 77, P < 0.001). The WHOQOL-psychological domain score was lower for men with KS compared to the healthy reference population (KS: 63.6; s.d. 17.8, n = 193; healthy reference population: 67.8; s.d. 15.6, n = 1324, P < 0.05) but higher compared to the psychiatric reference population (45.9; s.d. 26.0), n = 77, P < 0.001). The social domain score on the WHOQOL questionnaire was found to be lower in men with Klinefelter syndrome (KS) compared to the healthy reference population (KS: 60.0; s.d. 21.6, n = 193; healthy reference population: 68.2; s.d. 13.8, n = 1324, P < 0.001). However, this score was similar to that of the psychiatric reference population (61.0; s.d. 17.0, n = 77, P = 0.5). The WHO environment domain score of men with KS (70.0; s.d. 15.0, n = 193) was similar to the healthy reference population (70.5; s.d. 20.7, n = 1324) but higher compared to the psychiatric reference population (61.9; s.d. 20.8, n = 77, P = 0.002). Experienced discrimination, less social activities, and the presence of chronic health problems were associated with significantly decreased QOL in men with KS. Overall QOL in European men with KS is significantly worse compared to a healthy European reference population. Especially, the presence of discrimination, less social activities, and chronic health problems is associated with lower physical, psychological, and social QOL. Further studies are necessary to investigate if a multidisciplinary approach may help to provide adequate counselling and psychosocial support to improve QOL.

Effects of lipodystrophy and physical exercise on bioimpedance parameters in people living with HIV: A cross-sectional study

ObjectiveThe aim of this study was to evaluate the effects of lipodystrophy and physical exercise on the parameters of bioimpedance spectroscopy (BIS) and bioimpedance vector analysis (BIVA) of people living with HIV (PLWHIV). MethodsSeventy patients were divided into two groups: PLWHIV with lipodystrophy (PLWHIV-L) and PLWHIV without lipodystrophy (PLWHIV-NL). The phase angle (PhA) and the BIVA were determined from the values of resistance and reactance collected by the BIS. The percentage of fat mass and lean soft tissue (LST) were determined by dual-energy x-ray absorptiometry. For comparisons between the PLWHIV-L and PLWHIV-NL groups, the t test for independent samples or the Mann–Whitney test was used. From the BIVA, the average of the impedance vectors of the two groups was calculated with the 95% confidence ellipse, and the individual vectors of the patients divided by sex were also compared with the tolerance ellipses of 50%, 75%, and 95% of the healthy reference population. The relationships between the variables of interest were determined by the Pearson or Spearman correlation coefficient and the coefficient of determination. Analysis of covariance was used for comparisons between groups, adjusted for possible confounding variables. ResultsPLWIV-L showed better hydration conditions (P <0.01), higher LST (P <0.01), and lower percent of fat mass (P <0.01). No differences in PhA were observed between PLWHIV who practiced or did not practice physical exercise. There was a significant difference between the impedance vectors of the groups with and without lipodystrophy (T = 42.4 and P <0.01). Additionally, most of the patients who were positioned beyond the ellipse limits of 50% of tolerance fell into the areas of edema and cachexia. The extracellular to intracellular water ratio explained 81% of the PhA variations. When PhA was adjusted for height2, fat mass/height2 and LST, it was significantly different between groups of the female sex (PhA: P <0.01). ConclusionLipodystrophy and the practice of physical exercise do not present direct involvement in the PhA values, with sex, body composition, and hydration variables being the main influences on this variable. BIVA was able to show differences in the body composition of the groups even when the PhA values were similar.

Myocardial Injury Thresholds for 4 High-Sensitivity Troponin Assays in U.S. Adults

BackgroundMyocardial injury is currently defined as a cardiac troponin above the sex-specific 99th percentile of a healthy reference population (upper reference limit [URL]). ObjectivesThe purpose of this study was to estimate high-sensitivity (hs) troponin URLs in a representative sample of the U.S. adult population; overall and by sex, race/ethnicity, and age group. MethodsAmong adults participating in the 1999-2004 National Health and Nutrition Examination Survey (NHANES), we measured hs-troponin T using 1 assay (Roche) and hs-troponin I using 3 assays (Abbott, Siemens, and Ortho). In a strictly defined healthy reference subgroup, we estimated 99th percentile URLs for each assay using the recommended nonparametric method. ResultsOf 12,545 participants, 2,746 met criteria for the healthy subgroup (mean age 37 years, 50% men). The NHANES 99th percentile URL for hs-troponin T (19 ng/L) matched the manufacturer-reported URL (19 ng/L). NHANES URLs were 13 ng/L (95% CI: 10-15 ng/L) for Abbott hs-troponin I (manufacturer: 28 ng/L), 5 ng/L (95% CI: 4-7 ng/L) for Ortho hs-troponin I (manufacturer: 11 ng/L), and 37 ng/L (95% CI: 27-66 ng/L) for Siemens hs-troponin I (manufacturer: 46.5 ng/L). There were significant differences in URLs by sex, but none by race/ethnicity. Furthermore, the 99th percentile URLs for all 4 hs-troponin assays were statistically significantly lower in healthy adults aged <40 years compared with healthy adults ≥60 years (all P < 0.001 by rank sum testing). ConclusionsWe found URLs for hs-troponin I assays that were substantially lower than currently listed 99th percentile URLs. There were significant differences in hs-troponin T and I URLs by sex and by age group in healthy U.S. adults but none by race/ethnicity.

Functional Reference Limits: Describing Physiological Relationships and Determination of Physiological Limits for Enhanced Interpretation of Laboratory Results.

Functional reference limits describe key changes in the physiological relationship between a pair of physiologically related components. Statistically, this can be represented by a significant change in the curvature of a mathematical function or curve (e.g., an observed plateau). The point at which the statistical relationship changes significantly is the point of curvature inflection and can be mathematically modeled from the relationship between the interrelated biomarkers. Conceptually, they reside between reference intervals, which describe the statistical boundaries of a single biomarker within the reference population, and clinical decision limits that are often linked to the risk of morbidity or mortality and set as thresholds. Functional reference limits provide important physiological and pathophysiological insights that can aid laboratory result interpretation. Laboratory professionals are in a unique position to harness data from laboratory information systems to derive clinically relevant values. Increasing research on and reporting of functional reference limits in the literature will enhance their contribution to laboratory medicine and widen the evidence base used in clinical decision limits, which are currently almost exclusively contributed to by clinical trials. Their inclusion in laboratory reports will enhance the intellectual value of laboratory professionals in clinical care beyond the statistical boundaries of a healthy reference population and pave the way to them being considered in shaping clinical decision limits. This review provides an overview of the concepts related to functional reference limits, clinical examples of their use, and the impetus to include them in laboratory reports.

A repeatable CT protocol for quantifying caudal vena cava growth in medium and large breed dogs.

Developmental malformations can cause stunted or abnormal growth and clinical disease in dogs. In humans, measurements of the inferior vena cava are used as methods for detecting abnormal growth trajectories. The objectives of this retrospective, multicenter, analytical, cross-sectional study were to develop a repeatable protocol to measure the caudal vena cava (CVC) and generate growth curves in medium and large-breed dogs during development. Contrast-enhanced CT DICOM images from 438 normal dogs, aged from 1 to 18 months, from five specific breeds were included. A "best guess" measurement protocol was created. Dogs were stratified into medium or large breed groups based on growth rate trajectories. Linear regression models and logarithmic trend lines were used to evaluate the CVC growth over time. The CVC measurements were analyzed from four anatomical regions: thorax, diaphragm, intra-hepatic, and renal. The thoracic segment produced the most repeatable measurements with the highest explanatory power. The CVC thoracic circumference ranged from 2.5 to 4.9cm from 1 to 18 months of age. Medium and large breeds had similar CVC growth trajectories, with comparable estimated marginal means, however medium dogs reached 80% of predicted final CVC size approximately 4weeks earlier than large breed dogs. This new protocol provides a standardized technique for evaluation of the CVC circumference over time using contrast-enhanced CT and is most repeatable when taken at the thoracic level. This approach could be adapted for other vessels to predict their growth trajectories, generating healthy reference population data for comparison against patients with vascular anomalies.

Machine learning to improve false-positive results in the Dutch newborn screening for congenital hypothyroidism

ObjectiveThe Dutch Congenital hypothyroidism (CH) Newborn Screening (NBS) algorithm for thyroidal and central congenital hypothyroidism (CH-T and CH-C, respectively) is primarily based on determination of thyroxine (T4) concentrations in dried blood spots, followed by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurements enabling detection of both CH-T and CH-C, with a positive predictive value (PPV) of 21%. A calculated T4/TBG ratio serves as an indirect measure for free T4. The aim of this study is to investigate whether machine learning techniques can help to improve the PPV of the algorithm without missing the positive cases that should have been detected with the current algorithm. Design & methodsNBS data and parameters of CH patients and false-positive referrals in the period 2007–2017 and of a healthy reference population were included in the study. A random forest model was trained and tested using a stratified split and improved using synthetic minority oversampling technique (SMOTE). NBS data of 4668 newborns were included, containing 458 CH-T and 82 CH-C patients, 2332 false-positive referrals and 1670 healthy newborns. ResultsVariables determining identification of CH were (in order of importance) TSH, T4/TBG ratio, gestational age, TBG, T4 and age at NBS sampling. In a Receiver-Operating Characteristic (ROC) analysis on the test set, current sensitivity could be maintained, while increasing the PPV to 26%. ConclusionsMachine learning techniques have the potential to improve the PPV of the Dutch CH NBS. However, improved detection of currently missed cases is only possible with new, better predictors of especially CH-C and a better registration and inclusion of these cases in future models.