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The study aims to acquaint readers with six widely used machine learning (ML) techniques (Principal Component Analysis (PCA), Uniform Manifold Approximation and Projection (UMAP), k-means, hierarchical clustering and the decision tree models (rpart and random forest)) that might be useful for the analysis of laboratory data.

Although there are several indirect methods that can be used to verify reference limits, they have a common weakness in that they assume a low proportion of pathological values. This paper investigates whether a Gaussian decomposition algorithm can identify the non-pathological fraction even if it is not the main subset of mixed data.

The identification of a suitable distribution model is a prerequisite for the parametric estimation of reference intervals and other statistical laboratory tasks. Classification of normal vs. lognormal distributions from healthy populations is easy, but from mixed populations, containing unknown proportions of abnormal results, it is challenging. We demonstrate that Bowley’s skewness coefficient differentiates between normal and lognormal distributions. This classifier is robust and easy to calculate from the quartiles Q1–Q3 according to the formula (Q1 − 2 · Q2 + Q3)/(Q3 − Q1). We validate our algorithm with a more complex procedure, which optimizes the exponent λ of a power transformation. As a practical application, we show that Bowley’s skewness coefficient is suited selecting the adequate distribution model for the estimation of reference limits according to a recent International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommendation, especially if the data is right-skewed.

A successful transition of renal transplant recipients from pediatric to adult care requires a structured, need-adapted and multidisciplinary approach to preserve renal graft function during this critical period of life. In this article we present our clinical protocol for transition from pediatric to adult care, which we developed on the basis of the International Society of Nephrology (ISN)/International Pediatric Nephrology Association (IPNA) consensus guidelines influenced by our own experience. This transition program was established in our center in July 2017. The entire transition process is structured and accompanied by a transition key worker (social worker). From 12 years of age we train pediatric renal transplant recipients in medical knowledge, self-management skills and networking with self-help groups. The training is adapted to the individual patient‘s intellectual ability, lasts about 10 years and takes place with increasing intensity. Repeatedly we perform standardized informational interviews and check patient’s knowledge of transplant-related topics. Psychosocial and educational issues are evaluated concomitantly. The actual transfer takes place in a pediatric-adult-transition clinic. Relevant medical and psychosocial aspects are discussed and the future treatment regimen is established. The date of transfer is adapted to the individual patient’s need; it varies between 18 and 24 years of age. In periods of increased risk for non-adherence the transfer is postponed to intensify the efforts for training and assistance. After transfer a standardized evaluation of each individual patient takes place focusing on medical and psychosocial issues and on satisfaction with the transition process. Collection of these data is still in progress and will be analyzed systematically at a later stage in order to evaluate the impact of this new transition program on the stability of transplant function. That analysis might serve as a basis for negotiations about refunding with health insurance companies.

Acute infectious diseases of the respiratory tract are regularly associated with increased concentrations of neopterin in serum and/or urine. Most likely, the pteridine compound is not only a marker of an activated cellular immune system but may exert distinct biochemical functions in the process of infections as well. In response to viral contact, macrophages located in the nasal mucosa may represent a source for neopterin in the nasal cavity with potential hazardous effects on ciliary beat frequency (CBF), thus promoting chronic infectious processes. The aim of the present study was to investigate the effects of neopterin at different concentrations (10 nM, 100 nM, and 100 μM) on CBF in human nasal epithelial cells in vitro. Samples were taken from the inferior nasal turbinate and incubated with neopterin dissolved in either aqua destillata or in sodium chloride (0.9%) at the given amounts for 2, 5, 10, and 20 min. In a preliminary set of experiments, neopterin inhibited CBF following the 5 and 10 min. incubation protocol, respectively. However, analyses of pooled data from 28 experiments using sodium chloride (0.9%) as solvent could not confirm these findings: in no setting a significant reduction of CBF was detected at the end of the 20 min. experimental procedure. Therefore, we conclude that neopterin most likely does not affect the mucociliary clearance defense mechanisms in the course of infections of the nasal respiratory tract.

Regular night shift activities are associated with a series of adverse effects (e.g. chronic fatigue, increased yield loss rates, diseases) related to a disturbed circadian rhythm of the employee. According to current knowledge, the human circadian system is affected by visible light in the short wavelength range. In the present study, we investigated the effects of reduced short-wavelength components in the lighting environment of an office workplace on circadian markers, symptoms of lassitude, and personal mood in an experimental night shift setup. Nocturnal urinary neopterin excretion was different from known circadian rhythms under both filtered test light and bright light conditions. By contrast, urinary sulphatoxymelatonin concentrations could be adjusted to a normal diurnal profile in the test light environment. Mood rating inventories did not result in differences in the subjective perception between the two lighting environments with respect to the dimensions of "Activity", "Concentration, "Deactivation", and "Fatigue". In addition, changes in signs of vigour and weariness in the course of each night of the study were equally pronounced in test light and bright light. In conclusion, the present study shows that light with reduced short-wavelength components maintains the nocturnal profile of sulphatoxymelatonin but simultaneously exerts a wearisome effect on the participants. Therefore, a general implementation of test light to illuminate night shift workplaces implies further investigations.

Prolonged physical exercise is associated with multiple changes in the immune status indicating an acute phase response and an activation of the immune system. Eccentric muscle activation (e.g. downhill running) induces micro-trauma of skeletal muscles thus inducing an inflammatory response. At present there are no data to which extent the immune system is activated after a downhill marathon run and if there arc any correlations between immune activation and markers for muscle damage or functional impairment of leg muscles. As model for severe eccentric exercise we selected the Tyrolean Speed Marathon (42 km downhill run, 795 m vertical difference). 13 volunteers (12 male, 1 female; mean running time 224 min [range 193 - 266 min.]) finished the run. Blood from antecubital veins was collected 3-4 days before (T1 ), 3-4 hrs before (T2) and immediately after the marathon (T3) as well as on the morning after the run (T4). We measured serum neopterin concentrations, white blood cell count. C-reactive protein (CRP), creatine kinase (CK), myoglobin (Mb), cardiac troponin I (cTnl) and troponin Τ (cTnT). Moreover, isokinetic muscle tests were performed. Following significant changes were found (before vs. after the run): increase in neopterin, CRP, total leukocyte count, CK. Mb, cTnl, cTnT, whereas isokinetic dynamometry showed a reduction in peak hamstring torque of both thighs after the marathon. There were no significant correlations (Spearman's rank correlation coefficient) between the observed changes in neopterin and CRP, CK, Mb. cTnT, cTnl or between neopterin concentrations and parameters of isokinetic muscle tests. We could demonstrate that a 42 km downhill marathon is associated a) with an activation of the cellular immune system, as evidenced by the increase in serum-neopterin. b) pronounced micro-skeletal muscle damage with high serum creatine kinase and myoglobin, and c) eccentric hamstring fatigue. The absolute changes in neopterin were moderate and similar to other types of exercise (flat course and bicycle marathon, mountain hiking).

Increases in serum neopterin concentrations are a regular finding in patients with ovarian cancer. The strong correlation between neopterin and tumor progression might be explained by a direct influence of the pteridine compound on tumor cell growth. In the present study we investigated whether neopterin affects the production of the angiogenic promotors vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in the human ovarian carcinoma cell line OVCAR-3. VEGF and EPO gene expression were detected via RT-PCR. and a possible involvement of hypoxiainducible factor-1 was assessed by electrophoretic mobility shift assays. Neopterin amplified the hypoxia-induced VEGF and EPO gene expression as well as protein synthesis in a concentration-dependent manner. In addition, generation of both VEGF and EPO could be detected following incubation of cells with neopterin under normoxic conditions, too. Neopterin-induced synthesis of VEGF and EPO was preceeded by a stimulation of hypoxiainducible factor-1 uptake into the nucleus of OVCAR-3 cells. From these data we conclude that neopterin acts as a mediator of angiogenesis. Stimulation of VEGF and EPO generation in ovarian carcinoma cells may promote vascularization of the malignant tissue and thus tumor growth and development.

Recent studies have shown a strong association between indices of inflammation and metabolic Syndrome. Proinflammatory mediators like tumor necrosis factor-α may act as a trigger for insulin insensitivity. Therefore, patients with metabolic Syndrome might be at higher risk of insulin resistance when confronted with additional Stimuli of the immune system. These Stimuli are not restricted to the presence of pathogens but include environmental factors like physical exercise and hypoxemia as well. With respect to these interdependencies, one may assume higher risk for patients with metabolic Syndrome who perform physical exercise in alpine regions. We investigated the effects of a 3-weeks holiday with moderate sporting activities at moderate altitude (1700 m) on the conceiitrations of neopterin, tumor necrosis factor-α, serum soluble 75kD type TNF receptor (sTNF-R75), and interleukin-6 in vacationers with metabolic Syndrome. Only serum neopterin and sTNF-R75 concentrations transiently increased during the stay at moderate altitude compared to pre-altitude levels (P

In this review, we will summarize our investigations on the potential biochemical, physiological, and pathophysiological effects of neopterin in the course of infection and inflammation. In a number of in v/'iro-studies wc could show that the pteridine compound neopterin manifested distinct biochemical properties via interfering with cellular redox mechanisms. Among the observed actions of neopterin are the stimulation of inducible nitric oxide synthase gene expression and nitric oxide release, the activation of the transcription factor nuclear factor-κΒ, the induction of apoptotic ccll death, the inhibition of erythropoietin synthesis and release, and the stimulation of tumor necrosis factor-α generation in different cell culture as well as organic models. By these means, neopterin may represent a part of the host-defence reactions. In addition, an excessive or continous release of neopterin due to a chronically activated cellular immune system may contribute to the deleterious events commonly observed in progressive infectious or inflammatory diseases. Our data are supported by the findings of a strong correlation between raised levels of neopterin and the severity and the outcome of these disorders.

Earlier neopterin was demonstrated to inhibit hypoxia-induced erythropoietin synthesis in isolated perfused rat kidneys. The present experiments were performed to gain further insight into the mode of action underlying this effect. Numerous studies provided evidence of a link between neopterin and oxidative stress as well as intraccllular calcium concentrations. Thus, neopterin (200 μM) NQS added into the perfusion medium together with either the caclium Channel blocker Verapamil (5 μM) or the anti-oxidant N-acetylcysteine (200 μM). The addition of neopterin as a Single stimulus resulted in a significant decrease in the rate of hypoxia-induced eryihropoietin release accompanied by an augmented renal vascular resistance and a reduced perfusion flow rate. Although these data point towards an involvement of calcium and/or reactive oxygen species, verapamil or Nacetyleysteine were able to abrogate the suppression of erythropoietin generation which was induced by neopterin. Therefore, the mechanisms responsible for the impact of neopterin on the production of this growih lactor in the kidney remain to be elucidated.

In a Number of malignant diseases including ovarian carcinomas, increased serum or urine levels of neopterin serve as a valuable marker for the state of activation of the cellular immune system. Reported correlations benveen elevated neopterin concentrations and shorter survival time of the tumor host might be explained by direct biochemical actions exhibited by the pteridine compound. In the present study, we investigated the influence of neopterin on inducible nitric oxide synthase (iNOS) gene expression in two ovarian carcinoma cell lines. Qualitative and quantitative analyses of iNOS as well as measurements of nitric oxide (NO) metabolites in the cell supernatant revealed an inhibitory effect of neopterin (1000 11M) on NO generation induced by a combination ofinterferon-γ (100 U/ml), tumor necrosis factor-a (500 U/ml), and interleukin-1β (10 U/ml). Since NO is most likely involved in apoptotic cell death in ovarian carcinoma cells, it is conceivable that suppression of NO synthesis represents a biochemical mechanism mediated by neopterin that is advantageous to tumor progression and thus harmful to the host.

Author(s): Daniela Choukair [sup.1] [sup.2] , Susanne Rieger [sup.1] , Dirk Bethe [sup.1] , Dorothea Treiber [sup.1] , Georg F. Hoffmann [sup.1] [sup.2] , Corinna Grasemann [sup.3] , Peter Burgard [...], Background The structured transition of adolescents and young adults with chronic kidney disease (CKD) from pediatric to adult care is important, but data on the time and resources required for the necessary components of the transition process and the associated costs are lacking. Methods In a prospective single-center cohort study of 52 patients with pre-transplant CKD (CKD stage 1, n = 10; stage 2, n = 6; stage 3, n = 5; stage 4 and 5, 1 patient each) or kidney transplant recipients (KTR), resource use and costs were evaluated for the key elements of a structured transition pathway, including (i) assessment of patients&apos; disease-related knowledge and needs, (ii) required education and counseling sessions, and (iii) compiling an epicrisis and a transfer appointment of the patient with the current pediatric and the future adult nephrologist. Results Forty-four of 52 enrolled patients (84.6%) completed the transition pathway and were transferred to adult care. The mean time from the decision to start the transition process until the final transfer consultation was 514 ± 204 days. The process was significantly longer for KTR (624 ± 150 [range, 307-819] days) than for patients with pre-transplant CKD (365 ± 172 [range, 1-693] days; P < 0.0001). The cumulative costs of all counseling and education sessions performed including the transfer appointment were 763 ± 473 Euro; it was significantly higher in KTR (966 ± 457 Euro) than in patients with pre-transplant CKD (470 ± 320 Euro; P < 0.0001). Conclusions A structured transition pathway for patients with CKD is resource and time-consuming due to the complexity of the disease and should be sufficiently funded. Graphical Abstract

Endurance exercise induces several alterations in the immune and hematological system. At present it is unknown whether exercise under hypoxic conditions can modulate these changes. We investigated the effects of a prolonged endurance bicycle exercise in 8 healthy athletes (Oetztal Bicycle Marathon, OEBM; distance 230 km; vertical displacement 5000 m) on serum concentrations of interleukin-I[3 (IL-If3), interleukin- 6 (IL-6), tumor necrosis factor-a (TNF-a), neopterin as well as erythropoietin (EPO). Blood was collected before (A), immediately after the race (B), one (C), two (D), three (E) as well as five (F) days after the OEBM. We could demonstrate that IL-6 was increased significantly after exercise termination, whereas IL-I[3 and TNF-a were unchanged. Neopterin was significantly elevated from B to D, indicating an activation of the cellular immune system. Serum EPO was significantly increased from day 1 to day 5 after exercise which might reflect the combination of hypoxia and postexercise hemodilution.

Abstract Background National newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome. Methods In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated. Results Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two. Conclusions Physical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.

Abstract Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS.

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.