Characterising postural sway fluctuations in humans using linear and nonlinear methods

Introduction: Postural control is a prerequisite to many everyday and sporting activities which requires the interaction of multiple sensorimotor processes. As long as we have no balance disorders, the maintenance of an erect standing position is taken for granted with automatic running control processes. It is well known that with increasing age or disease balance problems occur which often cause fall-related injuries. To assess balance performance, posturography is widely applied in which body sway is traditionally viewed as a manifestation of random fluctuations. Thus, the amount of sway is solely used as an index of postural stability, that is, less sway is an indication of better control. But, traditional measures of variability fail to account for the temporal organisation of postural sway. The concept of nonlinear dynamics suggests that variability in the motor output is not random but structured. It provides the stimulus to reveal the functionality of postural sway. This thesis evaluates nonlinear analysis tools in addition to classic linear methods in terms of age-related modifications of postural control and under different standing conditions in order to broaden the existing knowledge of postural control processes. Methods: Static posturographic analyses were conducted which included the recording of centre of pressure (COP) time series by means of a force plate. Linear and nonlinear methods were used to quantify postural sway variability in order to evaluate both the amount and structure of sway. Classic time and frequency domain COP parameters were computed. In addition, wavelet transform (WT), multiscale entropy, detrended fluctuation analysis, and scaled windowed variance method were applied to COP signals in order to derive structural COP parameters. Two experiments were performed. 1) 16 young (26.1 ± 6.7 years), healthy subjects were asked to adopt a bipedal stance under single- and dual-task conditions. Three trials were conduced each with a different sampling duration: 30, 60, and 300 seconds [s]. 2) 26 young (28.15 ± 5.86 years) and 13 elderly (72 ± 7 years) subjects stood quietly for 60 s on five different surfaces which imposed different biomechanical constraints: level ground (LG), one foot on a step (ST), uphill (UH), downhill (DH), and slope (SL). Additional to COP recordings, limb load symmetry was assessed via foot pressure insoles. Results: We found a higher sensitivity of structural COP parameters to modulations of postural control and partly an improved evaluation of sway dynamics in longer COP recordings. WT revealed a reweighing of frequency bands in response to altered standing conditions. Scaling exponents and entropy values of COP signals were task-dependent. Higher entropy values were found under the dual-task and condition ST. The time scales affected under the altered standing positions differed between groups and sway directions. Mainly larger posturograms were found in the elderly. Age effects were especially revealed in position ST and concerning medial-lateral COP signals. Load asymmetry was stronger in elderly subjects for LG, UH, and DH positions. Discussion: Modifications of multiple time scales corresponds to an interplay of control subsystems to cope with the altered task demands. The affected time scales are age-dependent suggesting a change of control processes. Higher irregularity under the dual-task indicates a more complex motor output which is interpreted as less attentional investment into postural control. Larger complexity is evident for ST in contrast to LG position. ST obviously challenges lateral sway which is counteracted differently between groups. Load asymmetry suggests that especially elderly subjects adopt a step-initiation strategy. Conclusion: A continued application of nonlinear methods is necessary to broaden the understanding of postural control mechanisms and to identify classifiers for balance dysfunctions. Structural COP parameters provide a more comprehensive indication of postural control system properties between groups and task demands. COP recordings of at least 60 s are recommended to adequately quantify COP signal structure. The analysis of postural strategies in everyday activities increases the ecological validity of postural control studies and can provide valuable information regarding the development of effective rehabilitation programs.Die posturale Kontrolle ist eine Voraussetzung für viele Alltagsaktivitäten und sportliche Bewegungen. Man weiß heute, dass den Kontrollmechanismen eine komplexe Interaktion sensomotorischer Prozesse unterliegt (Horak and Mcpherson, 1996; Oie et al., 2002). Solange keine Gleichgewichtsdefizite vorliegen, nehmen wir es als selbstverständlich wahr aufrecht Stehen zu können, ohne uns der Komplexität posturaler Kontrollmechanismen bewusst zu sein. Studien haben gezeigt, dass es mit zunehmendem Alter zu Defiziten in der posturalen Kontrolle kommt (Pasquier et al., 2003; Woollacott, 1993). Oftmals ist ein erhöhtes Sturzrisiko die Folge, welches unter anderem mit Verletzungen, einer eingeschränkten Mobilitätsowie einer verminderten Lebensqualität einhergehen kann (Era et al., 1997; Frank and Patla, 2003). Seit vielen Jahren schon werden posturographische Untersuchungen durchgeführt mit dem Ziel, posturale Kontrollmechanismen abzuleiten undDysfunktionen im posturalen System zu diagnostizieren (Piirtola and Era, 2006). Jedoch sind die Mechanismen, die der posturalen Kontrolle unterliegen, bis heute nicht eindeutig verstanden. Neue Erkenntnisse konnten in den letzten Jahrenvor allem durch ein erweitertes Verständnis von Bewegungsvariabilität gewonnen werden (Stergiou and Decker, 2011; Lippens and Nagel, 2009). Traditionell werden posturale Analysen unter der Annahme durchgeführt und interpretiert, dass Variabilität eine Art “Rauschen” (white noise) ist und somit Ausdruck eines Fehlers. Posturale Schwankungen werden als zufällige, nicht intendierte Abweichungen gesehen (Loosch, 1997). Der Parameter “Schwankungsausmaß” wird zur Diagnostik des statischen Gleichgewichts herangezogen und bei einer größeren Schwankung wird eine schlechtere posturale Kontrolle diagnostiziert. Im Gegensatz dazu weist der systemdynamische Modellansatz auf die funktionale Rolle der Variabilität hin (van Emmerik and van Wegen, 2002). Variabilität ist Ausdruck der Anpassung und Flexibilität und somit notwendig, um auf ständige Umweltveränderungen reagieren zu können. Ein erhöhtes Schwankungsausmaß ist demnach nicht ausschließlich ein Zeichen für Instabilität (Newell et al., 1993). Eine größere Variabilität posturaler Schwankungen kann auch positiv im Sinne von mehr Umweltexploration interpretiert werden (Lacour et al., 2008). So konnte gezeigt werden, dass posturale Schwankungen nicht zufällig sind, sondern eine Struktur enthalten (Duarte and Zatsiorsky, 2000), dessen Charakterisierung zusätzliche Informationen über die Organisation des posturalen Kontrollsystems liefert (Stergiou and Decker, 2011). Die vorliegende Arbeit evaluiert nichtlineare Methoden unter dem systemdynamischen Ansatz zusätzlich zu den traditionell eingesetzten linearen Methoden. Ziel ist es, neben der Quantifizierung des Ausmaßes posturaler Schwankungen ihre Struktur zu charakterisieren, um das Verständnis für posturale Kontrollmechanismen zu erweitern. Die Evaluierung erfolgt zunächst über den Vergleich von Stehen mit und ohne kognitiver Zusatzaufgabe, wo Studien erste Hinweise auf eine veränderte COP1 Signalstruktur geben (Cavanaugh et al., 2007; Donker et al., 2007; Stins et al., 2009). Durch das Betrachten unterschiedlicher Signallängen und eines umfangreichen Methodenspektrums sollen Anhaltspunkte für die Applikation vonnichtlinearen in Kombination mit linearen Analyseverfahren abgeleitet werden. In einer zweiten Untersuchung werden diese dann in einem angewandten Studiendesign umgesetzt. Dabei wird die Veränderung posturaler Kontrollstrategien bei unterschiedlichen Standpositionen untersucht, welche alltägliche Situationen simulieren, unter Berücksichtigung altersbedingter Effekte. Dies ist ein erster Ansatz zur Erreichung einer hohen ökologischen Validität posturaler Studien (Frank and Patla, 2003; Visser et al., 2008). Erst kürzlich wurde gezeigt, dass bei älteren Menschen meist interne Auslöser (z.B. Gewichtsverlagerungen) ursächlich für Stürze sind (Robinovitch et al., 2013). Zudem haben ältere Personen größere Schwierigkeiten auf Umgebungsveränderungen zu reagieren (Nardone and Schieppati, 2010). Es ist jedoch bisher unbekannt, wie sich Defizite in der Gleichgewichtskontrolle älterer Menschen auf die Struktur posturaler Schwankungen auswirken. ..

Protocol of the IntenSify-Trial:An open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.</p

Sex-specific associations of basal steroid hormones and neuropeptides with Conduct Disorder and neuroendocrine mediation of environmental risk

Conduct Disorder (CD) is characterized by severe aggressive and antisocial behavior. The stress hormone system has frequently been investigated as a neurobiological correlate of CD, while other interacting neuroendocrine biomarkers of sex hormone or neuropeptide systems have rarely been studied, especially in females. We examined multiple basal neuroendocrine biomarkers in female and male adolescents with CD compared to healthy controls (HCs), and explored whether they mediate effects of environmental risk factors on CD. Within the FemNAT-CD study, salivary cortisol, alpha-amylase, testosterone, dehydroepiandrosterone-sulfate (DHEA-S), estradiol, progesterone, oxytocin, and arginine-vasopressin were measured under basal conditions in 166 pubertal adolescents with CD, and 194 sex-, age-, and puberty-matched HCs (60% females, 9-18 years). Further, environmental risk factors were assessed. Single hormone analyses showed higher DHEA-S, and lower estradiol and progesterone levels in both females and males with CD relative to HCs. When accounting for interactions between neuroendocrine systems, a male-specific sex hormone factor (testosterone/DHEA-S) predicted male CD, while estradiol and a stress-system factor (cortisol/alpha-amylase) interacting with oxytocin predicted female CD. Estradiol, progesterone, and oxytocin partly explained associations between early environmental risk and CD. Findings provide evidence for sex-specific associations between basal neuroendocrine measures and CD. Especially altered sex hormones (androgen increases in males, estrogen reductions in females) robustly related to CD, while basal stress-system measures did not. Early environmental risk factors for CD may act partly through their effects on the neuroendocrine system, especially in females. Limitations (e.g., basal neuroendocrine assessment, different sample sizes per sex, pubertal participants, exploratory mediation analyses) are discussed

Discontinuation of RAAS Inhibition in Children with Advanced CKD

Background and objectives Although renin-angiotensin-aldosterone system inhibition (RAASi) is a cornerstone in the treatment of children with CKD, it is sometimes discontinued when kidney function declines. We studied the reasons of RAASi discontinuation and associations between RAASi discontinuation and important risk markers of CKD progression and on eGFR decline in the Cardiovascular Comorbidity in Children with CKD study. Design, setting, participants,& measurements In this study, 69 children with CKD(67% male, mean age 13.7 years, mean eGFR 27 ml/min per 1.73m(2)) who discontinued RAASi during prospective follow-up were included. Initial change in BP, albuminuria, and potassium after discontinuation were assessed (median time 6 months). Rate of eGFR decline (eGFR slope) during a median of 1.9 years before and 1.2 years after discontinuation were estimated using linear mixed effects modeling. Results Physician-reported reasons for RAASi discontinuation were increase in serum creatinine, hyperkalemia, and symptomatic hypotension. After discontinuation of RAASi, BP and albuminuria increased, whereas potassium decreased. eGFR declined more rapidly after discontinuation of RAASi (23.9 ml/min per 1.73m2 per year; 95% confidence interval, 25.1 to 22.6) compared with the slope during RAASi treatment (21.5 ml/min per 1.73 m(2) per year; 95% confidence interval, 22.4 to 20.6; P=0.005). In contrast, no change in eGFR slope was observed in a matched control cohort of patients in whom RAASi was continued. Conclusions Discontinuation of RAASi in children with CKD is associated with an acceleration of kidney function decline, even in advanced CKD

Aspirin use and bleeding events during thrombocytopenia after autologous stem-cell transplantation for multiple myeloma

BackgroundIn patients with cardiovascular (CV) comorbidities that necessitate antiplatelet therapy (APT), its optimal management during chemotherapy-induced thrombocytopenia remains elusive, as the risk of bleeding has to be balanced against the risk of CV events. The purpose of this study was to assess the risk for bleeding with APT during thrombocytopenia in patients with multiple myeloma undergoing high-dose chemotherapy and subsequent autologous stem-cell transplantation (ASCT) with and without acetylsalicylic acid (ASA) as comedication.MethodsWe assessed patients who underwent ASCT at the Heidelberg University Hospital between 2011 and 2020 for bleeding events, management strategies for ASA intake during thrombocytopenia, transfusion requirements, and the occurrence of CV events.ResultsThere were 57/1,113 patients who continued ASA until at least 1 day after ASCT; thus, a continuous platelet inhibition during thrombocytopenia was assumed. Most of the patients (41/57) continued ASA until they had a platelet count of 20–50/nl. This range reflects the kinetics of thrombocytopenia and nondaily measurements of platelets during ASCT. A tendency toward a higher risk for bleeding events in the ASA group was demonstrated (1.9% (control group) vs. 5.3% (ASA), p = 0.082). The risk factors for bleeding in multivariate analysis were the duration of thrombocytopenia &lt; 50/nl, a history of gastrointestinal bleeding, and diarrhea. The factors predicting the duration of thrombocytopenia were age &gt;60 years, a hematopoietic stem-cell transplantation comorbidity index ≥3, and an impaired bone marrow reserve at admission. CV events occurred in three patients; none of them took ASA or had an indication for APT.ConclusionsThe intake of ASA until thrombocytopenia with a platelet count of 20–50/nl appears safe, although an elevated risk cannot be excluded. If ASA is indicated for the secondary prevention of CV events, the evaluation of risk factors for bleeding and a prolonged time of thrombocytopenia before conditioning is crucial to adapt the strategy for ASA intake during thrombocytopenia

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3-0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD

Relational aggression in adolescents with conduct disorder:sex differences and behavioral correlates

As most research on conduct disorder (CD) has been conducted on male participants, it has been suggested that female-specific symptoms may be underestimated based on current DSM-5 criteria. In particular, relational aggression, i.e. the hurtful, often indirect, manipulation of relationships with the intention of damaging the other’s social position, has been proposed as a characteristic of CD that is more common in females. In addition, sex-specific studies on correlates of relational aggressive behavior are lacking. Relational aggression may be strongly related to the correlates of proactive aggression, namely low affective empathy, and high levels of callous-unemotional (CU) traits and relational victimization. Thus, the present study investigated sex differences in relational aggression, and associations between relational aggression and correlates of proactive aggression in 662 adolescents with CD (403 females) and 849 typically-developing controls (568 females) aged 9–18 years (M = 14.74, SD = 2.34) from the European multi-site FemNAT-CD study. Females with CD showed significantly higher levels of relational aggression compared to males with CD, whereas no sex differences were seen in controls. Relational aggression was only partly related to correlates of proactive aggression in CD: Independent of sex, CU traits showed a positive association with relational aggression. In females only, cognitive, but not affective empathy, was negatively associated with relational aggression. Relational victimization was more strongly associated with relational aggression in males compared to females. Despite interesting sex specific correlates of relational aggression, effects are small and the potential clinical implications should be investigated in future studies

CDH12 as a Candidate Gene for Kidney Injury in Posterior Urethral Valve Cases:A Genome-wide Association Study Among Patients with Obstructive Uropathies

Background: Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development. Objective: To identify genetic variants associated with kidney injury in patients with obstructive uropathy. Design, setting, and participants: We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase

Resting autonomic nervous system activity is unrelated to antisocial behaviour dimensions in adolescents: Cross-sectional findings from a European multi-centre study

Purpose: Autonomic nervous system (ANS) functioning has long been studied in relation to antisocial behaviour, but relevant measures (heart rate, heart rate variability, pre-ejection period, respiration rate) have rarely been considered together. This study investigated the relationship between these measures and antisocial behaviour. Methods: Using a sample of 1010 youths with (47.8%) and without conduct disorder (52.2%) aged between 9 and 18. years (659 females, 351 males, mean age = 14.2. years, SD = 2.4), principal component analysis (PCA) was applied to various measures of psychopathology and antisocial behavior. Structural equation modelling was performed in order to test whether the ANS measures predicted PCA-dimensions. Cluster analysis was used in order to classify patterns of ANS activity. Analyses were performed separately for males/females and controlled for body-mass-index, age, caffeine use, cigarette smoking, sports, socioeconomic status, medication, cardiac problems. Results: The PCA yielded three components: antisocial behaviour/comorbid psychopathology, narcissistic traits, and callous-unemotional traits. ANS measures were only weakly correlated with these components. Cluster analysis yielded high and low arousal clusters in both sexes. When controlling for covariates, all associations disappeared. Conclusion: Our findings suggest that resting ANS measures are only weakly related to antisocial behaviour and indicate that smoking should be considered as an important covariate in future psychophysiological studies