OBJECTIVES:Midostaurin is an oral multitargeted tyrosine kinase inhibitor for the treatment of acute myeloid leukemia (AML). Therapeutic drug monitoring of midostaurin may support its safe use when suspecting toxicity or combined with strong CYP3A4 inhibitors.METHODS:A stable isotope dilution liquid chromatography-tandem mass spectrometry method was developed and validated for the determination and quantification of midostaurin in human plasma and serum. Midostaurin serum concentrations were analyzed in 12 patients with FMS-like tyrosine kinase 3 (FLT3)-mutated AML during induction chemotherapy with cytarabine, daunorubicin, and midostaurin. Posaconazole was used as prophylaxis of invasive fungal infections.RESULTS:Linear quantification of midostaurin was demonstrated across a concentration range of 0.01-8.00 mg/L. Inter- and intraday imprecisions of the proposed method were well within ±10%. Venous blood samples were taken in nine and three patients in the first and second cycle of induction chemotherapy. Median (range) midostaurin serum concentration was 7.9 mg/L (1.5-26.1 mg/L) as determined in 37 independent serum specimens.CONCLUSION:In a real-life cohort of AML patients, interindividual variability in midostaurin serum concentrations was high, highlighting issues concerning optimal drug dosing in AML patients. A personalized dosage approach may maximize the safety of midostaurin. Prospective studies and standardization of analytical methods to support such an approach are needed.

BACKGROUND:Little is known about the distribution of posaconazole in brain tissue and CSF. We therefore analysed trough concentrations of posaconazole in paediatric leukaemia patients in non-inflamed CSF. PATIENTS AND METHODS:The study included paediatric patients <18 years of age with acute leukaemia in remission who underwent repeat therapeutic lumbar punctures as part of their anti-leukaemia treatment. CSF and blood were obtained 20-24 h after dosing, and posaconazole was measured by LC-MS/MS. RESULTS:Six patients (median age: 10 years; range, 6-14) with acute lymphatic (three) or acute myeloid (three) leukaemia were included who received posaconazole gastroresistant tablets at weight-banded doses (five) or the oral solution (one). In contrast to 14 control samples, posaconazole was detectable in all 11 samples of treated patients. CSF concentrations ranged from 8.3 to 42 ng/mL with a median CSF concentration of 13.6 ng/mL. Concurrent serum concentrations were between 965 and 5177 ng/mL with a median of 1716 ng/mL. CONCLUSIONS:Trough concentrations of posaconazole in the CSF after systemic administration were low but detectable in all subjects. Concurrent serum concentrations were in the target range for prophylaxis and treatment in 100% and 90%, respectively.

BackgroundTacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation.Methods/designThe study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs).DiscussionThis study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents.Clinical Trial RegistrationEUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

Background: Midostaurin is a FLT3-inhibitor for the treatment of acute myeloid leukaemia (AML) that is metabolized via CYP3A4 and therefore has potential for drug-drug interactions (DDI) with triazole antifungals routinely administered for prophylaxis of invasive fungal disease (IFD). We determined midostaurin and posaconazole plasma concentrations and investigated adverse events (AE) resembling DDI when both drugs were administered concomitantly. Aims:Methods: Twice weekly trough levels were performed for both posaconazole and midostaurin with validated LC-MS/MS methods. Demographic and clinical characteristics of patients were collected. Potential DDI of midostaurin were documented and independently reviewed by two physicians and attributed to DDI or otherwise in a five-level scale. Results: Twenty-four patients were eligible for analysis (22 patients with AML, 2 patients with systemic mastocytosis with an associated hematological neoplasm). A high inter- and intra-individual variability of midostaurin and posaconazole plasma exposure was observed. Inter-individual concentrations ranged from <0.01 mg/l to 24.5 mg/l for midostaurin and from <30 µg/l to 2571 µg/l for posaconazole. In the DDI analysis exanthema (1/24; 4,2%) was evaluated as possibly related to increased midostaurin exposure. Prolonged QTc interval on electrocardiogram (2/24; 8,3%), perimyocarditis, hyperbilirubinemia/liver cell necrosis, diarrhea and nausea (each 1/24; 4,2%) were classified as probably related. Midostaurin dose was reduced in one patient by 50% and discontinued in three patients due to severe AE. Six patients (25%) developed IFD (two Aspergillus spp., one coinfection with Aspergillus spp. and Rhizomucor spp. and three possible IFD according to the revised 2019 EORTC/MSG criteria). Five patients had excessively high midostaurin plasma levels over 15 mg/l, however, clinical significance is hard to determine without larger studies. Table 1 Descriptive interaction analysis of patients with high midostaurin plasma exposureSummary/Conclusion: DDI of posaconazole and midostaurin are clinically meaningful. TDM may serve for decision-making when DDI with strong CYP3A4 inhibitors are suspected clinically and could help to individually adapt the doses of both medications to reduce toxicity. Keywords: FLT3, Anti-fungal prophylaxis, AML

This study explores the intriguing relationship between personality traits, self-rated fitness (SRF), and physical activity (PA) variables among German university students (N = 4244) and sheds light on the impact of personality on adherence to PA guidelines. Employing an online cross-sectional study, the short-form of the Big Five Inventory-2 assessed five domains of personality traits (Extraversion, Negative Emotionality, Agreeableness, Conscientiousness, and Open-Mindedness). PA, including sitting time, was assessed using the International Physical Activity Questionnaire (short-form). SRF and muscle-strengthening activities (MSA) were assessed with one item each. Multiple linear and logistic regression analyses examined associations of individual personality trait domains and all domains combined with SFR, PA variables, and adherence to PA guidelines, controlling for sociodemographic, behavioral, and (mental) health covariates. Most reliably, Extraversion and Conscientiousness revealed positive associations with PA variables, while Negative Emotionality yielded inverse relationships with PA variables. For instance, each unit increase in Extraversion corresponded to an additional 17 min of weekly MSA. On the contrary, daily sitting time was unrelated to personality. Of note, high Open-Mindedness was associated with lower odds for adhering to current PA guidelines. The findings have implications for developing targeted interventions that promote a physically active lifestyle and support students' well-being and academic success.

Hip and knee osteoarthritis are associated with functional limitations, pain and restrictions in quality of life and the ability to work. Furthermore, with growing prevalence, osteoarthritis is increasingly causing (in)direct costs. Guidelines recommend exercise therapy and education as primary treatment strategies. Available options for treatment based on physical activity promotion and lifestyle change are often insufficiently provided and used. In addition, the quality of current exercise programmes often does not meet the changing care needs of older people with comorbidities and exercise adherence is a challenge beyond personal physiotherapy. The main objective of this study is to investigate the short- and long-term (cost-)effectiveness of the SmArt-E programme in people with hip and/or knee osteoarthritis in terms of pain and physical functioning compared to usual care. This study is designed as a multicentre randomized controlled trial with a target sample size of 330 patients. The intervention is based on the e-Exercise intervention from the Netherlands, consists of a training and education programme and is conducted as a blended care intervention over 12 months. We use an app to support independent training and the development of self-management skills. The primary and secondary hypotheses are that participants in the SmArt-E intervention will have less pain (numerical rating scale) and better physical functioning (Hip Disability and Osteoarthritis Outcome Score, Knee Injury and Osteoarthritis Outcome Score) compared to participants in the usual care group after 12 and 3 months. Other secondary outcomes are based on domains of the Osteoarthritis Research Society International (OARSI). The study will be accompanied by a process evaluation. After a positive evaluation, SmArt-E can be offered in usual care, flexibly addressing different care situations. The desired sustainability and the support of the participants’ behavioural change are initiated via the app through audio-visual contact with their physiotherapists. Furthermore, the app supports the repetition and consolidation of learned training and educational content. For people with osteoarthritis, the new form of care with proven effectiveness can lead to a reduction in underuse and misuse of care as well as contribute to a reduction in (in)direct costs. German Clinical Trials Register, DRKS00028477. Registered on August 10, 2022.

Peripheral neuropathy is a common side effect of cancer treatment with paclitaxel. The mechanisms by which paclitaxel is transported into neurons, which are essential for preventing neuropathy, are not well understood. We studied the uptake mechanisms of paclitaxel into neurons using inhibitors for endocytosis, autophagy, organic anion-transporting polypeptide (OATP) drug transporters, and derivatives of paclitaxel. RT-qPCR was used to investigate the expression levels of OATPs in different neuronal tissues and cell lines. OATP transporters were pharmacologically inhibited or modulated by overexpression and CRISPR/Cas9-knock-out to investigate paclitaxel transport in neurons. Through these experiments, we identified OATP1A1 and OATP1B2 as the primary neuronal transporters for paclitaxel. In vitro inhibition of OATP1A1 and OAT1B2 by glycyrrhizic acid attenuated neurotoxicity, while paclitaxel's antineoplastic effects were sustained in cancer cell lines. In vivo, glycyrrhizic acid prevented paclitaxel-induced toxicity and improved behavioral and electrophysiological measures. This study indicates that a set of OATPs are involved in paclitaxel transport into neurons. The inhibition of OATP1A1 and OATP1B2 holds a promising strategy to prevent paclitaxel-induced peripheral neuropathy.

Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively affect podocytes, direct effects of MMF on podocytes remain largely unknown. The present study examines the effects of MMF’s active component Mycophenolic Acid (MPA) on the transcriptome of podocytes and investigates its biological significance. We performed transcriptomics in cultured murine podocytes exposed to MPA to generate hypotheses on podocyte-specific effects of MPA. Accordingly, we further analyzed biological MPA effects on actin cytoskeleton morphology after treatment with bovine serum albumin (BSA) by immunofluorescence staining, as well as on cell survival following exposure to TNF-α and cycloheximide by neutral red assay. MPA treatment significantly (adjusted p < 0.05) affected expression of 351 genes in podocytes. Gene Ontology term enrichment analysis particularly clustered terms related to actin and inflammation-related cell death. Indeed, quantification of the actin cytoskeleton of BSA treated podocytes revealed a significant increase of thickness and number of actin filaments after treatment with MPA. Further, MPA significantly reduced TNFα and cycloheximide induced cell death. MPA has a substantial effect on the transcriptome of podocytes in vitro, particularly including functional clusters related to non-immune cell dependent mechanisms. This may provide a molecular basis for direct beneficial effects of MPA on the structural integrity and survival of podocytes under pro-inflammatory conditions.

Glia are critical players in defining synaptic contacts and maintaining neuronal homeostasis. Both astrocytes as glia of the central nervous system (CNS), as well as satellite glial cells (SGC) as glia of the peripheral nervous system (PNS), intimately interact with microglia, especially under pathological conditions when glia regulate degenerative as well as regenerative processes. The chemotherapeutic agent paclitaxel evokes peripheral neuropathy and cognitive deficits; however, the mechanisms underlying these diverse clinical side effects are unclear. We aimed to elucidate the direct effects of paclitaxel on the function of astrocytes, microglia, and SGCs, and their glia-glia and neuronal-glia interactions. After intravenous application, paclitaxel was present in the dorsal root ganglia of the PNS and the CNS of rodents. In vitro, SGC enhanced the expression of pro-inflammatory factors and reduced the expression of neurotrophic factor NT-3 upon exposure to paclitaxel, resulting in predominantly neurotoxic effects. Likewise, paclitaxel induced a switch towards a pro-inflammatory phenotype in microglia, exerting neurotoxicity. In contrast, astrocytes expressed neuroprotective markers and increasingly expressed S100A10 after paclitaxel exposure. Astrocytes, and to a lesser extent SGCs, had regulatory effects on microglia independent of paclitaxel exposure. Data suggest that paclitaxel differentially modulates glia cells regarding their (neuro-) inflammatory and (neuro-) regenerative properties and also affects their interaction. By elucidating those processes, our data contribute to the understanding of the mechanistic pathways of paclitaxel-induced side effects in CNS and PNS.

Studies have repeatedly pointed to a high burden of complaints among students and have led universities to become increasingly involved in student health management, with the aims of developing health-promoting structures and individual resources in the university setting. In this regard, the physical activity and mental health of students are points of departure. Internationally, there are clear correlations between the movement behaviour of students and mental health, but so far only a few national surveys are available; which limits their transferability to the German higher education landscape. This article examines how the current exercise recommendations, consisting of aerobic physical activities, sitting time and muscle-strengthening activities are related to various indicators of mental health in the target group. In the summer semester of 2019, 4244 students took part in a university-wide survey. In addition to exercise behaviour, stress experiences were surveyed and screenings were carried out for core elements of a depressive and anxiety-related disorder as well as for psychological stress. Positive aspects of mental health were recorded via a scale for assessing student engagement. As a measure of association, adjusted odds ratios were calculated taking into account socio-demographic and behavioural confounding variables. According to the findings, all criteria of the exercise recommendations were met by 9.6% of the students. 48% of respondents experienced a high level of stress and 29% were mentally stressed. Adherence to all the criteria of the physical activity recommendations was associated with significantly lower odds for psychological stress indicators, with the strongest association being found for depressive symptoms. Student engagement was not significantly associated with achieving the physical activity recommendations. The results confirmed the high psychological stress of students and indicated the potential for optimization of physical activity promotion. Conclusively, universities should systematically and continuously analyse the study conditions and the health behaviour of students in order to derive and evaluate suitable behavioural and situation-oriented measures such as exercise -oriented teaching, campus development and expansion of the university sports programmes.

ZusammenfassungStudien haben wiederholt auf eine hohe Beschwerdelast Studierender hingewiesen und Hochschulen veranlasst, sich zunehmend im studentischen Gesundheitsmanagement zu engagieren, das darauf abzielt, gesundheitsfördernde Strukturen zu entwickeln sowie individuelle Ressourcen im Setting Hochschule zu fördern. Die körperliche Aktivität und mentale Gesundheit Studierender stellen hierfür Ansatzpunkte dar. International zeigen sich eindeutige Zusammenhänge zwischen dem Bewegungsverhalten Studierender und der psychischen Gesundheit, jedoch liegen bisher nur wenige nationale Erhebungen vor, was die Übertragbarkeit auf die deutsche Hochschullandschaft einschränkt. Dieser Beitrag untersucht, wie in dieser Zielgruppe die aktuellen Bewegungsempfehlungen, bestehend aus den Kategorien ausdauerorientierte körperliche Aktivitäten, Sitzzeiten und muskelkräftigende Aktivitäten, mit verschiedenen Indikatoren mentaler Gesundheit zusammenhängen.Im Sommersemester 2019 nahmen 4.244 Studierende an einer hochschulweiten Umfrage teil. Neben dem Bewegungsverhalten wurden das Stresserleben erhoben und Screenings auf Kernelemente einer depressiven und angstbezogenen Störung sowie auf eine psychische Belastung durchgeführt. Positive Aspekte mentaler Gesundheit wurden über eine Skala zur Beurteilung studentischen Engagements erfasst. Als Assoziationsmaß wurden adjustierte Odds Ratios unter Berücksichtigung soziodemografischer und behavioraler Störvariablen berechnet.Sämtliche Kriterien der Bewegungsempfehlungen werden von 9,6% der Studierenden erreicht. 48% der Befragten weisen ein hohes Stresserleben auf und 29% gelten als psychisch belastet. Das Befolgen aller Kriterien der Bewegungsempfehlungen ist mit signifikant geringeren Chancen für psychische Belastungsindikatoren assoziiert, wobei der stärkste Zusammenhang für depressive Symptome gefunden wurde. Studentisches Engagement war nicht signifikant mit dem Erreichen der Bewegungsempfehlungen assoziiert.Die Ergebnisse bestätigen die hohe psychische Belastung Studierender und deuten das Optimierungspotenzial aus Sicht der Bewegungsförderung an. Hochschulen sollten die Studienbedingungen und das Gesundheitsverhalten der Studierenden systematisch und fortlaufend analysieren, um geeignete verhaltens- und verhältnisorientierte Maßnahmen wie bewegungsorientierte Lehre, Campusentwicklung und Ausbau des Hochschulsportangebots abzuleiten und zu evaluieren.

University students frequently engage in unhealthy behaviors. However, there is a lack of studies examining a wide range of their lifestyle characteristics by sex and academic level of study. This cross-sectional survey of students enrolled in BSc, MSc, or PhD programs at one university in Germany (N = 3389) assessed physical activity (PA), sedentary behavior (SB), nutrition, sleep quality, and alcohol, tobacco, and other drug (ATOD) use by sex and academic level and was conducted with EvaSys version 8.0. Chi-squared tests compared categorical variables by sex, and binary logistic regression analyses adjusted for sex with Bonferroni adjustments evaluated differences across academic level. Although 91% of students achieved the aerobic PA guidelines, only 30% achieved the muscle strengthening exercises (MSE) guidelines, and 44% had high SB. Likewise, <10% met the fruit and vegetable consumption (FVC) recommendations, >40% of students experienced impaired sleep, and >30% had hazardous alcohol consumption. Less than 20% of the sample achieved the guideline/recommendation of all three PA, MSE and SB. Some behaviors exhibited significant sex and academic level differences. The identified at-risk groups included males (lower FVC), females (eating more during stress), and BSc students (poorer nutrition/sleep quality, more ATOD use). Given the above findings, multipronged strategies are needed with an overarching focus highlighting the health–academic achievement links. Behavioral interventions and environmental policies are required to raise awareness and promote student health.

Insufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes. Randomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10. Among 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1–8.7) and without TDM (8.2 points; 95% CI 7.5–9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5–1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5–6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7–7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9–6.9, p < 0.001). TDM-guided therapy showed no beneficial effect in patients with sepsis and continuous infusion of piperacillin/tazobactam with regard to the mean SOFA score. Larger studies with strategies to ensure optimization of antimicrobial exposure are needed to definitively answer the question.

Beach handball is a young discipline that is characterized by numerous high-intensity actions. By following up on previous work, the objective was to perform in-depth analyses evaluating external load (e.g., distance traveled, velocity, changes in direction, etc.) in beach handball players. In cross-sectional analyses, data of 69 players belonging to the German national or prospective team were analyzed during official tournaments using a local positioning system (10 Hz) and inertial measurement units (100 Hz). Statistical analyses comprised the comparison of the first and second set and the effects of age and sex (female adolescents vs. male adolescents vs. male adults) and playing position (goalkeepers, defenders, wings, specialists, and pivots) on external load measures. We found evidence for reduced external workload during the second set of the matches (p = 0.005, ηp2 = 0.09), as indicated by a significantly lower player load per minute and number of changes in direction. Age/sex (p < 0.001, ηp2 = 0.22) and playing position (p < 0.001, ηp2 = 0.29) also had significant effects on external load. The present data comprehensively describe and analyze important external load measures in a sample of high-performing beach handball players, providing valuable information to practitioners and coaches aiming at improving athletic performance in this new sport.

University students' mental health and well-being is a growing public health concern. There is a lack of studies assessing a broad range of mental health domains by sex and academic level of study. This cross-sectional online survey of BSc, MSc, and PhD students (n = 3353, 67% female) enrolled at one university in Germany assessed a wide scope of mental health domains, covering positive (i.e., self-rated health, self-esteem, student engagement) and negative aspects (i.e., perceived stress, irritation, and screening positive for depression, anxiety, comorbidity, and psychological distress). We evaluated differences in mental health by sex and academic level. Overall, although self-rated health did not differ by sex and academic level, females and lower academic level were associated with less favorable mental health. Males reported higher prevalence of high self-esteem, and higher engagement (all p ≤ 0.04). Conversely, mean perceived stress and cognitive/emotional irritation were higher among females, as were rates for positive screenings for anxiety, anxiety and depression comorbidity, and psychological distress (p < 0.001 for all). Likewise, lower academic level (BSc) was associated with lower rates of high self-esteem (p ≤ 0.001), increased perceived stress (p < 0.001), and higher prevalence of positive screening for depression, anxiety, comorbidity, and psychological distress (p ≤ 0.002 for all), while higher academic level (PhD) was linked to increased student engagement (p < 0.001 for all). Although the effect sizes of sex and academic level on student mental health were modest, these findings support a need for action to establish and expand early detection and prevention programs, on-campus advisory services, and peer counseling that focus on the sex-specific and academic-study-level-specific factors, as well as mental health and career development resources for students. Academics and policy makers need to consider multipronged intervention strategies to boost confidence of students and their academic career.

AimsTo describe the population pharmacokinetics (PK) and probability of target attainment (PTA) of continuous infusion (CI) of meropenem in septic patients receiving renal replacement therapy (RRT).MethodsFifteen patients without RRT, 13 patients receiving sustained low‐efficiency dialysis and 12 patients receiving continuous veno‐venous haemodialysis were included. Population PK analysis with Monte Carlo simulations for different dosing regimens was performed. For minimum inhibitory concentration 2 mg/L was chosen. The target was set as 50% time ≥4× minimum inhibitory concentration.ResultsThe PK of meropenem was best described by a 1‐compartment model with linear elimination. Serum creatinine, residual diuresis and time on RRT, with no difference between sustained low‐efficiency dialysis and continuous veno‐venous haemodialysis, were found to be significant covariates affecting clearance, explaining >20% of the clearance between subject variability. PTA analysis showed that in patients with RRT, 2 g/24 h, meropenem CI achieved a PTA of 95%. In patients without RRT, the target was achieved with 3 g/24 h CI or prolonged infusion of 1 g meropenem over 8 hours but not with bolus application of 1 g meropenem for 8 hours. Only 2 patients (both without RRT) had meropenem concentrations below the target level. However, approximately half of the patients with RRT receiving CI 3 g/24 h meropenem had toxic concentrations.ConclusionWe found relevant PK variability for meropenem CI in septic patients with or without RRT, leading to a substantial risk for overdosing in patients with RRT. This finding highlights the strong demand for personalized dosing in critically ill patients.

Introduction Critically ill patients in neonatal intensive-care units (NICU) are exposed to a large number of drugs. Clinical trials for safety, dosing and efficacy are lacking although age-dependent alterations of pharmacokinetics (PK), drug-drug-interactions (DDIs), as well as intravenous admixture incompatibilities (IAI) may impact drug efficacy and trigger side-effects in this vulnerable population. Consequently, implementation of a routinely used DDIs checking regimen may help guide in decision making and will assist clinicians to avoid serious and preventable events. Therefore, the goal of the present work is to identify and assess the risk of relevant DDIs of drugs commonly used in the NICU. Evidence acquisition A literature review study was performed to identify and further assess the risk of relevant DDIs of 48 drugs frequently used in the tertiary care NICU of the University Hospital of Cologne. DDIs were categorized into five different classes according to their severity (contraindicated, minor, moderate, and major DDI, IAI), based on the classification used in the Micromedex database. In the database a major interaction is defined as any interaction that can be life threatening and/or demands medical intervention to avoid severe adverse effects. Moderate interactions can lead to a degradation of the patient's status and demand an adjustment in the therapy, and minor interactions only have a limited clinical effect. All identified DDIs in the present study are presented as a Visual Interaction Triangle (VIT) and recommendations on the management of clinically significant DDIs are provided. Evidence synthesis According to the classification used in the Micromedex database: a total of 160 (13.2%) possible interactions (DDI, IAI) were found. Fifty-five (4.9%) cases were categorized as serious interactions (DDI-major), 48 (4.2%) were less severe (DDI-moderate/minor) and in 52 (4.6%) cases an intravenous admixture drug interaction was found. Five (0.4%) drug-combinations were contraindicated. Conclusions In this web-based study, a total of 160 DDIs were identified. Although only 4.9% were classified as clinically relevant, practitioners can use the presented VIT as a unique clinical reference to avoid possible predictable adverse effects and to uncover possible drug-interaction potential.

Peripheral neuropathy is a common side effect of paclitaxel. Clinical studies suggest that different paclitaxel formulations influence the severity and time course of paclitaxel-induced peripheral neuropathy. We compared two paclitaxel formulations, nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and Cremophor EL paclitaxel (CreEL-paclitaxel), for their toxicity, distribution, and clearance in the peripheral nervous system. Neuronal F11 cells were used to detect changes in morphology, cell nuclei size, and cell viability after nab- or CreEL-paclitaxel treatment via MTT Assay and immunohistochemistry. C57BL/6 mice were treated with 50 mg/kg of nab-paclitaxel or CreEL-paclitaxel. Paclitaxel levels in serum, liver, dorsal root ganglia (DRG), and sciatic nerve (SCN) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Accumulation of paclitaxel in DRG neurons and SCN was visualized by immunostainings. Neurotoxicity was evaluated after a 4-week treatment regime with nab- or CreEL-paclitaxel by nerve morphology, behavioral, and functional assays. In vitro cell nuclei size and morphology were similar between the two treatment groups. Viability was increased in neurons exposed to nab-paclitaxel compared to CreEL-paclitaxel. In vivo paclitaxel mostly accumulated in DRG. SCN displayed lower paclitaxel uptake. The two paclitaxel formulations mainly accumulated in neurofilament 200-positive large-caliber neurons and less in Isolectin B4-, or calcitonin gene-related peptide-positive small-caliber neurons. Sensory nerve conduction studies demonstrated increased sensory latencies after 11 days in nab-paclitaxel treated animals, while an increase occurred after 22 days in CreEL-paclitaxel treated animals. Behavioral testing did not reveal significant differences between the different groups. Skin denervation, axon count, myelin thickness, and F4/80-positive cell accumulation were comparable between the two treatment groups. Our findings indicate that different drug formulations impact the severity of neuropathy induced by paclitaxel via different tissue uptake. Neurotoxicity was comparable between the two paclitaxel formulations.

Heading in soccer involves repetitive head accelerations that may be detrimental for brain health. One way to mitigate adverse effects may be to increase head-neck stabilization and thus reduce the kinematic response after intentional headers. This study aimed to (a) assess associations between neck strength and head kinematics and (b) evaluate an exercise intervention designed to increase strength and attenuate head acceleration during intentional heading in youth soccer players. In 22 athletes, we used accelerometers to assess associations between neck strength and peak linear acceleration (PLA). We attached the accelerometers to the occiput and sternum, allowing us to differentiate between total, trunk, and head PLA. Longitudinally, we evaluated the effects of a 14-week twice-weekly resistance training in a subsample of 14 athletes compared with regular soccer training (N = 13). Results showed that female athletes had lower isolated neck strength (p <= 0.004), lower functional neck strength (p <= 0.017), and higher total PLA during purposeful headers compared with males (17.2 +/- 3.5 g and 13.0 +/- 2.3 g, respectively, at 9.6 m.s(-1) ball velocity during impact; p = 0.003). The intervention group showed moderate to large strength gains (eta(2)(rho) = 0.16-0.42), resulting in lower PLA (total -2.4 g, trunk -0.8 g, and head -1.5 g) during headers. We conclude that a resistance training focusing on cervical and trunk musculature is practicable in youth soccer, elicits strength gains, and helps to mitigate PLA during purposeful heading. Results should encourage youth strength and conditioning professionals to incorporate neck exercises as a risk reduction strategy into their training routine.

Background Mental health is an emerging topic on university campuses, with students reporting higher levels of psychological distress than the general population of the same age. Increasing physical activity and reducing sedentary time have been proved promising measures to promote mental health in the general population. However, to derive and implement effective measures to promote mental health among university students, further exploration of the associations between physical activity, sedentary time, and perceived stress in this specific setting is needed. Objective This study aims to identify associations between physical activity, sedentary time, and perceived stress after controlling for sociodemographic and behavioral variables among university students in Germany. We hypothesize that perceived stress is inversely related to physical activity and positively associated with sedentary time. Furthermore, we hypothesize that combined associations of concurrently high physical activity and low sedentary time on perceived stress are stronger compared with either alone and that the association between physical activity and perceived stress depends on activity intensity. Methods We conducted cross-sectional analyses from a large-scale internet-based student health survey (n=4189; response rate=10.0%). Physical activity, sedentary time, and engaging in moderate and vigorous activity intensities were assessed using the International Physical Activity Questionnaire Short Form with categorization into low, intermediate, and high levels. We measured perceived stress using the 10-item Perceived Stress Scale (range 0-40). Results The results indicate that higher physical activity and lower sedentary time are associated with reduced levels of perceived stress. Following adjustment for gender, BMI, income, fruit and vegetable intake, alcohol consumption, and sleep quality, perceived stress scores were lower for students reporting high physical activity levels and low sedentary time compared with the least active and highly sedentary students (Perceived Stress Scale –2.2, 95% CI –2.9 to –1.5, P<.001 for physical activity and –1.1, CI 95% –1.7 to –0.5, P<.001 for sedentary time). Combined associations with perceived stress revealed that students concurrently reporting high total physical activity and low sedentary time reported the lowest perceived stress scores of all possible combinations following adjustment for confounders (Perceived Stress Scale –3.5, CI 95% –4.6 to –2.5, P<.001 compared with students reporting low physical activity levels and concurrently high sedentary time). Associations between vigorous physical activities and perceived stress were not stronger compared with moderate activity intensities. Conclusions Self-reported physical activity and low sedentary time are favorably associated with perceived stress, while the intensity of physical activities seems to be of minor importance. These results help to effectively implement health-promoting measures on campus among university students through increasing physical activity and reducing sedentary time.