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Abstract At present, the immune response of pigs in relation to Staphylococcus aureus carriage is poorly understood. This study was aimed at investigating the dynamics of the anti-staphylococcal humoral immune response in methicillin-susceptible S. aureus (MSSA)-positive piglets and at assessing the effect of the experimental introduction of a methicillin-resistant S. aureus (MRSA) Sequence Type (ST) 398 strain. Therefore, serum samples were collected at different times from 31 weaned piglets originating from four different sows. Twenty-four out of the 31 piglets were challenged with MRSA ST398. The serum samples were analyzed for IgG antibodies to 39 S. aureus antigens, using a multiplex bead-based assay (xMAP technology, Luminex Corporation). Though antibody responses showed broad inter-individual variability, serological results appeared to be clustered by litter of origin. For most antigens, an age-related response was observed with an apparent increase in antibody titers directed against staphylococcal microbial surface components recognizing adhesive matrix molecules (MSCRAMM), which have been shown to play a role in S. aureus colonization. In most animals, antibody titers directed against staphylococcal toxins or immune-modulating proteins decreased with age, possibly reflecting the absence of bacterial invasion. The introduction of MRSA ST398 did not elicit a significant humoral immune reaction. This study describes, for the first time, the humoral immune response in weaned pigs colonized with S. aureus.

Background: Care pathways are increasingly used in healthcare systems globally to guide patient care and improve outcomes. These pathways offer a structured approach to managing patient care processes, potentially reducing costs and enhancing efficiency. However, the dynamic and complex nature of healthcare presents challenges in analyzing and improving these pathways, particularly due to the unique and varied patient journeys. This study focuses on the use of administrative data to map care pathways for pediatric Traumatic Brain Injury (TBI) patients, a population significantly impacted by high mortality and disability rates., Objective: The objective of this research is to map and analyze care pathways using a novel methodology inspired by Hidden Markov chains. The study aims to overcome challenges in analyzing the dynamic and complex nature of the healthcare processes, particularly in a heterogeneous patient population. By using administrative data, the goal is to provide valuable insights into care pathways of these patients., Methods: The study utilizes a study case dataset comprising of 4074 children admitted to Belgian hospitals for TBI in 2016, with administrative data encompassing healthcare services up to one-year post-TBI. The proposed methodology involves representing care pathways as Hidden Markov chains, where the transition between states is determined by the current medical treatment. Hierarchical clustering based on similarity of care paths, volume, and median timepoint is applied to identify subpopulations., Results: Hierarchical clustering reveals distinct clusters, each characterized by unique care pathways. The clusters show variations in the length of care pathways, proportion of mild to severe cases, and vary with unique treatment events. Visualization of these pathways provides a comprehensive understanding of the treatment patterns within each cluster., Conclusion: The study introduces a novel methodology for mapping care pathways. Uncovering these different care pathways enhances the understanding of the variation in care and might lead to improving the quality of care received by patients., Competing Interests: Declaration of competing interest All Authers report no financial interests or potential conflicts of interest., (Copyright © 2025. Published by Elsevier B.V.)

Background: Verona integron-encoded metallo-β-lactamase-producing Pseudomonas aeruginosa (VIM-PA) outbreaks are frequently linked to contaminated sink-drains in the intensive care unit (ICU). This study aims to investigate a VIM-PA outbreak occurring at 4 ICUs in a Belgian university center., Methods: Between 01/01/2019 and 30/07/2023, data were retrospectively retrieved. Whole-genome sequencing of VIM-PA was carried out for available isolates and the core genome multilocus sequencing typing (cgMLST) was used to confirm clonality. New case incidence was estimated by analyzing the weekly data of at-risk and VIM-PA-colonized patients, fitting a regression model., Results: Fifty-one patients were colonized, among them, 32 (63%) were infected by VIM-PA, which contributed to 7 deaths. The outbreak investigation showed that 19 (47%) of the examined sink-drains grew at least once a VIM-PA. Two major clusters were observed by cgMLST: ST111 (59 clones with 40 clinical isolates), and ST17 (8 clones with 6 clinical isolates). The estimated incidence rate of new cases was significantly higher in one unit., Conclusions: A 5-year prolonged outbreak at the UZ Brussel ICUs was caused by only 2 VIM-PA clones, both linked to sink-drains, with minimal mutations occurring throughout the years. Statistical modeling found different incidence rates between units. Tailored interventions were hence prioritized., (Copyright © 2024 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

In several orthopedic procedures, the accurate use of surgical power tools is critical to avoid damage to surrounding tissues. As such, various guidance techniques and safety measures were developed. Augmented reality (AR) guidance shows promise but requires validation. We evaluated a new approach using an inside-out infrared tracking solution for the HoloLens to compensate for its limited tracking performance. Eighteen participants with varying levels of experience (student, trainee, expert) each drilled twelve trajectories (six perpendicular, six oblique) in equidimensional wooden logs. Three different techniques were evaluated: freehand drilling; proprioception-guided drilling towards the contralateral index finger; and AR-guided drilling using a tracked drill and a virtual overlay of the log with predefined guidance vectors. The angular errors between planned and performed trajectories were compared using a mixed-design ANOVA. The results demonstrated that guidance technique (p < 0.001) and drilling direction (p < 0.001) significantly affected drilling accuracy, while experience (p = 0.75) did not. AR outperformed both other techniques, particularly for oblique trajectories (p < 0.001). For perpendicular trajectories, it only outperformed proprioception guidance (p = 0.04). Target plots revealed an important scatter perpendicular to the longitudinal axis of the log during freehand and proprioception-guided drilling, especially for oblique trajectories. This inaccuracy disappeared during AR-guided drilling. As such, we were able to conclude that AR guidance using inside-out infrared tracking reduced angular uncertainty during directional drilling, resulting in improved drilling accuracy. This improvement was particularly noticeable for complex trajectories and angles. The benefits of AR guidance were observed across all experience levels, highlighting its potential for orthopedic applications. We believe this study opens the way for the methodical evaluation of AR guidance in specific orthopedic use cases., (© 2024. The Author(s).)

Introduction: Advancements in rectal cancer (RC) treatment not only led to an increase in lives saved but also improved quality of life (QoL). Notwithstanding these benefits, RC treatment comes at the price of gastrointestinal morbidity in many patients. Health economic modelling poses an opportunity to explore the societal burden of such side-effects. This study aims to quantify radiation-induced late small bowel (SB) toxicity in survivors of RC for Three-Dimensional Conformal Radiation Therapy (3D-CRT), Intensity Modulated Radiation Therapy (IMRT) and Intensity Modulated Radiation Therapy - Image Guided Radiation Therapy (IMRT/IGRT)., Materials and Methods: Materials and A model-based health economic evaluation was performed. The theoretical cohort consists of a case-mix of survivors of RC aged 25-99 years according to Belgian age-specific incidence rates. A societal perspective was adopted. The base case analysis was complemented with one-way deterministic analyses, deterministic scenario analyses and probabilistic sensitivity analysis (1,000 iterations). Results were presented as mean lifetime incremental cost (€) and utility (QALYs) per patient., Results: The analyses showed that the use of innovative radiotherapy (RT) improves lifetime QoL in survivors of RC by 0.11 QALYs and 0.05 QALYs by preferring IMRT/IGRT and IMRT over 3D-CRT, respectively. The use of IMRT/IGRT and IMRT results in an incremental cost-saving of €3,820 and €1,863 per patient, solely by radiation-induced SB toxicity, compared to 3D-CRT., Discussion and Conclusion: It is important to consider late toxicity effects in decisions regarding investments and reimbursement as our analysis highlighted the potential long-term cost-savings and improved QoL of novel RT techniques in patients with rectal cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kimpe, Parmentier, Busschaert, De Mey, Barbé, De Ridder and Putman.)

xCT (Slc7a11), the specific subunit of the cystine/glutamate antiporter system x c - , is present in the brain and on immune cells, where it is known to modulate behavior and inflammatory responses. In a variety of cancers -including pancreatic ductal adenocarcinoma (PDAC)-, xCT is upregulated by tumor cells to support their growth and spread. Therefore, we studied the impact of xCT deletion in pancreatic tumor cells (Panc02) and/or the host (xCT -/- mice) on tumor burden, inflammation, cachexia and mood disturbances. Deletion of xCT in the tumor strongly reduced tumor growth. Targeting xCT in the host and not the tumor resulted only in a partial reduction of tumor burden, while it did attenuate tumor-related systemic inflammation and prevented an increase in immunosuppressive regulatory T cells. The latter effect could be replicated by specific xCT deletion in immune cells. xCT deletion in the host or the tumor differentially modulated neuroinflammation. When mice were grafted with xCT-deleted tumor cells, hypothalamic inflammation was reduced and, accordingly, food intake improved. Tumor bearing xCT -/- mice showed a trend of reduced hippocampal neuroinflammation with less anxiety- and depressive-like behavior. Taken together, targeting xCT may have beneficial effects on pancreatic cancer-related comorbidities, beyond reducing tumor burden. The search for novel and specific xCT inhibitors is warranted as they may represent a holistic therapy in pancreatic cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Little is known about type D personality in patients with obstructive sleep apnea (OSA). The DS-14 questionnaire is the standard tool to assess this personality type, but it has not been properly validated in patients with OSA, nor has it been correlated with clinical features in these patients., Purpose: To determine the internal consistency and test-retest reliability of the DS-14 questionnaire, as well as the prevalence of type D personality in the overall OSA sample and subgroups. We assessed the influence of type D on perceived symptoms and its congruence with self-reported measures of personality, depression, fatigue, anxiety, quality of life, and quality of sleep., Methods: Patients with OSA completed the DS-14 questionnaire, Big Five Inventory-2 questionnaire, Hospital Anxiety and Depression Scale, SF-36 Health Survey Questionnaire, Epworth Sleepiness Scale and Stanford Sleepiness Scale, Pittsburgh Sleep Quality Index and Insomnia Severity Index, Fatigue Assessment Scale, and Checklist Individual Strength. After 1 month, the DS-14 questionnaire was repeated., Results: The overall prevalence of type D personality was 32%. Internal consistency (negative affectivity: α = 0.880, social inhibition: α = 0.851) and diagnostic test-retest reliability (kappa value = 0.664) of the DS-14 questionnaire were high. Significantly more symptoms of anxiety, depression, poor sleep quality, fatigue, and a worse health perception were found in OSA with type D. Neither OSA severity nor REM predominance altered these observations., Conclusion: The DS-14 questionnaire showed excellent psychometric properties in patients with OSA. The prevalence of type D personality in patients with OSA was higher than in the general population. The presence of type D personality was associated with higher symptom burden., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Children conceived through assisted reproductive technologies (ART) have an elevated risk of lower birthweight, yet the underlying cause remains unclear. Our study explores mitochondrial DNA (mtDNA) variants as contributors to birthweight differences by impacting mitochondrial function during prenatal development. We deep-sequenced the mtDNA of 451 ART and spontaneously conceived (SC) individuals, 157 mother-child pairs and 113 individual oocytes from either natural menstrual cycles or after ovarian stimulation (OS) and find that ART individuals carried a different mtDNA genotype than SC individuals, with more de novo non-synonymous variants. These variants, along with rRNA variants, correlate with lower birthweight percentiles, independent of conception mode. Their higher occurrence in ART individuals stems from de novo mutagenesis associated with maternal aging and OS-induced oocyte cohort size. Future research will establish the long-term health consequences of these changes and how these findings will impact the clinical practice and patient counselling in the future., (© 2024. The Author(s).)

Purpose: A shift towards (ultra-)hypofractionated breast irradiation can have important implications for the practice of contemporary radiation oncology. This paper presents a systematic analysis of the impact of different fractionation schedules on multiple key performance indicators, namely resource use, costs, work times, throughput and waiting times., Materials and Methods: Time-driven activity-based costing (TD-ABC) is applied to calculate the costs and resources consumed where the perspective of the radiotherapy department in adopted. Three fractionation regimens are considered: ultra-hypofractionation (5 x 5.2 Gy, UHF), moderate hypofractionation (15 x 2.67 Gy, HF) and conventional fractionation (25 x 2 Gy, CF). Subsequently, a discrete event simulation (DES) model of the radiotherapy care pathway is developed and scenarios are compared in which the following factors are varied: distribution of fractionation regimens, patient volume and operating hours., Results: The application of (U)HF can permit radiotherapy departments to reduce the use of scarce resources, realise work time and cost savings, increase throughput and reduce waiting times. The financial advantages of (U)HF are, however, reduced in cases of excess capacity and cost savings may therefore be limited in the short-term. Moreover, although an extension of operating hours has favourable effects on throughput and waiting times, it may also reduce cost differences between fractionation schedules by increasing the capacity of resources., Conclusion: By providing an in-depth analysis of the consequences associated with a shift towards (U)HF in breast cancer, the present study demonstrates how a DES model based on TD-ABC costing can assist radiotherapy professionals in making data-driven decisions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Rationale: Although promising responses are obtained in patients treated with immune checkpoint inhibitors targeting programmed death ligand 1 (PD-L1) and its receptor programmed death-1 (PD-1), only a fraction of patients benefits from this immunotherapy. Cancer vaccination may be an effective approach to improve the response to immune checkpoint inhibitors anti-PD-L1/PD-1 therapy. However, there is a lack of research on the dynamics of PD-L1 expression in response to cancer vaccination. Methods: We performed non-invasive whole-body imaging to visualize PD-L1 expression at different timepoints after vaccination of melanoma-bearing mice. Mice bearing ovalbumin (OVA) expressing B16 tumors were i.v. injected with the Galsome mRNA vaccine: OVA encoding mRNA lipoplexes co-encapsulating a low or a high dose of the atypical adjuvant α-galactosylceramide (αGC) to activate invariant natural killer T (iNKT) cells. Serial non-invasive whole-body immune imaging was performed using a technetium-99m ( 99m Tc)-labeled anti-PD-L1 nanobody, single-photon emission computerized tomography (SPECT) and X-ray computed tomography (CT) images were quantified. Additionally, cellular expression of PD-L1 was evaluated with flow cytometry. Results: SPECT/CT-imaging showed a rapid and systemic upregulation of PD-L1 after vaccination. PD-L1 expression could not be correlated to the αGC-dose, although we observed a dose-dependent iNKT cell activation. Dynamics of PD-L1 expression were organ-dependent and most pronounced in lungs and liver, organs to which the vaccine was distributed. PD-L1 expression in lungs increased immediately after vaccination and gradually decreased over time, whereas in liver, vaccination-induced PD-L1 upregulation was short-lived. Flow cytometric analysis of these organs further showed myeloid cells as well as non-immune cells with elevated PD-L1 expression in response to vaccination. SPECT/CT imaging of the tumor demonstrated that the expression of PD-L1 remained stable over time and was overall not affected by vaccination although flow cytometric analysis at the cellular level demonstrated changes in PD-L1 expression in various immune cell populations following vaccination. Conclusion: Repeated non-invasive whole-body imaging using 99m Tc-labeled anti-PD-L1 nanobodies allows to document the dynamic nature of PD-L1 expression upon vaccination. Galsome vaccination rapidly induced systemic upregulation of PD-L1 expression with the most pronounced upregulation in lungs and liver while flow cytometry analysis showed upregulation of PD-L1 in the tumor microenvironment. This study shows that imaging using nanobodies may be useful for monitoring vaccine-mediated PD-L1 modulation in patients and could provide a rationale for combination therapy. To the best of our knowledge, this is the first report that visualizes PD-L1 expression upon cancer vaccination., Competing Interests: Competing Interests: Nick Devoogdt and Marleen Keyaerts are founders and shareholders in Abscint. Nick Devoogdt is a consultant for Precirix and reports grants, personal fees, and non-financial support from Precirix, and non-financial support from Abscint. Marleen Keyaerts and Karine Breckpot have ongoing collaborations with Precerix for which they receive non-financial support. Karine Breckpot, Katrijn Broos, Nick Devoogdt and Marleen Keyaerts hold a patent on 'Human pd-l1-binding immunoglobulins' (WO2019166622A1). Ine Lentacker, Stefaan De Smedt, Rein Verbeke and Heleen Dewitte have a patent application on 'Therapeutic nanoparticles and methods of use thereof”. (WO2020/058239)., (© The author(s).)

Objective: In the management of epilepsy, there is an ongoing quest to discover new biomarkers to improve the diagnostic process, the monitoring of disease progression, and the evaluation of treatment responsiveness. In this regard, biochemical traceability in biofluids is notably absent in contrast to other diseases. In the present preclinical study, we investigated the potential of neurofilament light chain (NfL) as a possible diagnostic and response fluid biomarker for epilepsy., Methods: We gained insights into NfL levels during the various phases of the intrahippocampal kainic acid mouse model of temporal lobe epilepsy-namely, the status epilepticus (SE) and the chronic phase with spontaneous seizures. To this end, NfL levels were determined directly in the cerebral interstitial fluid (ISF) with cerebral open flow microperfusion as sampling technique, as well as in cerebrospinal fluid (CSF) and plasma. Lastly, we assessed whether NfL levels diminished upon curtailing SE with diazepam and ketamine., Results: NfL levels are higher during SE in both cerebral ISF and plasma in kainic acid-treated mice compared to sham-injected mice. Additionally, ISF and plasma NfL levels are lower in mice treated with diazepam and ketamine to stop SE compared with the vehicle-treated mice. In the chronic phase with spontaneous seizures, higher NfL levels could only be detected in ISF and CSF samples, and not in plasma. No correlations could be found between NfL levels and seizure burden, nor with immunohistological markers for neurodegeneration/inflammation., Significance: Our findings demonstrate the translational potential of NfL as a blood-based fluid biomarker for SE. This is less evident for chronic epilepsy, as in this case higher NfL levels could only be detected in ISF and CSF, and not in plasma, acknowledging the invasive nature of CSF sampling in chronic epilepsy follow-up., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: We developed Eforto®, an innovative system for (self-)monitoring of grip strength (GS) and muscle fatigability (Fatigue Resistance (FR = time until GS decreased to 50% of maximum during sustained contraction) and grip work (GW = area under the strength-time curve)). The Eforto® system consists of a rubber bulb that is wirelessly connected to a smartphone-based application, and a telemonitoring platform. The aim was to evaluate the validity and reliability of Eforto® to measure muscle fatigability., Methods: Community-dwelling older persons (n = 61), geriatric inpatients (n = 26) and hip fracture patients (n = 25) were evaluated for GS and muscle fatigability. In community dwellers fatigability was tested twice in the clinic (once with Eforto®, once with Martin Vigorimeter (MV), standard analog handgrip system) and for six consecutive days as a self-assessment at home with Eforto®. In hospitalized participants, fatigability was tested twice using Eforto®, once by a researcher and once by a health professional., Results: Criterion validity was supported by good to excellent correlations between Eforto® and MV for GS (r = 0.95) and muscle fatigability (FR r = 0.81 and GW r = 0.73), and no significant differences in measurements between both systems. Inter-rater and intra-rater reliability for GW were moderate to excellent (intra-class correlation: 0.59-0.94). The standard error of measurement for GW was small for geriatric inpatients and hip fracture patients (224.5 and 386.5 kPa*s) and higher for community-dwellers (661.5 kPa*s)., Discussion/conclusion: We established the criterion validity and reliability of Eforto® in older community-dwelling persons and hospitalized patients, supporting the implementation of Eforto® for (self-)monitoring of muscle fatigability., (© 2023. The Author(s).)

Objectives: Suppression of viral replication in patients on antiretroviral therapy (ART) is determined by plasma viral load (pVL) measurement. Whenever pVL reaches values below the limit of quantification, the qualitative parameter 'target detected' or 'target not detected' is available but often not reported to the clinician. We investigated whether qualitative pVL measurements can be used to estimate the viral reservoir size., Design: The study recruited 114 people with HIV (PWH) who are stable on ART between 2016 and 2018. The percentage of pVL measurements qualitatively reported as 'target detected' (PTD) within a 2-year period was calculated., Methods: t-DNA and US-RNA were used to estimate viral reservoir size and were quantified on peripheral blood mononuclear cells (PBMCs) using droplet digital PCR., Results: A median of 6.5 pVL measurements over a 2-year period was evaluated for each participant to calculate PTD. A positive correlation was found between t-DNA and PTD (r = 0.24; P = 0.011) but not between US-RNA and PTD (r = 0.1; P = 0.3). A significantly lower PTD was observed in PWH with a small viral reservoir, as estimated by t-DNA less than 66 copies/106 PBMCs and US-RNA less than 10 copies/106 PBMCs, compared with PWH with a larger viral reservoir (P = 0.001). We also show that t-DNA is detectable whenever PTD is higher than 56% and that ART regimen does not affect PTD., Conclusion: Our study shows that PTD provides an efficient parameter to preselect participants with a small viral reservoir based on already available pVL data for future HIV cure trials., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Early memories of pain contribute to fear and may underlie the maintenance and development of chronic pain into adulthood. Accordingly, understanding determinants that may impact children's pain memory development is key. This study examined (a) the effect of a brief engaging pain educational video in healthy children before undergoing an experimental pain task upon children's recalled pain intensity and pain-related fear and (b) the moderating role of parental pain- and non-pain-attending verbalizations before and after the pain task., Methods: Seventy-seven children (8-15 years old) participated in an experimental heat pain task, including actual heat pain stimuli delivered through a thermode on their forearm. Children were randomized to the experimental group (i.e., watching a pain educational video) or the control group (i.e., no video). Children's recalled pain intensity and pain-related fear were elicited 2 weeks later., Results: Findings showed that recalled pain intensity (but not recalled pain-related fear) of children who watched the pain educational video was significantly lower compared to the control group (p = .028). Further, parental pain-attending verbalizations before the pain task moderated the impact of the video upon children's recalled pain intensity (p = .038). Specifically, children in the control group, but not the experimental group, whose parents used less pain-attending verbalizations recalled higher pain intensity, whereas children whose parents used more pain-attending verbalizations recalled lower pain intensity., Conclusions: As children's pain memories have important implications for pain assessment, treatment, and health across the lifespan, these findings might have important implications for the prevention of development or maintenance of maladaptive pain-related outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Interim analysis is the practice of performing a statistical analysis when the data have only been partially collected, for example, to save resources or to handle the uncertainty of the true effect size. Most statistical designs featuring interim analysis have been developed either in a general statistical setting or for application in clinical trials. As a result, most of them make assumptions and have conditions that in a preclinical setting are usually not met. In this paper, we present necessary changes to the most common forms of interim analysis enhanced for animal experiments, specifically for the t-test and the one-way ANOVA. Finally, we present software that allows freeware use to serve the research community to facilitate the design of experiments featuring interim analyses. The app can be found at icds.be/gsdesigner. It is in the public domain and its code can be found on github.com/ICDS-vubUZ/gsd-designer. In this GitHub folder, one can also find a tutorial for the app., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ensemble modeling is an increasingly popular data science technique that combines the knowledge of multiple base learners to enhance predictive performance. In this paper, the idea was to increase predictive performance by holding out three algorithms when testing multiple classifiers: (a) the best overall performing algorithm (based on the harmonic mean of sensitivity and specificity (HMSS) of that algorithm); (b) the most sensitive model; and (c) the most specific model. This approach boils down to majority voting between the predictions of these three base learners. In this exemplary study, a case of identifying a prolonged QT interval after administering a drug-drug interaction with increased risk of QT prolongation (QT-DDI) is presented. Performance measures included accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Overall performance was measured by calculating the HMSS. Results show an increase in all performance measure characteristics compared to the original best performing algorithm, except for specificity where performance remained stable. The presented approach is fairly simple and shows potential to increase predictive performance, even without adjusting the default cut-offs to differentiate between high and low risk cases. Future research should look at a way of combining all tested algorithms, instead of using only three. Similarly, this approach should be tested on a multiclass prediction problem.

The cystine/glutamate antiporter system x c - has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT -/- ) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT -/- mice led to the hypothesis that system x c - deletion would negatively affect life- and healthspan. Still, till now the role of system x c - in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT -/- mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT +/+ mice, was attenuated in xCT -/- mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT -/- mice. Targeting system x c - is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging., (© 2022. The Author(s).)

By integrating data of the PLCO cancer screening trial, SCORE-risk charts and radiotherapy excess ratios, we were able to create risk charts estimating radiotherapy-induced lung cancer and cardiovascular mortality in female breast cancer patients. These risk models might be useful to individualize radiotherapy and optimize lung cancer and cardiovascular prevention and screening., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: This study aimed to simplify and optimize the distinction between nonfunctional overreaching (NFO) and overtraining syndrome (OTS) by developing a multivariate approach (discriminant analysis [DA]) including hormonal and psychological changes measured during the Training Optimization (TOP) test., Methods: Sensitivity of previously defined cutoff values for hypothalamic-pituitary-adrenal axis hormonal changes were recalculated on a larger database (n = 100). Discriminant analysis including hormonal and psychological variables measured during the TOP test was used to discriminate between NFO and OTS and predict the diagnosis of new cases., Results: Adrenocorticotrophic hormone (ACTH) and prolactin (PRL) responses to the second exercise test were most sensitive to NFO and OTS. Cutoff values for ACTH and PRL response to the second test (NFO > cutoff value (200%) > OTS), showed a sensitivity of 67% for ACTH and 93% for PRL in case of OTS and 74% for both ACTH and PRL in case of NFO. A DA including hormonal and psychological changes measured during the TOP test, resulted in the accurate diagnosis of NFO and OTS with 98% sensitivity. The ACTH and PRL responses to the first and second exercise tests and feeling of fatigue were the most discriminating variables., Conclusions: The ACTH and PRL responses during the TOP test are the most sensitive markers to discriminate between NFO and OTS. Discriminant analysis including hormonal and psychological responses during the TOP test, can be used to optimize the diagnosis of NFO and OTS.

Background and Purpose: Stereotactic radiotherapy (SRT, SBRT) is widely used in oligometastatic cancer, but the heterogeneity of the population complicates estimation of the prognosis. We investigated the role of different clinical and inflammatory parameters., Materials and Methods: We included all patients treated with SRT for 1-5 oligometastases between 2003 and 2017 in our center. Patients were randomized between a model training set (2/3) and a separate validation set (1/3). A Cox regression model was built, validated and risk points were attributed to the resulting parameters., Results: 403 patients received SRT for 760 metastases. Treated sites were mainly lung, liver, nodal areas, and brain. Most common primaries were colorectal and lung cancer. Median follow-up for living patients reached 42 months and median overall survival (MS) was 26.6 months (95% CI 23.8-29.3). Five independent adverse factors were discriminated: male sex, synchronous timing of oligometastases, brain metastasis, non-adenocarcinoma histology, KPS <80. A risk score is formed by summation of the points of each factor (M:4, T:2, B:7, N:7, K:8). Four risk groups were defined: (1) 0-2 points: MS 41.2 months (95% CI 30.2-52.3); (2) 3-8 points: 29.3 months (24.6-34.0); (3) 9-13 points: 17.4 months (10.1-24.7), and (4) 14-28 points: 7.9 months (5.5-10.3)., Conclusion: We propose a prognostic score applicable in a variety of primary tumors and disease locations, including presence of brain metastases. The nomogram and risk groups can be used to stratify patients in new trials and to support individualized care for oligometastatic patients. An online calculator will become available at predictcancer.org., (Copyright © 2019 Elsevier B.V. All rights reserved.)

High-frequency radio energy is applied to tissue therapeutically in a number of different medical applications. The ability to model the effects of RF energy on the collagen, elastin, and liquid content of the target tissue would allow for the refinement of the control of the energy in order to improve outcomes and reduce negative side-effects. In this paper, we study the time-varying impedance spectra of the circuit. It is expected that the collagen/elastin ratio does not change over time such that the time-varying impedance is a function of the liquid content. We apply a non-parametric model in which we characterize the measured impedance spectra by its frequency response function. The measurements indicate that the changing impedance as a function of time exhibit a polynomial shift which we characterize by a polynomial regression. Finally, we quantify the uncertainty to obtain prediction intervals for the estimated polynomial describing the time variation of the impedance spectra.

In the last years attempts to develop a non-invasive glucose system based on the glucose levels in sweat have been studied. In this paper, 32 metal oxide semiconductor (MOS) sensors operating at different temperatures have been used to develop a multisensor olfactory system that allows to study the glucose levels in sweat. In order to develop repeatable experiments, artificial sweat at different glucose concentrations were developed in the laboratory. The obtained results suggest high viability of the approach. Although, the sensitivity of the sensors system needs to be improved.