A prebiotic intervention improves mood in everyday life in healthy women but not in men: Exploratory results from a larger double-blind placebo controlled cross-over study.

Prebiotic dietary fiber (PDF) may reduce feelings of stress or improve mood in healthy individuals. Yet gut intervention studies that focus on mood in daily life are lacking and few studies include extensive biological sample analyses to gain mechanistic insights. As part of a larger randomized placebo-controlled crossover study including healthy individuals, we explored the effects of 12 weeks of PDF (acacia gum and carrot powder) on everyday mood, as measured with ecological momentary assessment (EMA).

Open-Label Interventional Study in Healthy Volunteers to Evaluate NO-Mediated Vasodilation by Dermal Allyl Isothiocyanate Challenge and Whole-Body Heat Stress.

Dermal allyl isothiocyanate (AITC) administration and whole-body heat stress (WBHS) are two challenge models that are used to evaluate physiological mechanisms of vasodilation and pharmacological activity in humans. Their exact vasodilatory mechanisms in humans are not fully elucidated but are likely to be nitric oxide (NO)-mediated. This study aimed to evaluate whether there is overlap in the vasodilatory pathways of dermal AITC application and WBHS by combining the challenges.

Microvascular effects of a mixed meal tolerance test: a model validation study.

Purpose: Endothelial dysfunction is a pathophysiological change preceding many cardiovascular events. Measuring improvements of endothelial function is challenging when function is already optimal, which may be remediated using a physiological challenge. This study aimed to determine whether imaging assessments can detect microvascular effects of a mixed meal tolerance test (MMTT).

Individualized 3D-printed applicators for magnetic resonance imaging-guided brachytherapy in nasal vestibule cancer.

Background And Purpose: Brachytherapy is treatment of choice for early stage nasal vestibule cancer. Over the years improvements were achieved by means of image guided target definition, interstitial implant techniques and also individual mold techniques. The aim of this study was to improve the technique of the implant so that the need for interstitial catheters can be limited by making use of patient individualized 3D-printed applicators.

Adaptive brachytherapy for cervical cancer in combined 1.5 T MR/HDR suite: Impact of repeated imaging.

Introduction: At our department we have a dedicated 1.5 Tesla MRI/HDR brachytherapy suite, which provides the possibility of repeated MRI scanning before, during and after applicator insertion and before and/or after irradiation for patients with advanced cervical cancer. In this study we analysed the effect of this adaptive workflow.

Extending the IMQ Model: Deep Characterization of the Human TLR7 Response for Early Drug Development.

Imiquimod (IMQ; brand name Aldara®) is a registered topical agent that has been proven to induce local inflammation via the Toll-like receptor (TLR)7 pathway. The purpose of this study was to characterize TLR7-mediated inflammation following 7 days (168 h) of topical IMQ exposure in healthy volunteers, and to compare the effects of short exposure (48 h-72 h) with prolonged exposure (120 h-168 h). IMQ (100mg) was applied under occlusion to 5 different tape-stripped treatment sites on the back of 10 healthy participants for a maximum of 7 consecutive days.

Robotic MR-guided high dose rate brachytherapy needle implantation in the prostate (ROBiNSon)-a proof-of-concept study.

A robotic needle implant device for MR-guided high-dose-rate (HDR) prostate brachytherapy was developed. This study aimed to assess the feasibility and spatial accuracy of HDR brachytherapy using the robotic device, for a single intraprostatic target point.Five patients were treated from November 2019-June 2022 with the robot.

Immune responsiveness in stable kidney transplantation patients: Complete inhibition of T-cell proliferation but residual T-cell activity during maintenance immunosuppressive treatment.

The recommended immunosuppressive treatment after kidney transplantation consists of tacrolimus, mycophenolate mofetil, and low-dose corticosteroids. Drug concentrations are monitored using therapeutic drug monitoring (TDM), which does not necessarily correlate with pharmacodynamic activity. To find the balance between optimal efficacy and minimal toxicity, it might be more informative to monitor patients' immunological status rather than drug concentrations.

Immunomodulating effects of the single bacterial strain therapy EDP1815 on innate and adaptive immune challenge responses - a randomized, placebo-controlled clinical trial.

The gut microbiome can modulate systemic inflammation and is therefore target for immunomodulation. Immunomodulating effects of EDP1815, a bacterial commensal strain of Prevotella histicola, were studied in healthy participants. Effects on adaptive immunity were evaluated by a neo-antigen challenge with keyhole limpet haemocyanin (KLH), while effects on innate immunity were evaluated by topical toll-like receptor 7 (TLR7) agonist imiquimod.

The oral IRAK4 inhibitors zabedosertib and BAY1830839 suppress local and systemic immune responses in a randomized trial in healthy male volunteers.

This study evaluated and characterized the pharmacological activity of the orally administered interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors BAY1834845 (zabedosertib) and BAY1830839 in healthy male volunteers. Participants received one of either IRAK4 inhibitors or a control treatment (prednisolone 20 mg or placebo) twice daily for 7 days. Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3 days, starting at Day 3 of treatment.

Impact of fibre supplementation on microbiome and resilience in healthy participants: A randomized, placebo-controlled clinical trial.

Background And Aims: The gut microbiome exerts important roles in health, e.g., functions in metabolism and immunology.

Repeated upslope biome shifts in Saxifraga during late-Cenozoic climate cooling.

Mountains are among the most biodiverse places on Earth, and plant lineages that inhabit them have some of the highest speciation rates ever recorded. Plant diversity within the alpine zone - the elevation above which trees cannot grow-contributes significantly to overall diversity within mountain systems, but the origins of alpine plant diversity are poorly understood. Here, we quantify the processes that generate alpine plant diversity and their changing dynamics through time in Saxifraga (Saxifragaceae), an angiosperm genus that occurs predominantly in mountain systems.

A phase 1 trial of AP30663, a K2 channel inhibitor in development for conversion of atrial fibrillation.

Aims: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca activated K (K2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial.

Methods: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs.

Oral prednisolone suppresses skin inflammation in a healthy volunteer imiquimod challenge model.

Imiquimod (IMQ) is a topical agent that induces local inflammation the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model.

Heart rate stability in a clinical setting and after a short exercise in healthy male volunteers.

Introduction: Limited data exist on heart rate stabilization in the domiciled nature of phase I clinical studies, particularly when frequent measurements of QT intervals are involved. The present analysis aimed to evaluate heart rate stability in the domiciled nature of, and stabilization after a short exercise.

Methods: Fifty-six healthy male subjects were included in this analysis.

Immune Monitoring of Mycophenolate Mofetil Activity in Healthy Volunteers Using T Cell Function Assays.

Mycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as "one-dose-fits-all" together with a calcineurin inhibitor (CNI). Although drug concentrations are frequently monitored, there is still a group of patients who experience side effects related to excessive or insufficient immune suppression. We therefore aimed to identify biomarkers that reflect the overall immune status of the patient and might support individualized dosing.

Characterization of the Pharmacokinetic and Pharmacodynamic Profile of Apraglutide, a Glucagon-Like Peptide-2 Analog, in Healthy Volunteers.

Apraglutide (FE 203799) is a glucagon-like peptide-2 (GLP-2) analog under development for the treatment of intestinal failure associated with short bowel syndrome (SBS-IF) and graft-versus-host disease (GvHD). Compared with native GLP-2, apraglutide has slower absorption, reduced clearance, and higher protein binding, enabling once-weekly dosing. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults.

A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator.

Background: Loss-of-function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA-PD). GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), a promising target for a possible first disease-modifying therapy. LTI-291 is an allosteric activator of GCase, which increases the activity of normal and mutant forms of GCase.

Identification of peripheral vascular function measures and circulating biomarkers of mitochondrial function in patients with mitochondrial disease.

The development of pharmacological therapies for mitochondrial diseases is hampered by the lack of tissue-level and circulating biomarkers reflecting effects of compounds on endothelial and mitochondrial function. This phase 0 study aimed to identify biomarkers differentiating between patients with mitochondrial disease and healthy volunteers (HVs). In this cross-sectional case-control study, eight participants with mitochondrial disease and eight HVs matched on age, sex, and body mass index underwent study assessments consisting of blood collection for evaluation of plasma and serum biomarkers, mitochondrial function in peripheral blood mononuclear cells (PBMCs), and an array of imaging methods for assessment of (micro)circulation.

A multimodal, comprehensive characterization of a cutaneous wound model in healthy volunteers.

Development of pharmacological interventions for wound treatment is challenging due to both poorly understood wound healing mechanisms and heterogeneous patient populations. A standardized and well-characterized wound healing model in healthy volunteers is needed to aid in-depth pharmacodynamic and efficacy assessments of novel compounds. The current study aims to objectively and comprehensively characterize skin punch biopsy-induced wounds in healthy volunteers with an integrated, multimodal test battery.

A Biomarker Study in Patients with GBA1-Parkinson's Disease and Healthy Controls.

Background: Molecules related to glucocerebrosidase (GCase) are potential biomarkers for development of compounds targeting GBA1-associated Parkinson's disease (GBA-PD).

Objectives: Assessing variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA-PD, idiopathic PD (iPD), and healthy volunteers (HVs).

Methods: Data from five studies were combined.

Immunosuppression by hydroxychloroquine: mechanistic proof in in vitro experiments but limited systemic activity in a randomized placebo-controlled clinical pharmacology study.

Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To gain insight in this relationship, we performed in vitro experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor (TLR)3/TLR7/TLR9/RIG-I-induced cytokine production.

Recurrence characteristics after focal salvage HDR brachytherapy in prostate cancer.

Background And Purpose: Radiorecurrent prostate cancer is often confined to the prostate, predominantly near the index lesion. The purpose of this study was to look at recurrence characteristics in patients treated with focal salvage high dose-rate (HDR) brachytherapy.

Materials And Methods: Patients treated with MRI-guided HDR brachytherapy, with a single fraction of 19 Gy from July 2013 to October 2021 as focal salvage treatment, were prospectively included in the current study.

Impact of oral administration of single strain spp. on immune responses to keyhole limpet hemocyanin immunization and gut microbiota: A randomized placebo-controlled trial in healthy volunteers.

Introduction: spp. has been associated with promising immunomodulatory results in preclinical trials. The aim of this study was to investigate the pharmacodynamic (PD) effects of three monoclonal microbial formulations of spp.