Understanding and Streamlining Dose Finding: From Dose Simulation to Dose Estimation.

Understanding drug dosing to fulfill safety and efficacy requirements in a patient population is an essential part of dose finding in clinical practice and drug development. The majority of current dose finding methods are simulation-based, which can be time consuming and resource intensive. Model-based simulations also do not guarantee that the dose, that will optimally fulfill the safety and efficacy endpoints, will be found.

Nutrient Digestibility in Zoo-Kept Tapirs (Tapirus spp) as Compared to Other Herbivores.

Tapirs are hindgut fermenters with a natural diet dominated by browse, with a certain proportion of wild fruit. By contrast, diets fed to tapirs in zoos are often dominated by domestic fruit and other sources of easily digestible carbohydrates, which have been linked to obesity and various health problems. We aimed at better understanding the digestive physiology of tapirs, measuring the digestive efficiency of 13 lowland (Tapirus terrestris) and five Malayan (Tapirus indicus) tapirs from five zoos on various zoo diets by recording intake and total faecal excretion.

Persistent Eosinophilic Inflammation Is Not a Feature of Type 2 CRS Patients Failing Anti-IL-5R Therapy and Requiring Class Switching to Anti-IL-4/13.

Background: Type 2 inflammation dominates eosinophilic chronic rhinosinusitis (eCRS) and adult onset asthma. IL-4, -5, and -13 are prominent disease mediators. Disease control can be achieved with biologic therapies.

Identification of a binding site for small molecule inhibitors targeting human TRPM4.

Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid derivative NBA is a potent and specific TRPM4 inhibitor, but its binding site in TRPM4 has been unknown, although this information is crucial for drug development targeting TRPM4. We determine three cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs without inhibitor, bound to NBA, and an anthranilic acid derivative, IBA.

Mechanisms of Lipid-Associated Macrophage Accrual in Metabolically Stressed Adipose Tissue.

Adipose tissue (AT) inflammation, a hallmark of the metabolic syndrome, is triggered by overburdened adipocytes sending out immune cell recruitment signals during obesity development. An AT immune landscape persistent throughout weight loss and regain constitutes an immune-obesogenic memory that hinders long-term weight loss management. Lipid-associated macrophages (LAMs) are emerging as major players in diseased, inflamed metabolic tissues and may be key contributors to an obesogenic memory in AT.

Aspirin-free strategies after percutaneous coronary intervention: Old habits, consolidated evidence and future perspectives.

For almost two decades, dual antiplatelet therapy (DAPT) has been considered the cornerstone of pharmacological treatment in patients undergoing percutaneous coronary intervention (PCI). DAPT composition and duration have considerably evolved in the last decade moving from fixed treatment durations to tailored strategies based on the individual ischemic and bleeding risks. The increasing awareness of the prognostic relevance of bleeding events after PCI and the need for tailoring DAPT according to the individual bleeding and ischemic risks paved the way to newer DAPT modulation strategies by early aspirin withdrawal which have been shown to decrease bleeding without affecting therapeutic efficacy.

Beyond COVID-19, the case for collecting, analysing and using sex-disaggregated data and gendered data to inform outbreak response: a scoping review.

Introduction: Understanding sex and gender differences during outbreaks is critical to delivering an effective response. Although recommendations and minimum requirements exist, the incorporation of sex-disaggregated data and gender analysis into outbreak analytics and response for informed decision-making remains infrequent. A scoping review was conducted to provide an overview of the extent of sex-disaggregated data and gender analysis in outbreak response within low- and middle-income countries (LMICs).

Purification and characterization of recombinant human mitochondrial proton-pumping nicotinamide nucleotide transhydrogenase.

The human mitochondrial nicotinamide nucleotide transhydrogenase (NNT) uses the proton motive force to drive hydride transfer from NADH to NADP and is a major contributor to the generation of mitochondrial NADPH. NNT plays a critical role in maintaining cellular redox balance. NNT-deficiency results in oxidative damage and its absence results in familial glucocorticoid deficiency.

Alterations in resting-state EEG functional connectivity in patients with major depressive disorder receiving electroconvulsive therapy: A systematic review.

Electroconvulsive therapy (ECT) is highly efficacious for the treatment of major depressive disorder (MDD), but its mechanisms still require clarification. Even though depression is associated with alterations in functional connectivity (FC), EEG studies investigating effects of ECT on FC have not been systematically reviewed. Understanding these effects may help to identify the role of functional brain circuits in depression and its remission.

Incorporating ethics into infectious disease clinical practice guidelines.

Background: Incorporating ethics into clinical practice guidelines (CPGs) can be challenging. This is particularly evident for infectious diseases (ID) CPGs due to the complexity of ID ethics (IDE) and the multiplicity of populations at-risk for infections.

Objectives: The OPENING project (IncOrPorating Ethics iN ClINical Guidelines: Practical Indications) was initiated by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Ethics Advisory Committee (EEAC) in collaboration with the ESCMID Guidelines Subcommittee to generate guidelines for the systematic inclusion of ethics principles into ID CPGs.

Machine learning reveals novel compound for the improved production of chitooligosaccharides in Escherichia coli.

In order to improve predictability of outcome and reduce costly rounds of trial-and-error, machine learning models have been of increasing importance in the field of synthetic biology. Besides applications in predicting genome annotation, process parameters and transcription initiation frequency, such models have also been of help for pathway optimization. The latter is a common strategy in metabolic engineering and improves the production of a desirable compound by optimizing enzyme expression levels of the production pathway.

PBT/PMT assessment of active pharmaceutical ingredients.

The EU Commission proposal for a new EU pharmaceutical legislation considers PBT (persistence-bioaccumulation-toxicity) and PMT (persistence-mobility-toxicity) criteria for pharmaceuticals. Under current environmental risk assessment guidance, a PBT assessment is required regardless of the predicted environmental concentrations. However, consumption volumes of pharmaceuticals are contingent on marketing approval by EMA and are therefore predictable and their toxicological potency is established prior to any regulatory approval.

« Augmented radiotherapy » in the management of high-risk prostate cancer (PCa): a systematic review.

Background: In patients with high-risk (HR) prostate cancer (PCa) treated with radiotherapy and androgen deprivation therapy (ADT), intensification with androgen receptor pathway inhibitor (ARPI) improves overall survival (OS), at the cost of significant side-effects. We hypothesized that "augmented RT" schedules (defined as either dose-escalation on the prostate gland over 78Gy and/or addition of whole pelvic radiotherapy (WPRT)), combined with long-term ADT can reach excellent prostate cancer specific survival (PCSS) in this population with little detrimental impact on quality of life.

Methods: We searched Pubmed database until February 8, 2024.

The complexities of aeronautical transfer of acutely unwell neurosurgical patients.

Objective: Neurosurgical care is difficult to access in many scenarios. Aeromedical evacuation of acutely unwell neurosurgical patients from remote, isolated or poorly equipped locations can be considered. This article aims to provide a framework of logistical factors which deserve special consideration in the preparation of these patients for transfer.

Clinical predictors in acute optic neuritis: Analysis based on clinical trial data.

Purpose: To identify baseline clinical predictors of visual outcomes six months after acute optic neuritis using data from our completed clinical neuroprotection trial (TONE study).

Design: Secondary analysis of data from the TONE study cohort (NCT01962571).

Subjects: Total of 103 patients presenting within 10 days of a first episode of acute unilateral optic neuritis as a clinically isolated syndrome with baseline high contrast visual acuity (HCVA) < 20/40 Snellen (logMAR 0.

Effect of e-cigarettes for smoking cessation on depressive and anxiety symptoms: Secondary analysis of a randomized controlled trial.

Objective: This study aims to assess differences in depressive and anxiety symptoms at 6-month follow-up in a smoking cessation trial using e-cigarettes as quitting aids.

Methods: We conducted a secondary analysis of the Swiss multicentre ESTxENDS smoking cessation randomized controlled trial (RCT) assessing differences in depressive (Patient Health Questionnaire-9, PHQ-9, range: 0-27) and anxiety symptoms (General Anxiety Disorder-7, GAD-7, range: 0-21) at 6-month follow-up comparing participants who received e-cigarettes to those who received smoking cessation counseling alone.

Results: Of 1244 participants 913 completed the PHQ-9 and 884 the GAD-7 at 6-month follow-up.

PTV Margins in MR-guided and Beam-gated SBRT of Liver Metastases: GTV Dose Escalation Can Reduce the Required PTV.

Aims: Determining appropriate PTV margins for SBRT of liver metastases is a non-trivial task, especially with motion management included. The widely used analytical van Herk margin recipe (van Herk et al., 2000) could break down due to (i) a low number of fractions, (ii) non-Gaussian errors, or (iii) non-homogenous dose distributions.

Heart rate and salivary cortisol as indicators of arousal and synchrony in clients, therapy horses and therapist in equine-assisted therapy.

Background: This exploratory study aimed to analyse physiological interaction processes in equine-assisted-therapy (EAT) between client, therapy horse and therapist.

Methods: We measured heart rate (HR), heart rate variability (HRV) and cortisol levels before, during and after a standardized therapy session and a control condition in one therapist, four therapy horses and ten female clients in emerging adulthood (Mn = 21.8 years, SD = 3.

First evidence that antibiotic-resistant bacteria are inactivated by chemical species produced through the solar photosensitization of ciprofloxacin in water.

For the first time, using a chemical pollutant (an antibiotic) as a photosensitizer to improve the elimination of a microbiological contaminant of emerging concern (antibiotic-resistant bacteria) is presented. The effect of ciprofloxacin (CIP) on the inactivation of three light-promoted antibiotic-resistant bacteria (ARB) was evaluated. Ciprofloxacin-resistant Escherichia coli, ciprofloxacin-resistant Staphylococcus aureus, and carbapenem-resistant Klebsiella pneumoniae.

Automation of on-site microbial water quality monitoring from source to tap: Challenges and perspectives.

Ensuring the provision of safe drinking water necessitates thorough monitoring of microbial water quality. While traditional culture-based enumeration of bacterial indicators has served as the gold standard in compliance monitoring since the late 19th century, recent advancements in microbial sensor technology, driven by automation and digitalization, are revolutionizing on-site monitoring capabilities. These innovations offer unparalleled potential for automated, high temporal frequency monitoring with remote, real-time data transmission.

Biology-inspired dynamic microphysiological system approaches to revolutionize basic research, healthcare and animal welfare.

The regular workshops held by the Center for Alternatives to Animal Testing (CAAT) on biology-inspired microphysiological systems (MPS) taking place every four years, have become a reliable measure to assess fundamental scientific, industrial and regulatory trends for translational science in the MPS-field from a bird's eye view. The 2023 workshop participants at that time concluded that the technology as used within academia has matured significantly, underlined by the broad use of MPS and the steadily increasing number of high quality research publications - yet, broad industry adoption of MPS has been slow, despite strong interest. Academic research using MPS primarily aims to accurately recapitulate human biology in MPS-based organ models in areas where traditional models have been lacking key elements of human physiology, thereby enabling breakthrough discoveries for life sciences.

Standardisation of the Brazilian version of Lucerne ICF-based multidisciplinary observational scale (LIMOS) into a patient-reported outcome measure (PROM).

Purpose: The LIMOS is a validated observational tool designed to assess stroke rehabilitation within hospital settings. To enable its application in outpatient settings in Brazil and similar low- and middle-income countries, it is necessary to adapt LIMOS into a Patient-Reported Outcome Measure (PROM). Accordingly, this study aimed to translate, cross-culturally adapt, and standardise LIMOS for the Brazilian context (LIMOS-Br) and transform it into a PROM.

Impact of Varicocele on The Expression of Testicular Enzymes Involved in The Transsulfuration Pathway.

Background: Oxidative aggression is a hallmark of varicocele and may depend on decreased reactive ability of the endogenous antioxidant system following heat stress. We aimed to investigate the underlying mechanisms. Therefore, the expression of the main enzyme proteins involved in the generation of endogenous antioxidant power, cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), heme oxygenase (HO-1), and also, some of the metabolites (methionine, homocysteine, taurine and vitamin B6) reporting on their activity was investigated using a surgical varicocele model in rats.

A lyophilised formulation of chimpanzee adenovirus vector for long-term stability outside the deep-freeze cold chain.

Background: The adenovirus-vaccine platform has come to prominence with the COVID-19 vaccination campaigns. The objective of this study was to validate a formulation that was suitable for lyophilisation and long-term storage at 5 (2-8) °C.

Methods: Vaccine stability was assessed up to five years at 5 °C using a lyophilised formulation of the chimpanzee-adenovirus vector ChAd155 encoding a respiratory syncytial virus (RSV) antigen.

Sex differences in the time trends of sepsis biomarkers following polytrauma.

Sepsis is a major cause of death in polytrauma patients, with delayed antibiotics increasing mortality. Although biological sex influences immune function and disease outcomes, gender-specific differences in inflammatory response and sepsis progression remain underexplored. This study examined the time-dependent behavior of C-reactive protein (CRP), procalcitonin (PCT), and white blood cell count (WBC) in male and female polytrauma patients to evaluate their predictive value for sepsis.