Use of a Non-Endoscopic Capsule-Sponge Triage Test for Reflux Symptoms: Results From the NHS England Prospective Real-World Evaluation.

Background: Acid reflux is a common presentation in primary care leading to a high volume of referrals to endoscopy that are often normal.

Aims: To determine whether a non-endoscopic capsule sponge biomarker test could triage patients with low-risk reflux symptoms, reduce endoscopy waiting lists and identify Barrett's oesophagus in a real-world setting.

Methods: Patients with reflux symptoms on NHS endoscopy waiting lists who were offered a capsule sponge (test group) between February 2021 and August 2022 were included in this national multicentre prospective cohort study and compared with eligible patients on the standard endoscopy pathway (counterfactual group).

Prevention of Stroke in Intracerebral Haemorrhage Survivors with Atrial Fibrillation: Rationale and Design for PRESTIGE-AF Trial.

Adequate secondary prevention in survivors of intracerebral hemorrhage (ICH) who also have atrial fibrillation (AF) is a long-standing clinical dilemma because these patients are at increased risk of recurrent ICH as well as of ischemic stroke. The efficacy and safety of oral anticoagulation, the standard preventive medication for ischemic stroke patients with AF, in ICH patients with AF are uncertain. PRESTIGE-AF is an international, phase 3b, multi-center, randomized, open, blinded end-point assessment (PROBE) clinical trial that compared the efficacy and safety of direct oral anticoagulants (DOACs) with no DOAC (either no antithrombotic treatment or any antiplatelet drug).

The Impact of Head Position on Neurological and Histopathological Outcome Following Controlled Automated Reperfusion of the Whole Body (CARL) in a Pig Model.

Based on extracorporeal circulation, targeted reperfusion strategies have been developed to improve survival and neurologic recovery in refractory cardiac arrest: Controlled Automated Reperfusion of the whoLe Body (CARL). Furthermore, animal and human cadaver studies have shown beneficial effects on cerebral pressure due to head elevation during conventional cardiopulmonary resuscitation. Our aim was to evaluate the impact of head elevation on survival, neurologic recovery and histopathologic outcome in addition to CARL in an animal model.

Therapeutic drug monitoring of osimertinib in non-small cell lung cancer and short bowel syndrome: A case report.

Short bowel syndrome (SBS) following extensive intestinal resection is often characterized by impaired absorption of orally administered drugs, including tyrosine kinase inhibitors (TKI). We report the case of a patient with EGFR-mutated non-small cell lung carcinoma treated with 80 mg/day of the TKI osimertinib who achieved partial response of the tumour, but was subsequently subjected to a double-barrelled jejunostomy due to ileus. Due to the development of SBS after the bypass surgery, plasma concentrations of osimertinib were monitored using mass spectrometry.

The Effects of COVID-19 on General Surgery Residency Programs in the United States.

Introduction: The COVID-19 pandemic impacted multiple aspects of surgical education. This survey delineates steps taken by general surgery residency programs to meet changing patient-care needs while continuing to provide adequate education.

Methods: A survey was administered to program directors and coordinators of all United States general surgery residency programs to assess the early effects of the pandemic on residents from March 1 through May 31, 2020.

CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults.

Background And Objective: Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug-drug interaction trial in healthy participants (N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CL).

Methods: At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were given to estimate their clearances (CL).

Time course of CYP3A activity during and after metamizole (dipyrone) in healthy volunteers.

Aims: In patients of all ages, metamizole is a frequently used analgesic. Recently, metamizole has been identified as an inducer of, among others, cytochrome P450 (CYP) 3A activity, but the time course of this interaction has not been evaluated.

Methods: Using repeated oral microdoses (30 μg) of the CYP3A index substrate midazolam, we assessed changes in midazolam pharmacokinetics (area under the concentration-time curve from 2-4 h: AUC and estimated partial metabolic clearance: eCl ) before, at steady-state, and after discontinuation of 3 × 1000 mg metamizole/day orally for 8 days.

Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach.

Purpose: We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose.

Methods: In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated.

Frailty as a Marker for the Plasma Concentrations of Direct Oral Anticoagulants in Older Patients: Results of an Exploratory Study.

Background: Frailty makes older adults vulnerable to adverse health outcomes and can modify pharmacokinetics and drug exposure.

Objective: We aimed to explore the relationship between different frailty assessments and trough plasma concentrations of direct oral anticoagulants in older patients.

Methods: The frailty status of adults aged ≥ 70 years receiving regular direct oral anticoagulant medication was assessed by four different instruments: Fried physical phenotype, Rockwood frailty index, Short Physical Performance Battery, and FRAIL scale.

Oral bioavailability of microdoses and therapeutic doses of midazolam as a 2-dimensionally printed orodispersible film in healthy volunteers.

Purpose: The use of two-dimensional (2D) printing technologies of drugs on orodispersible films (ODF) can promote dose individualization and facilitate drug delivery in vulnerable patients, including children. We investigated midazolam pharmacokinetics after the administration of 2D-printed ODF.

Methods: Midazolam doses of 0.

Improved Macro- and Micronutrient Supply for Favorable Growth and Metabolomic Profile with Standardized Parenteral Nutrition Solutions for Very Preterm Infants.

Very preterm infants are at high risk for suboptimal nutrition in the first weeks of life leading to insufficient weight gain and complications arising from metabolic imbalances such as insufficient bone mineral accretion. We investigated the use of a novel set of standardized parenteral nutrition (PN; MUC PREPARE) solutions regarding improving nutritional intake, accelerating termination of parenteral feeding, and positively affecting growth in comparison to individually prescribed and compounded PN solutions. We studied the effect of MUC PREPARE on macro- and micronutrient intake, metabolism, and growth in 58 very preterm infants and compared results to a historic reference group of 58 very preterm infants matched for clinical characteristics.

The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models.

Background: Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors.

Methods: We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG.

[Diagnostic Criteria of PTSD in ICD10, ICD-11 and DSM 5: Relevance for expert opinion].

The diagnostic criteria of PTSD differ in the ICD-10, ICD-11 and DSM-5 manuals. The main diagnostic criteria are presented. The psychopathological findings obtained in a structured interview are essential for the diagnosis.

Clinical examination and patients' history are not suitable for neonatal hip screening.

Purpose: To assess the percentage of missed developmental dysplasia of the hip, which escape the German criteria for newborn hip high-risk screening, we analyzed our data gained from the general neonatal sonographic hip screening performed at our department. The aim of the study was to determine the number of potentially belatedly treated developmental dysplasia of the hip.

Methods: The data from 1145 standardized newborn hip ultrasound examinations according to the Graf technique were analyzed retrospectively comparing findings for general neonatal sonographic hip screening and high-risk screening subgroups.

Simultaneous Quantification and Pharmacokinetic Characterization of Doxapram and 2-Ketodoxapram in Porcine Plasma and Brain Tissue.

Atrial fibrillation (AF) is an arrhythmia associated with an increased stroke risk and mortality rate. Current treatment options leave unmet needs in AF therapy. Recently, doxapram has been introduced as a possible new option for AF treatment in a porcine animal model.

Oral Drugs Against COVID-19.

Background: Five-day oral therapies against early COVID-19 infection have recently been conditionally approved in Europe. In the drug combination nirmatrelvir + ritonavir (nirmatrelvir/r), the active agent, nirmatrelvir, is made bioavailable in clinically adequate amounts by the additional administration of a potent inhibitor of its first-pass metabolism by way of cytochrome P450 [CYP] 3A in the gut and liver. In view of the central role of CYP3A in the clearance of many different kinds of drugs, and the fact that many patients with COVID-19 are taking multiple drugs to treat other conditions, it is important to assess the potential for drug interactions when nirmatrelvir/r is given, and to minimize the risks associated with such interactions.

Evaluation of CYP2C19 activity using microdosed oral omeprazole in humans.

Purpose: To investigate the suitability of microdosed oral omeprazole for predicting CYP2C19 activity in vivo in combination with simultaneous assessment of CYP3A and CYP2D6 activity using both microdosed midazolam and yohimbine.

Methods: An open, fixed-sequence study was carried out in 20 healthy participants. Single microdosed (100 µg) and therapeutic (20 mg) doses of omeprazole were evaluated without comedication and after administration of established CYP2C19 perpetrators fluconazole (inhibition) and rifampicin (induction).

Low Exposure to Direct Oral Anticoagulants Is Associated with Ischemic Stroke and Its Severity.

Background And Purpose: In acute stroke patients, plasma concentrations of direct oral anticoagulants (DOAC) at hospital admission only poorly mirror DOAC exposure or the coagulation status at the time of the event. Here, we evaluated whether DOAC exposure and DOAC plasma concentration at the time of transient ischemic attacks (TIA) and ischemic strokes correlate with their likelihood of occurrence.

Methods: Prospectively, consecutive DOAC patients with acute ischemic stroke or TIA were included.

Does the circulating ketoconazole metabolite N-deacetyl ketoconazole contribute to the drug-drug interaction potential of the parent compound?

Ketoconazole is a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and of P-glycoprotein (P-gp) and is often used as an index inhibitor especially for CYP3A4-mediated drug metabolism. A preliminary physiologically based pharmacokinetic (PBPK) model for drug-drug interactions indicated possible involvement of a metabolite to the perpetrator potential of ketoconazole. Still unknown for humans, in rodents, N-deacetyl ketoconazole (DAK) has been identified as the major ketoconazole metabolite.

[Diagnostic Criteria of PTSD in ICD10, ICD-11 and DSM 5: Relevance for expert opinion].

The diagnostic criteria of PTSD differ in the ICD-10, ICD-11 and DSM-5 manuals. The main diagnostic criteria are presented. The psychopathological findings obtained in a structured interview are essential for the diagnosis.

Treatment with Edoxaban Attenuates Acute Stroke Severity in Mice by Reducing Blood-Brain Barrier Damage and Inflammation.

Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury.

Perpetrator Characteristics of Azole Antifungal Drugs on Three Oral Factor Xa Inhibitors Administered as a Microdosed Cocktail.

Background: Factor Xa inhibitors (FXaIs) are increasingly used without having sufficient drug-drug interaction data. Using a microdosed cocktail methodology could support filling the knowledge gap quickly.

Methods: In a randomised crossover trial, we investigated the drug-drug interactions between six oral azole antifungals and a microdosed FXaI cocktail containing 25 µg rivaroxaban, 25 µg apixaban, and 50 µg edoxaban.

Effect of Pantoprazole on the Absorption of Hydroxychloroquinea A Randomized Drug-Drug Interaction Trial in Healthy Adults.

Hydroxychloroquine as a weak basic compound with two amines is strongly enriched in cell compartments with low pH, suggesting that modification of gastric pH by coadministered proton pump inhibitors might reduce its solubility and absorption and thus its efficacy in patients. We addressed this question in a single-center, open-label, randomized, parallel drug-drug interaction trial in healthy adults (EudraCT No. 2020-001470-30).

Bioanalysis of selinexor in mouse plasma micro-samples utilizing UPLC-MS/MS.

Selinexor, a first-in-class inhibitor of the nuclear export protein Exportin-1 (XPO1), was recently approved for the treatment of multiple myeloma in combination with dexamethasone, and as monotherapy for diffuse large B-cell lymphoma. To enable investigations of selinexor in mice, we established and validated an ultrahigh-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) assay in the plasma concentration range of 1-1000 ng/mL using plasma microsamples of 5 µL. Protein depletion with acetonitrile was used for efficient isolation of selinexor which was followed by a dilution step, resulting in a scalable sample processing.