Rejected

Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day- 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.

To evaluate the performance of two screening tools, respectively Pain Detect Questionnaire (PDQ) and Douleur Neuropathique 4 questions (DN4), and the optimal cut-off point of the sural nerve cross-sectional area (CSA), in identifying the neuropathic pain features suggestive of a small fiber neuropathy (SFN), in patients with fibromyalgia syndrome (FM).

Acral vascular syndrome clinically presents as digital ischemia with Raynaud's phenomenon and erythromelalgia but can be rarely seen in the malignant condition. Patients may present pain, permanent digital blanching or cyanosis, and desquamation or ulceration of the fingers. Acral vascular syndrome is rarely associated with lymphoid neoplasm and is associated with smoking, autoimmune connective tissue diseases, and vasculitis. Here, we describe a 79-year-old female who was diagnosed with vitiligo and peripheral T cell lymphoma Lennert type stage 4 with anemia of chronic disease with digital acral vascular syndrome.

The objective of this study was to examine the impact of around-the-clock (ATC) administration of intravenous (IV) acetaminophen following robot-assisted radical prostatectomy (RARP). Intravenous infusion of acetaminophen was started on the day of the operation at 1000 mg/dose every 6 h, and the infusion was continued on a fixed schedule until postoperative day 2 a.m. In a retrospective observational study, we compared 127 patients who were administered IV acetaminophen on a fixed schedule (ATC group) with 485 patients who were administered analgesic drugs only as needed (PRN group). We investigated postoperative pain intensity and additional analgesic consumption on postoperative day 0, 1, 2, 3, and 5 between the two groups. Postoperative pain scores were significantly lower in the ATC group than in the PRN group at 1 and 2 days, and this period matched the duration of ATC administration of IV acetaminophen. Postoperative frequency of rescue analgesia was significantly lower in the ATC group than in the PRN group at postoperative 0, 1, and 2 days. ATC administration of IV acetaminophen has the potential to be a very versatile and valuable additional dose to achieve appropriate postoperative analgesia in patients with RARP.

As a typical consequence of bleeding into muscles and joints, patients with severe hemophilia suffer from acute and chronic pain. In spite of its high prevalence, pain in this patient group is not always sufficiently considered or treated in an effective manner.

Data on chronic postsurgical pain (CPSP) after otorhinolaryngological surgery are sparse. Adult in-patients treated in 2017 were included into the prospective PAIN OUT registry. Patients' pain on the first postoperative day (D1), after six months (M6) and 12 months (M12) were evaluated. Determining factor for CPSP was an average pain intensity ≥ 3 (numeric rating scale 0-10) at M6. Risk factors associated with CPSP were evaluated by univariate and multivariate analyses. 10% of 191 included patients (60% male, median age: 52 years; maximal pain at D1: 3.5 ± 2.7), had CPSP. Average pain at M6 was 0.1 ± 0.5 for patients without CPSP and 4.2 ± 1.2 with CPSP. Average pain with CPSP still was 3.7 ± 1.1 at M12. Higher ASA status (Odds ratio [OR] = 4.052; 95% confidence interval [CI] = 1.453-11.189; p = 0.007), and higher minimal pain at D1 (OR = 1.721; CI = 1.189-2.492; p = 0.004) were independent predictors of CPSP at M6. Minimal pain at D1 (OR = 1.443; CI = 1.008-2.064; p = 0.045) and maximal pain at M6 (OR = 1.665; CI = 1.340-2.069; p < 0.001) were independent predictors for CPSP at M12. CPSP is an important issue after otorhinolaryngological surgery. Better instrument for perioperative assessment should be defined to identify patients at risk for CPSP.

Caring affects carers' psychological and physical health, mortality, and quality of life (QoL) negatively. Lower spiritual QoL is associated with anxiety and depression, but the spiritual dimension is rarely investigated in carers. The present study aimed to explore which patient- and carer-related characteristics were associated with spiritual QoL in carers of patients with advanced cancer.

While prolactinoma patients have high bone turnover, current data are inconclusive when it comes to determining whether correction of hyperprolactinemia and associated hypogandism improves osteodensitometric data in men and women over the long term. In a large cohort of including 40 men and 60 women, we studied the long-term impact of prolactinoma treatment on bone mineral density (BMD) in men versus women, assessed adverse effects of a primary surgical or medical approach, and evaluated data for risk factors for impaired BMD at last follow-up using multivariate regression analyses. Median duration of follow-up was 79 months (range 13-408 months). Our data indicate that the prevalence of impaired BMD remained significantly higher in men (37%) than in women (7%, p < 0.001), despite the fact that hyperprolactinemia and hypogonadism are under control in the majority of men. We found that persistent hyperprolactinemia and male sex were independent risk factors for long-term bone impairment. Currently, osteoporosis prevention and treatment focus primarily on women, yet special attention to bone loss in men with prolactinomas is advised. Bone impairment as "end organ" reflects the full range of the disease and could become a surrogate marker for the severity of long-lasting hyperprolactinemia and associated hypogonadism.

Prospective clinical pilot study and cadaveric study.