Serum antimüllerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: A longitudinal study

Objective: The aim of this study was to assess which of the basal ovarian reserve markers provides the best reflection of the changes occurring in ovarian function over time (i.e., reproductive aging). Design: Prospective longitudinal study. Setting: Healthy volunteers in an academic research center. Patient(s): Eighty-one women with normal reproductive performance during the course of their lives were longitudinally assessed. In this select group of women, becoming chronologically older was considered as a proxy variable for becoming older from a reproductive point of view. Intervention(s): The women were assessed twice, with on average a 4-year interval (T 1 and T 2). The number of antral follicles on ultrasound (AFC) and blood levels of antimüllerian hormone (AMH), FSH, inhibin B, and E 2 were assessed. Main Outcome Measure(s): Longitudinal changes of the markers mentioned and the consistency of these parameters over time. Result(s): The mean ages at T 1 and T 2 were 39.6 and 43.6 years, respectively. Although AFC was strongly associated with age in a cross-sectional fashion, it did not change over time. The AMH, FSH, and inhibin B levels showed a significant change over time, in contrast to E 2 levels. The AMH and AFC were highly correlated with age both at T 1 and T 2, whereas FSH and inhibin B predominantly changed in women more than 40 years of age. To assess the consistency of these parameters over time, we investigated whether a woman's individual level above or below the mean of her age group at T 1 remained above or below the mean of her age group at T 2. Serum AMH concentrations showed the best consistency, with AFC as second best. The FSH and inhibin B showed only modest consistency, whereas E 2 showed no consistency at all. Conclusion(s): These results indicate that serum AMH represents the best endocrine marker to assess the age-related decline of reproductive capacity

Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors

UNLABELLED: BACKGROUND: In clinical and experimental settings, antibody-based anti-CD20/rituximab and small molecule proteasome inhibitor (PI) bortezomib (BTZ) treatment proved effective modalities for B cell depletion in lymphoproliferative disorders as well as autoimmune diseases. However, the chronic nature of these diseases requires either prolonged or re-treatment, often with acquired resistance as a consequence. METHODS: Here we studied the molecular basis of acquired resistance to BTZ in JY human B lymphoblastic cells following prolonged exposure to this drug and examined possibilities to overcome resistance by next generation PIs and anti-CD20/rituximab-mediated complement-dependent cytotoxicity (CDC). RESULTS: Characterization of BTZ-resistant JY/BTZ cells compared to parental JY/WT cells revealed the following features: (a) 10-12 fold resistance to BTZ associated with the acquisition of a mutation in the PSMB5 gene (encoding the constitutive $β$5 proteasome subunit) introducing an amino acid substitution (Met45Ile) in the BTZ-binding pocket, (b) a significant 2-4 fold increase in the mRNA and protein levels of the constitutive $β$5 proteasome subunit along with unaltered immunoproteasome expression, (c) full sensitivity to the irreversible epoxyketone-based PIs carfilzomib and (to a lesser extent) the immunoproteasome inhibitor ONX 0914. Finally, in association with impaired ubiquitination and attenuated breakdown of CD20, JY/BTZ cells harbored a net 3-fold increase in CD20 cell surface expression, which was functionally implicated in conferring a significantly increased anti-CD20/rituximab-mediated CDC. CONCLUSIONS: These results demonstrate that acquired resistance to BTZ in B cells can be overcome by next generation PIs and by anti-CD20/rituximab-induced CDC, thereby paving the way for salvage therapy in BTZ-resistant disease

Proteasome inhibition and mechanism of resistance to a synthetic, library-based hexapeptide

Chemical Immunolog

Statistical Mechanics of Horizontal Gene Transfer in Evolutionary Ecology

The biological world, especially its majority microbial component, is strongly interacting and may be dominated by collective effects. In this review, we provide a brief introduction for statistical physicists of the way in which living cells communicate genetically through transferred genes, as well as the ways in which they can reorganize their genomes in response to environmental pressure. We discuss how genome evolution can be thought of as related to the physical phenomenon of annealing, and describe the sense in which genomes can be said to exhibit an analogue of information entropy. As a direct application of these ideas, we analyze the variation with ocean depth of transposons in marine microbial genomes, predicting trends that are consistent with recent observations using metagenomic surveys.Comment: Accepted by Journal of Statistical Physic

Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder

ABCDE of prehospital ultrasonography: a narrative review

Contains fulltext : 196153.pdf (publisher's version ) (Open Access)Prehospital point-of-care ultrasound used by nonradiologists in emergency medicine is gaining ground. It is feasible on-scene and during aeromedical transport and allows health-care professionals to detect or rule out potential harmful conditions. Consequently, it impacts decision-making in prioritizing care, selecting the best treatment, and the most suitable transport mode and destination. This increasing relevance of prehospital ultrasonography is due to advancements in ultrasound devices and related technology, and to a growing number of applications. This narrative review aims to present an overview of prehospital ultrasonography literature. The focus is on civilian emergency (trauma and non-trauma) setting. Current and potential future applications are discussed, structured according to the airway, breathing, circulation, disability, and environment/exposure (ABCDE) approach. Aside from diagnostic implementation and specific protocols, procedural guidance, therapeutic ultrasound, and challenges are reviewed

[Task shifting and quality of care in practice; physician assistants compared with anaesthesiology residents in the preoperative anaesthesiology outpatient clinic]

Item does not contain fulltextOBJECTIVE: To compare the clinical competencies of second-year anaesthesiology residents and physician assistants (PA) in the preoperative anaesthesiology outpatient clinic. DESIGN: Comparative qualitative observational study. METHOD: The two study groups were compared using 5 test stations representing 5 different cases of varying degrees of complexity with standardized patients. For each case, the patients and two anaesthesiologists assessed the results of the PAs and the residents using a quantitative scoring system for 4 clinical skills relevant to the preoperative anaesthesiology outpatient clinic. These skills were history-taking, physical examination, communication, and reporting. At each station, a score was calculated for each skill. The groups' scores were subsequently compared. RESULTS: 9 PAs and 11 residents carried out the station tests. There were no significant differences between the two groups of participants. CONCLUSION: In this study in a preoperative anaesthesiology outpatient clinic no difference in clinical competencies was found between PAs and second-year anaesthesiology residents

The risk of abdominal injury to women during sport

Item does not contain fulltextBACKGROUND: Poor inter-professional collaboration might negatively influence adequate planning of operative procedures. Interventions capable of improving inter-professional collaboration will positively impact professional practice and health care outcomes. Radboud University Medical Center (UMC) redesigned their operating room (OR) scheduling method by implementing cross-functional teams (CFTs). In this center, positive effects of CFTs were already demonstrated in a mono-center study. This study aims to confirm these effects by comparing the Radboud data with data from 6 other similar centers using a nationwide OR benchmark collaborative. STUDY DESIGN: The effect of CFTs was measured by the performance indicator "raw utilization." The Kruskal-Wallis one-way ANOVA was applied to compare OR performance among all 7 centers. The Wilcoxon-Mann-Whitney test was used to determine differences in OR performance between Radboud UMC and the control group. RESULTS: Operating room performance differed significantly among all 7 centers (p < 0.0005). Radboud UMC demonstrated the highest median raw utilization of 94% vs 85% in the control group (p < 0.0005). Box-and-whisker plots validated the reduced variation during the years, indicating an organizational learning effect. Therefore, not only a better performance than the control group, but also a gradual improvement of this performance during the years. CONCLUSIONS: This study shows that multidisciplinary collaboration in CFTs during the perioperative phase has a positive influence on OR scheduling and use of OR time. Other national databases considering mortality rates also support the idea that introducing CFTs is not only an important condition for improving OR performance, but also for improving quality of care