Nodular Regenerative Hyperplasia Secondary to Neoadjuvant Chemotherapy for Colorectal Liver Metastases

Liver resection is the only curative treatment for patients with colorectal liver metastases (CLMs). Neoadjuvant chemotherapy can improve resectability but has a potential harmful effect on the nontumorous liver. Patients with chemotherapy-induced hepatic injury undergoing liver surgery have higher risks of post-resectional morbidity. We present two cases of patients without pre-existent liver disease treated with oxaliplatin-based chemotherapy followed by surgical resection of their CLMs. Their intra-operative liver specimen showed morphologic abnormalities characteristic of nodular regenerative hyperplasia (NRH). NRH led to portal hypertension in both patients that resulted in deleterious post-resectional complications and death of one patient. Interestingly, the other patient underwent two repeat nonanatomic liver resections because of recurrent CLMs. The intra-operative liver specimen still showed signs of NRH and sinusoidal congestion, but the post-resectional courses were uneventful. Nevertheless, caution is recommended in patients with suspected NRH. Careful volumetric analysis should guide the operative strategy. When future remnant liver volume is regarded insufficient, portal vein embolization or restrictive surgery should be considered

Regulation of histone H3K4 tri-methylation and PAF complex recruitment by the Ccr4-Not complex

Efficient transcription is linked to modification of chromatin. For instance, tri-methylation of lysine 4 on histone H3 (H3K4) strongly correlates with transcriptional activity and is regulated by the Bur1/2 kinase complex. We found that the evolutionarily conserved Ccr4-Not complex is involved in establishing H3K4 tri-methylation in Saccharomyces cerevisiae. We observed synthetic lethal interactions of Ccr4-Not components with BUR1 and BUR2. Further analysis indicated that the genes encoding the Not-proteins are essential for efficient regulation of H3K4me3, but not H3K4me1/2, H3K36me2 or H3K79me2/3 levels. Moreover, regulation of H3K4me3 levels by NOT4 is independent of defects in RNA polymerase II loading. We found NOT4 to be important for ubiquitylation of histone H2B via recruitment of the PAF complex, but not for recruitment or activation of the Bur1/2 complex. These results suggest a mechanism in which the Ccr4-Not complex functions parallel to or downstream of the Bur1/2 kinase to facilitate H3K4me3 via PAF complex recruitment

The Dutch multidisciplinary guideline osteoporosis and fracture prevention, taking a local guideline to the international arena

Background: In 2018, a grant was provided for an evidence-based guideline on osteoporosis and fracture prevention based on 10 clinically relevant questions. Methods: A multidisciplinary working group was formed with delegates from Dutch scientific and professional societies, including representatives from the patient’s organization and the Dutch Institute for Medical Knowledge. The purpose was to obtain a broad consensus among all participating societies to facilitate the implementation of the updated guideline. Results: Novel recommendations in our guideline are as follows: - In patients with an indication for DXA of the lumbar spine and hips, there is also an indication for VFA. - Directly starting with anabolic drugs (teriparatide or romosozumab) in patients with a very high fracture risk; - Directly starting with zoledronic acid in patients 75 years and over with a hip fracture (independent of DXA); - Directly starting with parenteral drugs (denosumab, teriparatide, zoledronic acid) in glucocorticoid-induced osteoporosis with very high fracture risk; - A lifelong fracture risk management, including lifestyle, is indicated from the start of the first treatment. Conclusion: In our new multidisciplinary guideline osteoporosis and fracture prevention, we developed 5 “relatively new statements” that are all a crucial step forward in the optimization of diagnosis and treatment for fracture prevention. We also developed 5 flowcharts, and we suppose that this may be helpful for individual doctors and their patients in daily practice and may facilitate implementation.</p

The Dutch multidisciplinary guideline osteoporosis and fracture prevention, taking a local guideline to the international arena

Background: In 2018, a grant was provided for an evidence-based guideline on osteoporosis and fracture prevention based on 10 clinically relevant questions. Methods: A multidisciplinary working group was formed with delegates from Dutch scientific and professional societies, including representatives from the patient’s organization and the Dutch Institute for Medical Knowledge. The purpose was to obtain a broad consensus among all participating societies to facilitate the implementation of the updated guideline. Results: Novel recommendations in our guideline are as follows: - In patients with an indication for DXA of the lumbar spine and hips, there is also an indication for VFA. - Directly starting with anabolic drugs (teriparatide or romosozumab) in patients with a very high fracture risk; - Directly starting with zoledronic acid in patients 75 years and over with a hip fracture (independent of DXA); - Directly starting with parenteral drugs (denosumab, teriparatide, zoledronic acid) in glucocorticoid-induced osteoporosis with very high fracture risk; - A lifelong fracture risk management, including lifestyle, is indicated from the start of the first treatment. Conclusion: In our new multidisciplinary guideline osteoporosis and fracture prevention, we developed 5 “relatively new statements” that are all a crucial step forward in the optimization of diagnosis and treatment for fracture prevention. We also developed 5 flowcharts, and we suppose that this may be helpful for individual doctors and their patients in daily practice and may facilitate implementation.</p

The APPLe Study: A Randomized, Community-Based, Placebo-Controlled Trial of Azithromycin for the Prevention of Preterm Birth, with Meta-Analysis

In a randomized trial in Malawi of azithromycin versus placebo in over 2,000 pregnant women, Jim Neilson and colleagues show no benefit of azithromycin for a number of outcomes including preterm birth and prenatal death

Phosphorylation of Not4p Functions Parallel to BUR2 to Regulate Resistance to Cellular Stresses in Saccharomyces cerevisiae

Background The evolutionarily conserved Ccr4-Not and Bur1/2 kinase complexes are functionally related in Saccharomyces cerevisiae. In this study, we further explore the relationship between the subunits Not4p and Bur2p. Methodology/Principal Findings First, we investigated the presence of post-translational modifications on the Ccr4-Not complex. Using mass spectrometry analyses we identified several SP/TP phosphorylation sites on its Not4p, Not1p and Caf1p subunits. Secondly, the influence of Not4p phosphorylation on global H3K4 tri-methylation status was examined by immunoblotting. This histone mark is severely diminished in the absence of Not4p or of Bur2p, but did not require the five identified Not4p phosphorylation sites. Thirdly, we found that Not4p phosphorylation is not affected by the kinase-defective bur1-23 mutant. Finally, phenotypic analyses of the Not4p phosphomutant (not4S/T5A) and bur2Δ strains showed overlapping sensitivities to drugs that abolish cellular stress responses. The double-mutant not4S/T5A and bur2Δ strain even revealed enhanced phenotypes, indicating that phosphorylation of Not4p and BUR2 are active in parallel pathways for drug tolerance. Conclusions Not4p is a phospho-protein with five identified phosphorylation sites that are likely targets of a cyclin-dependent kinase(s) other than the Bur1/2p complex. Not4p phosphorylation on the five Not4 S/T sites is not required for global H3K4 tri-methylation. In contrast, Not4p phosphorylation is involved in tolerance to cellular stresses and acts in pathways parallel to BUR2 to affect stress responses in Saccharomyces cerevisiae

Affective Man-Machine Interface: Unveiling human emotions through biosignals

As is known for centuries, humans exhibit an electrical profile. This profile is altered through various psychological and physiological processes, which can be measured through biosignals; e.g., electromyography (EMG) and electrodermal activity (EDA). These biosignals can reveal our emotions and, as such, can serve as an advanced man-machine interface (MMI) for empathic consumer products. However, such a MMI requires the correct classification of biosignals to emotion classes. This chapter starts with an introduction on biosignals for emotion detection. Next, a state-of-the-art review is presented on automatic emotion classification. Moreover, guidelines are presented for affective MMI. Subsequently, a research is presented that explores the use of EDA and three facial EMG signals to determine neutral, positive, negative, and mixed emotions, using recordings of 21 people. A range of techniques is tested, which resulted in a generic framework for automated emotion classification with up to 61.31% correct classification of the four emotion classes, without the need of personal profiles. Among various other directives for future research, the results emphasize the need for parallel processing of multiple biosignals

Selection tools and student diversity in health professions education:a multi-site study

Student diversity in health professions education (HPE) can be affected by selection procedures. Little is known about how different selection tools impact student diversity across programs using different combinations of traditional and broadened selection criteria. The present multi-site study examined the chances in selection of subgroups of applicants to HPE undergraduate programs with distinctive selection procedures, and their performance on corresponding selection tools. Probability of selection of subgroups (based on gender, migration background, prior education, parental education) of applicants (N = 1935) to five selection procedures of corresponding Dutch HPE undergraduate programs was estimated using multilevel logistic regression. Multilevel linear regression was used to analyze performance on four tools: prior-education grade point average (pe-GPA), biomedical knowledge test, curriculum-sampling test, and curriculum vitae (CV). First-generation Western immigrants and applicants with a foreign education background were significantly less likely to be selected than applicants without a migration background and with pre-university education. These effects did not vary across programs. More variability in effects was found between different selection tools. Compared to women, men performed significantly poorer on CVs, while they had higher scores on biomedical knowledge tests. Applicants with a non-Western migration background scored lower on curriculum-sampling tests. First-generation Western immigrants had lower CV-scores. First-generation university applicants had significantly lower pe-GPAs. There was a variety in effects for applicants with different alternative forms of prior education. For curriculum-sampling tests and CVs, effects varied across programs. Our findings highlight the need for continuous evaluation, identifying best practices within existing tools, and applying alternative tools.</p

A survey of spectral models of gravity coupled to matter

This is a survey of the historical development of the Spectral Standard Model and beyond, starting with the ground breaking paper of Alain Connes in 1988 where he observed that there is a link between Higgs fields and finite noncommutative spaces. We present the important contributions that helped in the search and identification of the noncommutative space that characterizes the fine structure of space-time. The nature and properties of the noncommutative space are arrived at by independent routes and show the uniqueness of the Spectral Standard Model at low energies and the Pati-Salam unification model at high energies.Comment: An appendix is added to include scalar potential analysis for a Pati-Salam model. 58 Page