[Should we switch from saline to lactated Ringer's solution? Limited benefits, medication warning system required]. / Moeten we over van NaCl 0,9% naar Ringer-lactaat?

In recent years, there has been a growing advocacy to implement the use of balanced solutions like lactated Ringer's solution instead of normal saline as fluid therapy in non-critically ill patients. Currently, evidence shows that there might be a limited benefit of the use of Lactated Ringer's solution over saline in both in critically ill and non-critically ill patients. Lactated Ringer's solution is, in contrast to saline, incompatible with blood products and various frequently used intravenously administered drugs. The use of these drugs in conjunction with lactated Ringer's solution therefore requires additional precautionary measures. A hospital-wide transition from saline to lactated Ringer's solution might be beneficial for a subset of patients. However, a medication warning system is required for safe implementation.

Comparing the Safety and Efficacy of L-Glutamine, Voxelotor, and Crizanlizumab for Reducing the Frequency of Vaso-Occlusive Crisis in Sickle Cell Disease: A Systematic Review.

Sickle cell disease (SCD) is a group of inherited red blood cell disorders affecting millions worldwide. The median life expectancy of someone with SCD remains significantly low despite improvements in standards of care and the implementation of hydroxyurea therapy. Notably, a 20-year interval existed (after the implementation of hydroxyurea therapy) prior to the approval of other sickle cell medications, namely, l-glutamine, voxelotor, and crizanlizumab. In this systematic review, these new medications' impact on the occurrences of vaso-occlusive crisis (VOC) events were analyzed and the adverse events of each were noted. Further, a secondary analysis was conducted to determine the effect of combination therapies, whether synergistic, antagonistic, or additive. The systematic review was conducted following the PRISMA 2020 guidelines. The effect-based and dose-effect-based approaches were utilized to determine the combined drugs combination index based on the recommended dosage to achieve an efficacy of 50%. L-glutamine and crizanlizumab were effective in reducing the frequency of VOC (p= 0.0216 and p = 0.02). Voxelotor effect on the reduction of VOC occurrences was not significant, however, its effect on increasing hemoglobin levels was significant (p= <0.001). In all three therapies, pain was the most common adverse event reported by participants. The analysis of combination therapies revealed that voxelotor plus l-glutamine was synergistic, voxelotor plus crizanlizumab was antagonistic, and l-glutamine plus crizanlizumab was additive. Thus, voxelotor plus l-glutamine combination therapy may be more beneficial to sickle cell disease patients. As such, robust combination drug studies for approved therapies used in SCD should be initiated with a specific focus on voxelotor plus l-glutamine. Additionally, the development of medications that lessen the pain burden in sickle cell disease patients should also be prioritized.

Placental Abruption and Partial Placental Prolapse During Induction of Labor in a 31-Year-Old Female With Intrahepatic Cholestasis of Pregnancy: A Case Report.

Placental abruption during induction of labor in females with intrahepatic cholestasis of pregnancy is not exceptionally common and there are no documented reports of placental prolapse following abruption in the literature. The aim of this study is to discuss the possibility of placental abruption and partial prolapse of a low-lying placenta during a prolonged induction of labor in a female with recurrent intrahepatic cholestasis of pregnancy following a cholecystectomy. We describe a 31-year-old G4P3003 female with recurrent intrahepatic cholestasis of pregnancy, with no family history of the condition and surgical history of cholecystectomy, whose induction of labor at 37+3/7 gestational weeks for intrahepatic cholestasis of pregnancy was complicated by placental abruption and partial prolapse of the low-lying placenta. Emergency cesarean section was required for the delivery of her healthy baby. Postpartum was complicated by severe postpartum hemorrhage, post-hemorrhagic anemia, hypotension, blood transfusion reaction, endometritis, and pneumonia. The pathophysiology of intrahepatic cholestasis of pregnancy is not fully understood. Intrahepatic cholestasis of pregnancy increases maternal morbidity, may reoccur in subsequent pregnancies, and is associated with adverse perinatal outcomes. Timely intervention at 37-38 gestational weeks can reduce adverse fetal and maternal outcomes. This case report supports the possibility of 1) a correlation between cholecystectomy and the continued recurrence of intrahepatic cholestasis of pregnancy, 2) placental abruption, and 3) partial prolapse of a low-lying placenta, related to the induction of labor in females with intrahepatic cholestasis of pregnancy. Thus, encouraging further studies to facilitate a greater level of understanding.

A Better Understanding of Moyamoya in Trisomy 21: A Systematic Review.

Moyamoya disease is defined as stenosis of the internal carotid artery or the middle, anterior or posterior cerebral arteries with considerable collateral development. This collateral vessel has a particular appearance in angiographic examinations. Moyamoya syndrome is a term used to describe when moyamoya disease occurs in conjunction with other systemic disorders. One of the associations is Down syndrome. Moyamoya syndrome is very common in patients with Down syndrome, and the cause for this is unknown. The majority of patients present in their first decade, with the clinical presentation varying with age. The cause of moyamoya syndrome in people with trisomy 21 is unknown. This research aimed to learn more about the genesis and pathology of moyamoya syndrome in people with Down syndrome. The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were used to conduct this systematic review. Several publications connected to this topic were searched through a comprehensive database search. They were narrowed down to a final number of ten articles after applying inclusion and exclusion criteria and analyzing the quality of each work. Several possibilities were presented in these final papers to explain the link between moyamoya syndrome and trisomy 21. Trisomy 21 patients have a genetic predisposition to vascular problems. The RNF213 gene may interact with the genes on chromosome 21 that influence vascular physiology and elasticity in patients with Down syndrome, resulting in the whole picture of moyamoya syndrome.

A comparative study of peri-operative outcomes for 100 consecutive post-chemotherapy and primary robot-assisted and open retroperitoneal lymph node dissections.

PURPOSE: To describe and compare differences in peri-operative outcomes of robot-assisted (RA-RPLND) and open (O-RPLND) retroperitoneal lymph node dissection performed by a single surgeon where chemotherapy is the standard initial treatment for Stage 2 or greater non-seminomatous germ cell tumour. METHODS: Review of a prospective database of all RA-RPLNDs (28 patients) and O-RPLNDs (72 patients) performed by a single surgeon from 2014 to 2020. Peri-operative outcomes were compared for patients having RA-RPLND to all O-RPLNDs and a matched cohort of patients having O-RPLND (20 patients). Further comparison was performed between all patients in the RA-RPLND group (21 patients) and matched O-RPLND group (18 patients) who had previous chemotherapy. RA-RPLND was performed for patients suitable for a unilateral template dissection. O-RPLND was performed prior to the introduction of RA-RPLND and for patients not suitable for RA-RPLND after its introduction. RESULTS: RA-RPLND showed improved peri-operative outcomes compared to the matched cohort of O-RPLND-median blood loss (50 versus 400 ml, p < 0.00001), operative duration (150 versus 195 min, p = 0.023) length-of-stay (1 versus 5 days, p < 0.00001) and anejaculation (0 versus 4, p = 0.0249). There was no statistical difference in complication rates. RA-RPLND had lower median lymph node yields although not significant (9 versus 13, p = 0.070). These improved peri-operative outcomes were also seen in the post-chemotherapy RA-RPLND versus O-RPLND analysis. There were no tumour recurrences seen in either group with median follow-up of 36 months and 60 months, respectively. CONCLUSIONS: Post-chemotherapy RA-RPLND may have decreased blood loss, operative duration, hospital length-of-stay and anejaculation rates in selected cases and should, therefore, be considered in selected patients. Differences in oncological outcomes require longer term follow-up.

A strategy to incorporate prior knowledge into correlation network cutoff selection.

Correlation networks are frequently used to statistically extract biological interactions between omics markers. Network edge selection is typically based on the statistical significance of the correlation coefficients. This procedure, however, is not guaranteed to capture biological mechanisms. We here propose an alternative approach for network reconstruction: a cutoff selection algorithm that maximizes the overlap of the inferred network with available prior knowledge. We first evaluate the approach on IgG glycomics data, for which the biochemical pathway is known and well-characterized. Importantly, even in the case of incomplete or incorrect prior knowledge, the optimal network is close to the true optimum. We then demonstrate the generalizability of the approach with applications to untargeted metabolomics and transcriptomics data. For the transcriptomics case, we demonstrate that the optimized network is superior to statistical networks in systematically retrieving interactions that were not included in the biological reference used for optimization.

Systematic Evaluation of Normalization Methods for Glycomics Data Based on Performance of Network Inference.

Glycomics measurements, like all other high-throughput technologies, are subject to technical variation due to fluctuations in the experimental conditions. The removal of this non-biological signal from the data is referred to as normalization. Contrary to other omics data types, a systematic evaluation of normalization options for glycomics data has not been published so far. In this paper, we assess the quality of different normalization strategies for glycomics data with an innovative approach. It has been shown previously that Gaussian Graphical Models (GGMs) inferred from glycomics data are able to identify enzymatic steps in the glycan synthesis pathways in a data-driven fashion. Based on this finding, here, we quantify the quality of a given normalization method according to how well a GGM inferred from the respective normalized data reconstructs known synthesis reactions in the glycosylation pathway. The method therefore exploits a biological measure of goodness. We analyzed 23 different normalization combinations applied to six large-scale glycomics cohorts across three experimental platforms: Liquid Chromatography - ElectroSpray Ionization - Mass Spectrometry (LC-ESI-MS), Ultra High Performance Liquid Chromatography with Fluorescence Detection (UHPLC-FLD), and Matrix Assisted Laser Desorption Ionization - Furier Transform Ion Cyclotron Resonance - Mass Spectrometry (MALDI-FTICR-MS). Based on our results, we recommend normalizing glycan data using the 'Probabilistic Quotient' method followed by log-transformation, irrespective of the measurement platform. This recommendation is further supported by an additional analysis, where we ranked normalization methods based on their statistical associations with age, a factor known to associate with glycomics measurements.

Time perception and timed decision task performance during passive heat stress.

This study investigates the hypotheses that during passive heat stress, the change in perception of time and change in accuracy of a timed decision task relate to changes in thermophysiological variables gastrointestinal temperature and heart rate (HR), as well as subjective measures of cognitive load and thermal perception. Young adult males (N = 29) participated in two 60-min head-out water immersion conditions (36.5°C-neutral and 38.0°C-warm). Cognitive task measurements included accuracy (judgment task), response time (judgment ask), and time estimation (interval timing task). Physiological measurements included gastrointestinal temperature and heart rate. Subjective measurements included cognitive task load (NASA-TLX), rate of perceived exertion, thermal sensation, and thermal comfort. Gastrointestinal temperature and HR were significantly higher in warm versus neutral condition (gastrointestinal temperature: 38.4 ± 0.2°C vs. 37.2 ± 0.2°C, p < 0.01; HR: 105 ± 8 BPM vs. 83 ± 9 BPM, p < 0.01). The change in accuracy was significantly associated with the change in gastrointestinal temperature, and attenuated by change in thermal sensation and change in HR (r2=0.40, p< 0.01). Change in response time was significantly associated with the change in gastrointestinal temperature (r2=0.26, p< 0.002), and change in time estimation was best explained by a change in thermal discomfort (r2=0.18, p< 0.01). Changes in cognitive performance during passive thermal stress are significantly associated with changes in thermophysiological variables and thermal perception. Although explained variance is low (<50%), decreased accuracy is attributed to increased gastrointestinal temperature, yet is attenuated by increased arousal (expressed as increased HR and warmth thermal sensation).

Core body temperature speeds up temporal processing and choice behavior under deadlines.

Evidence suggests that human timing ability is compromised by heat. In particular, some studies suggest that increasing body temperature speeds up an internal clock, resulting in faster time perception. However, the consequences of this speed-up for other cognitive processes remain unknown. In the current study, we rigorously tested the speed-up hypothesis by inducing passive hyperthermia through immersion of participants in warm water. In addition, we tested how a change in time perception affects performance in decision making under deadline stress. We found that participants underestimate a prelearned temporal interval when body temperature increases, and that their performance in a two-alternative forced-choice task displays signatures of increased time pressure. These results show not only that timing plays an important role in decision-making, but also that this relationship is mediated by temperature. The consequences for decision-making in job environments that are demanding due to changes in body temperature may be considerable.

Advancing Personalized Medicine Through the Application of Whole Exome Sequencing and Big Data Analytics.

There is a growing attention toward personalized medicine. This is led by a fundamental shift from the 'one size fits all' paradigm for treatment of patients with conditions or predisposition to diseases, to one that embraces novel approaches, such as tailored target therapies, to achieve the best possible outcomes. Driven by these, several national and international genome projects have been initiated to reap the benefits of personalized medicine. Exome and targeted sequencing provide a balance between cost and benefit, in contrast to whole genome sequencing (WGS). Whole exome sequencing (WES) targets approximately 3% of the whole genome, which is the basis for protein-coding genes. Nonetheless, it has the characteristics of big data in large deployment. Herein, the application of WES and its relevance in advancing personalized medicine is reviewed. WES is mapped to Big Data "10 Vs" and the resulting challenges discussed. Application of existing biological databases and bioinformatics tools to address the bottleneck in data processing and analysis are presented, including the need for new generation big data analytics for the multi-omics challenges of personalized medicine. This includes the incorporation of artificial intelligence (AI) in the clinical utility landscape of genomic information, and future consideration to create a new frontier toward advancing the field of personalized medicine.

Nitric oxide-dependent attenuation of noradrenaline-induced vasoconstriction is impaired in the canine model of Duchenne muscular dystrophy.

KEY POINTS: We developed a novel method to study sympatholysis in dogs. We showed abolishment of sarcolemmal nNOS, and reduction of total nNOS and total eNOS in the canine Duchenne muscular dystrophy (DMD) model. We showed sympatholysis in dogs involving both nNOS-derived NO-dependent and NO-independent mechanisms. We showed that the loss of sarcolemmal nNOS compromised sympatholysis in the canine DMD model. We showed that NO-independent sympatholysis was not affected in the canine DMD model. ABSTRACT: The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to the delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma. Sarcolemmal nNOS plays an important role in sympatholysis, a process of attenuating reflex sympathetic vasoconstriction during exercise to ensure blood perfusion in working muscle. Delocalization of nNOS compromises sympatholysis resulting in functional ischaemia and muscle damage in DMD patients and mouse models. Little is known about the contribution of membrane-associated nNOS to blood flow regulation in dystrophin-deficient DMD dogs. We tested the hypothesis that the loss of sarcolemmal nNOS abolishes protective sympatholysis in contracting muscle of affected dogs. Haemodynamic responses to noradrenaline in the brachial artery were evaluated at rest and during contraction in the absence and presence of NOS inhibitors. We found sympatholysis was significantly compromised in DMD dogs, as well as in normal dogs treated with a selective nNOS inhibitor, suggesting that the absence of sarcolemmal nNOS underlies defective sympatholysis in the canine DMD model. Surprisingly, inhibition of all NOS isoforms did not completely abolish sympatholysis in normal dogs, suggesting sympatholysis in canine muscle also involves NO-independent mechanism(s). Our study established a foundation for using the dog model to test therapies aimed at restoring nNOS homeostasis in DMD.

Publisher Correction: Network inference from glycoproteomics data reveals new reactions in the IgG glycosylation pathway.

Correction to: Nature Communications (2017) 8:1231. doi:10.1038/s41467-017-01525-0.

Highly efficient combustion with low excess air in a modern energy-from-waste (EfW) plant.

The effect of low excess air and high adiabatic combustion temperatures on CO and NOx formation has been investigated on a commercially operated energy-from-waste plant. With optimal combination of low O2 levels and stable combustion control, uncontrolled NOx levels could be lowered to 100-150mg/Nm3 (dry, at 11% O2) while keeping CO emissions at low levels. Even at adiabatic temperatures above 1400°C thermal NOx hardly contributed to the total NOx emissions in a grate-fired EfW plant. An advanced combustion control system allowed continuous operation with very little excess air (λ<1.2) while keeping CO and NOx at levels well below the legal emission limits.

Network inference from glycoproteomics data reveals new reactions in the IgG glycosylation pathway.

Immunoglobulin G (IgG) is a major effector molecule of the human immune response, and aberrations in IgG glycosylation are linked to various diseases. However, the molecular mechanisms underlying protein glycosylation are still poorly understood. We present a data-driven approach to infer reactions in the IgG glycosylation pathway using large-scale mass-spectrometry measurements. Gaussian graphical models are used to construct association networks from four cohorts. We find that glycan pairs with high partial correlations represent enzymatic reactions in the known glycosylation pathway, and then predict new biochemical reactions using a rule-based approach. Validation is performed using data from a GWAS and results from three in vitro experiments. We show that one predicted reaction is enzymatically feasible and that one rejected reaction does not occur in vitro. Moreover, in contrast to previous knowledge, enzymes involved in our predictions colocalize in the Golgi of two cell lines, further confirming the in silico predictions.

Recoil Inversion in the Photodissociation of Carbonyl Sulfide near 234 nm.

We report the observation of recoil inversion of the CO (v=0, J_{CO}=66) state in the UV dissociation of lab-frame oriented carbonyl sulfide (OCS). This state is ejected in the opposite direction with respect to all other (>30) states and in absence of any OCS rotation, thus resulting in spatial filtering of this particular high-J rovibrational state. This inversion is caused by resonances occurring in shallow local minima of the molecular potential, which bring the sulfur closer to the oxygen than the carbon atom, and is a striking example where such subtleties severely modify the photofragment trajectories. The resonant behavior is observed only in the photofragment trajectories and not in their population, showing that stereodynamic measurements from oriented molecules offer an indispensable probe for exploring energy landscapes.

Wavelength dependent photoelectron circular dichroism of limonene studied by femtosecond multiphoton laser ionization and electron-ion coincidence imaging.

Enantiomers of the monoterpene limonene have been investigated by (2 + 1) resonance enhanced multiphoton ionization and photoelectron circular dichroism employing tuneable, circularly polarized femtosecond laser pulses. Electron imaging detection provides 3D momentum measurement while electron-ion coincidence detection can be used to mass-tag individual electrons. Additional filtering, by accepting only parent ion tagged electrons, can be then used to provide discrimination against higher energy dissociative ionization mechanisms where more than three photons are absorbed to better delineate the two photon resonant, one photon ionization pathway. The promotion of different vibrational levels and, tentatively, different electronic ion core configurations in the intermediate Rydberg states can be achieved with different laser excitation wavelengths (420 nm, 412 nm, and 392 nm), in turn producing different state distributions in the resulting cations. Strong chiral asymmetries in the lab frame photoelectron angular distributions are quantified, and a comparison made with a single photon (synchrotron radiation) measurement at an equivalent photon energy.

IgG1 Fc N-glycan galactosylation as a biomarker for immune activation.

Immunoglobulin G (IgG) Fc N-glycosylation affects antibody-mediated effector functions and varies with inflammation rooted in both communicable and non-communicable diseases. Worldwide, communicable and non-communicable diseases tend to segregate geographically. Therefore, we studied whether IgG Fc N-glycosylation varies in populations with different environmental exposures in different parts of the world. IgG Fc N-glycosylation was analysed in serum/plasma of 700 school-age children from different communities of Gabon, Ghana, Ecuador, the Netherlands and Germany. IgG1 galactosylation levels were generally higher in more affluent countries and in more urban communities. High IgG1 galactosylation levels correlated with low total IgE levels, low C-reactive protein levels and low prevalence of parasitic infections. Linear mixed modelling showed that only positivity for parasitic infections was a significant predictor of reduced IgG1 galactosylation levels. That IgG1 galactosylation is a predictor of immune activation is supported by the observation that asthmatic children seemed to have reduced IgG1 galactosylation levels as well. This indicates that IgG1 galactosylation levels could be used as a biomarker for immune activation of populations, providing a valuable tool for studies examining the epidemiological transition from communicable to non-communicable diseases.

Pro-inflammatory pattern of IgG1 Fc glycosylation in multiple sclerosis cerebrospinal fluid.

BACKGROUND: Immunoglobulin G (IgG) effector functions are regulated by the composition of glycans attached to a conserved N-glycosylation site in the Fc part. Intrathecal production of IgG, especially IgG1, is a hallmark of multiple sclerosis (MS), but nothing is known about IgG Fc glycosylation in MS and in cerebrospinal fluid (CSF) in general. METHODS: We applied mass spectrometry of tryptic Fc glycopeptides to analyze IgG Fc glycosylation (sialylation, galactosylation, fucosylation, and bisecting N-acetylglucosamine (GlcNAc)) in 48 paired CSF and serum samples from adult patients with MS or a first demyelinating event highly suggestive of MS (designated as MS cases), and from healthy volunteers and patients with other non-inflammatory diseases (control group). p values were adjusted for multiple testing. RESULTS: Our experiments revealed four main results. First, IgG1 glycosylation patterns were different in CSF vs. serum, in the MS group and even in control donors without intrathecal IgG synthesis. Second, in MS patients vs. controls, IgG1 glycosylation patterns were altered in CSF, but not in serum. Specifically, in CSF from the MS group, bisecting GlcNAc were elevated, and afucosylation and galactosylation were reduced. Elevated bisecting GlcNAc and reduced galactosylation are known to enhance IgG effector functions. Third, hypothesis-free regression analysis revealed that alterations of afucosylation and bisecting GlcNAc in CSF from MS cases peaked 2-3 months after the last relapse. Fourth, CSF IgG1 glycosylation correlated with the degree of intrathecal IgG synthesis and CSF cell count. CONCLUSIONS: The CNS compartment as well as the inflammatory milieu in MS affect IgG1 Fc glycosylation. In MS, the CSF IgG1 glycosylation has features that enhance Fc effector functions.