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Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant plasma cell disorder with an etiology that is incompletely understood. Modifiable risk factors and genetic predispositions likely interact to increase MGUS risk in specific individuals and populations. Identifying geographic prevalence patterns and modifiable risk factors is critical for understanding the etiology of MGUS. The aim of this review was to outline original research on MGUS prevalence across geographic locations and modifiable risk factors. We conducted a systematic review of 39 eligible studies from PubMed®, Embase®, and Web of Science® written in English and published by February 2023. Our protocol was registered in accordance with PROSPERO guidelines. Studies were synthesized using Research Electronic Data Capture and appraised using the National Heart, Lung, and Blood Institute study quality assessment tools. The prevalence of MGUS ranged from 0.24% to 9% across geographic locations. Modifiable risk factors for MGUS include infections, autoimmune diseases, chronic inflammatory conditions, lifestyle factors, environmental exposures, and ionizing radiation. Therefore, the development of MGUS may be related to chronic antigenic stimulation and genetic aberrations that promote clonal proliferation of plasma cells. Prospective studies assessing gene–environment interactions are needed to further define risk factors for MGUS and inform screening and preventative strategies.

Abstract Gamma-hydroxybutyrate (GHB) remains a challenging clinical/forensic toxicology drug. Its rapid elimination to endogenous levels mainly causes this. Especially in drug-facilitated sexual assaults, sample collection often occurs later than the detection window for GHB. We aimed to investigate new GHB conjugates with amino acids (AA), fatty acids, and its organic acid metabolites for their suitability as ingestion/application markers in urine following controlled GHB administration to humans. We used LC–MS/MS for validated quantification of human urine samples collected within two randomized, double-blinded, placebo-controlled crossover studies (GHB 50 mg/kg, 79 participants) at approximately 4.5, 8, 11, and 28 h after intake. We found significant differences (placebo vs. GHB) for all but two analytes at 4.5 h. Eleven hours post GHB administration, GHB, GHB-AAs, 3,4-dihydroxybutyric acid, and glycolic acid still showed significantly higher concentrations; at 28 h only GHB-glycine. Three different discrimination strategies were evaluated: (a) GHB-glycine cut-off concentration (1 µg/mL), (b) metabolite ratios of GHB-glycine/GHB (2.5), and (c) elevation threshold between two urine samples (> 5). Sensitivities were 0.1, 0.3, or 0.5, respectively. Only GHB-glycine showed prolonged detection over GHB, mainly when compared to a second time- and subject-matched urine sample (strategy c).

[This corrects the article DOI: 10.1371/journal.pone.0238497.].

Background: Studies on post-COVID-19 condition (PCC) in adults have shown deterioration in pulmonary function tests (PFTs), mainly a diffusion limitation. Among the pediatric population, data are scarce. Aim: To characterize PFTs in children with PCC, including changes over time. Methods: A prospective longitudinal study of children with defined PCC and respiratory complaints who were referred to a designated multidisciplinary clinic from 11/2020 to 12/2022. Results: Altogether, 184 children with a mean age of 12.4 years (SD 4.06) were included. A mild obstructive pattern was demonstrated in 19/170 (11%) at presentation, as indicated by spirometry and/or positive exercise challenge test and/or reversibility post bronchodilators, only three had a previous diagnosis of asthma. Lung volumes and diffusion were normal in all but one patient (1/134, 0.7%). Exhaled nitric oxide levels were elevated in 32/144 (22%). A total of 33 children who had repeated PFTs had normal or near-normal PFTs on follow-up testing, including seven (21.2%) who had mild obstructive PFTs at presentation. Multivariate analysis identified older age [OR 1.36 (95% CI:1.07–1.75)], specific imaging findings (prominent bronchovascular markings (OR 43.28 (95% CI: 4.50–416.49)), and hyperinflation (OR 28.42, 95% CI: 2.18–370.84)] as significant predictors of an obstructive pattern on PFTs. Conclusions: In children with PCC and respiratory symptoms, the most common impairment was a mild obstructive pattern; most were without a history of asthma. Improvement was witnessed in long-term follow-up. In contrast to the adult population, no diffusion limitation was found. Empirical periodic inhaler therapy may be considered in children with factors associated with PFT abnormalities.

Background: Lung function deterioration in cystic fibrosis (CF) is typically measured by a decline in the forced expiratory volume in one second (FEV1%), which is thought to be a late marker of lung disease. Dynamic hyperinflation (DH) is seen in obstructive lung diseases while exercising. Our aim was to assess whether DH could predict pulmonary deterioration in CF; a secondary measure was the peak VO2. Methods: A retrospective study was conducted of people with CF who performed cardiopulmonary exercise tests (CPETs) during 2012–2018. The tests were classified as those demonstrating DH non-DH. Demographic, genetic, and clinical data until 12.2022 were extracted from patient charts. Results: A total of 33 patients aged 10–61 years performed 41 valid CPETs with valid DH measurements; sixteen (39%) demonstrated DH. At the time of the CPETs, there was no difference in the FEV1% measurements between the DH and non-DH groups (median 83.5% vs. 87.6%, respectively; p = 0.174). The FEV1% trend over 4 years showed a decline in the DH group compared to the non-DH group (p = 0.009). A correlation was found between DH and the lung clearance index (LCI), as well as the FEV1% (r = 0.36 and p = 0.019 and r = −0.55 and p = 0.004, respectively). Intravenous (IV) antibiotic courses during the 4 years after the CPETs were significantly more frequent in the DH group (p = 0.046). The peak VO2 also correlated with the FEV1% and LCI (r = 0.36 and p = 0.02 and r = −0.46 and p = 0.014, respectively) as well as with the IV antibiotic courses (r = −0.46 and p = 0.014). Conclusions: In our cohort, the DH and peak VO2 were both associated with lung function deterioration and more frequent pulmonary exacerbations. DH may serve as a marker to predict pulmonary deterioration in people with CF.

Abstract Numerous terpenes present in essential oils (EOs) display one or more chiral centers. Within the same genus the enantiomeric ratio of these compounds can be different. Thus, the determination of enantiomers is a valuable tool to evaluate authenticity and quality of EOs. In here, the terpene profile of primary and commercial pine EOs was analyzed by conventional and chiral gas chromatography coupled to a flame ionization detector. The enantiomeric excess of ( ±)-α-pinene was determined and significant differences between primary and commercially available EOs were observed. Primary EOs of Pinus sylvestris L. showed a positive enantiomeric excess of (+)-α-pinene whereas commercial EOs labeled as P. sylvestris L. exhibited an enantiomeric excess of (−)-α-pinene. Thus, chiral analysis provides useful information on the authenticity of pine EOs and allows to uncover possible mislabeling, the use of the wrong herbal substance and sources of adulteration in pine oil.

Introduction: Several dry-powder inhalers (DPIs) contain lactose which may be contaminated with milk proteins. Confusion exists pertaining to DPI use in patients with cow’s milk protein allergy (CMPA). Methods: A computerized survey sent via e-mail to pediatric pulmonologists and allergologists. Results: A total of 77 out of 232 (33.2%) doctors replied, of whom 80.5% were pediatric pulmonologists. A total of 69 of 77 (89.6%) were specialists, 37.6% with more than 15 years of experience. The most commonly used DPIs were formoterol + budesonide and vilanterol + fluticasone. A total of 62 out of 77 (80.5%) responders knew these DPIs contained lactose. A total of 35 out of 77 (45.5%) doctors who replied did not know that DPI leaflets list CMPA as a contra-indication to DPI administration. Of these, 4 (11.4%) stated that they would instruct patients with CMPA to stop DPIs, and 7 (20%) would avoid recommending DPIs. A total of 42 out of 77 (54.5%) responders were aware of this warning, yet 13 of these 42 (30.9%) continued to recommend lactose-containing DPIs without hesitation and 18 of these 42 (42.8%) responders prescribed DPIs but considered allergy severity. Conclusions: Almost half of certified, experienced pediatric pulmonologists and allergologists were unaware of the warning to administer DPIs to patients with CMPA. Most doctors who do know of this warning still continue to prescribe these DPIs.

Background: Scientific evidence is scarce for the antimicrobial effect of copper on bacteria characterized as more resistant. Using Mycobacterium avium subsp. paratuberculosis (MAP), a highly resistant microorganism, as a pathogen model, copper ion treatment has shown a significant bactericidal effect; however, the sustainability of MAP against copper toxicity was also reported in several studies. Accordingly, the present study aimed to evaluate the impacts of copper on MAP. Methodology: This study considered physicochemical properties and copper concentration in a buffer since it could modulate MAP response during the application of copper treatment. Results: Despite the efficacy of copper ions in significantly reducing the MAP load in Phosphate Buffered Saline, some MAP cells were able to survive. The copper concentration generated by the copper ion treatment device increased significantly with increasing exposure times. MAP bacterial load decreased significantly when treated with copper ions as the exposure times increased. An increase in pH decreased oxygen consumption, and an increase in conductivity was reported after treatment application. Conclusions: Even with higher concentrations of copper, the efficacy of MAP control was not complete. The concentration of copper must be a key element in achieving control of highly resistant microorganisms.

Human papilloma virus (HPV) causes a subset of head and neck squamous cell carcinomas (HNSCC) of the oropharynx. We combined targeted DNA- and genome-wide RNA-sequencing to identify genetic variants and gene expression signatures respectively from patients with HNSCC including oropharyngeal squamous cell carcinomas (OPSCC). DNA and RNA were purified from 35- formalin fixed and paraffin embedded (FFPE) HNSCC tumor samples. Immuno-histochemical evaluation of tumors was performed to determine the expression levels of p16INK4A and classified tumor samples either p16+ or p16-. Using ClearSeq Comprehensive Cancer panel, we examined the distribution of somatic mutations. Somatic single-nucleotide variants (SNV) were called using GATK-Mutect2 ("tumor-only" mode) approach. Using RNA-seq, we identified a catalog of 1,044 and 8 genes as significantly expressed between p16+ and p16-, respectively at FDR 0.05 (5%) and 0.1 (10%). The clinicopathological characteristics of the patients including anatomical site, smoking and survival were analyzed when comparing p16+ and p16- tumors. The majority of tumors (65%) were p16+. Population sequence variant databases, including gnomAD, ExAC, COSMIC and dbSNP, were used to identify the mutational landscape of somatic sequence variants within sequenced genes. Hierarchical clustering of The Cancer Genome Atlas (TCGA) samples based on HPV-status was observed using differentially expressed genes. Using RNA-seq in parallel with targeted DNA-seq, we identified mutational and gene expression signatures characteristic of p16+ and p16- HNSCC. Our gene signatures are consistent with previously published data including TCGA and support the need to further explore the biologic relevance of these alterations in HNSCC.

Superparamagnetic iron oxide nanoparticles, so called SPIONs, are used as tracers in medical imaging, e. g. for magnetic particle imaging (MPI) or magnetic resonance imaging (MRI). Since the half-life time of the SPIONs in the bloodstream is quite short because they are quickly absorbed by the reticuloendothelial system (RES), the particles are introduced into human red blood cells (RBCs) to increase their half-life time in the blood circulation. The hypotonic swelling procedure is used to incorporate the particles into the RBCs. Before the SPIONs are introduced into the RBCs, they are fluorescent labelled. To evaluate the result transmission electron microscopy, magnetic particle spectroscopy and fluorescence microscopy are used. Fluorescein isothiocyanate and rose Bengal were chosen as fluorescent dyes because their biocompatibility is guaranteed. The results suggest that the method hypotonic swelling can be used to successfully introduce the nanoparticles into RBCs and that the magnetic properties of the particles which are necessary for imaging are not influenced.

BACKGROUND Acute pain is the most common complaint of patients presenting to emergency departments (EDs). Effective pain management is a core ED mission, but numerous studies have pointed to insufficient pain treatment or oligoanalgesia. According to a 1997 national survey in Swiss EDs, a validated pain scale was used in only 14%, an analgesia protocol in

An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h-oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock–regulated glycolysis genes, ALDH3A2, ALDOC, HKDC1, PCK2, and PDHB with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene BMAL1 impacts on HKDC1 and leads to a time-dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy. Keywords: Circadian clock, Colorectal cancer, Metabolic rewiring, Tumor progression, High-throughput circadian data, Metabolic network reconstruction, Circadian regulation of metabolism, Treatment response, Glycolysis

Phototrophic microorganisms are promising resources for green biotechnology. Compared to heterotrophic microorganisms, however, the cellular economy of phototrophic growth is still insufficiently understood. We provide a quantitative analysis of light-limited, light-saturated, and light-inhibited growth of the cyanobacterium Synechocystis sp. PCC 6803 using a reproducible cultivation setup. We report key physiological parameters, including growth rate, cell size, and photosynthetic activity over a wide range of light intensities. Intracellular proteins were quantified to monitor proteome allocation as a function of growth rate. Among other physiological acclimations, we identify an upregulation of the translational machinery and downregulation of light harvesting components with increasing light intensity and growth rate. The resulting growth laws are discussed in the context of a coarse-grained model of phototrophic growth and available data obtained by a comprehensive literature search. Our insights into quantitative aspects of cyanobacterial acclimations to different growth rates have implications to understand and optimize photosynthetic productivity.

Locomotion circuits developed in simple animals, and circuit motifs further evolved in higher animals. To understand locomotion circuit motifs, they must be characterized in many models. The nematode Caenorhabditis elegans possesses one of the best-studied circuits for undulatory movement. Yet, for 1/6th of the cholinergic motor neurons (MNs), the AS MNs, functional information is unavailable. Ventral nerve cord (VNC) MNs coordinate undulations, in small circuits of complementary neurons innervating opposing muscles. AS MNs differ, as they innervate muscles and other MNs asymmetrically, without complementary partners. We characterized AS MNs by optogenetic, behavioral and imaging analyses. They generate asymmetric muscle activation, enabling navigation, and contribute to coordination of dorso-ventral undulation as well as anterio-posterior bending wave propagation. AS MN activity correlated with forward and backward locomotion, and they functionally connect to premotor interneurons (PINs) for both locomotion regimes. Electrical feedback from AS MNs via gap junctions may affect only backward PINs.

Pulsed electric fields (PEFs) and cold atmospheric pressure plasma (CAP) are currently both investigated for medical applications. The exposure of cells to PEFs can induce the formation of pores in cell membranes and consequently facilitate the uptake of molecules. In contrast, CAP mainly acts through reactive species that are generated in the liquid environment. The objective of this study was to determine, if PEFs combined with plasma-treated cell culture medium can mutually reinforce effects on viability of mammalian cells. Experiments were conducted with rat liver epithelial WB-F344 cells and their tumorigenic counterpart WB-ras for a direct comparison of non-tumorigenic and tumorigenic cells from the same origin. Viability after treatments strongly depended on cell type and applied field strength. Notably, tumorigenic WB-ras cells responded more sensitive to the respective treatments than non-tumorigenic WB-F344 cells. More cells were killed when plasma-treated medium was applied first in combination with treatments with 100-μs PEFs. For the reversed treatment order, i.e. application of PEFs first, the combination with 100-ns PEFs resulted in a stimulating effect for non-tumorigenic but not for tumorigenic cells. The results suggest that other mechanisms, besides simple pore formation, contributed to the mutually reinforcing effects of the two methods.

3,4-methylenedioxymethamphetamine (MDMA; ecstasy) metabolism is known to be stereoselective, with preference for S-stereoisomers. Its major metabolic step involves CYP2D6-catalyzed demethylenation to 3,4-dihydroxymethamphetamine (DHMA), followed by methylation and conjugation. Alterations in CYP2D6 genotype and/or phenotype have been associated with higher toxicity. Therefore, the impact of CYP2D6 function on the plasma pharmacokinetics of MDMA and its phase I and II metabolites was tested by comparing extensive metabolizers (EMs), intermediate metabolizers (IMs), and EMs that were pretreated with bupropion as a metabolic inhibitor in a controlled MDMA administration study. Blood plasma samples were collected from 16 healthy participants (13 EMs and three IMs) up to 24 h after MDMA administration in a double-blind, placebo-controlled, four-period, cross-over design, with subjects receiving 1 week placebo or bupropion pretreatment followed by a single placebo or MDMA (125 mg) dose. Bupropion pretreatment increased the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC24) of R-MDMA (9% and 25%, respectively) and S-MDMA (16% and 38%, respectively). Bupropion reduced the Cmax and AUC24 of the CYP2D6-dependently formed metabolite stereoisomers of DHMA 3-sulfate, DHMA 4-sulfate, and 4-hydroxy-3-methoxymethamphetamine (HMMA sulfate and HMMA glucuronide) by approximately 40%. The changes that were observed in IMs were generally comparable to bupropion-pretreated EMs. Although changes in stereoselectivity based on CYP2D6 activity were observed, these likely have low clinical relevance. Bupropion and hydroxybupropion stereoisomer pharmacokinetics were unaltered by MDMA co-administration. The present data might aid further interpretations of toxicity based on CYP2D6-dependent MDMA metabolism.

Spinal cord injury (SCI) is an irreversible condition causing damage to myelinated fiber tracts that carry sensation and motor signals to and from the brain. SCI is also associated with gray matter damage and often life-threatening secondary complications. This mini-review aims to provide the nonspecialist reader with a comprehensive description of recent advances made in 2008 using murine models of SCI. A variety of approaches, including advanced genetics and molecular techniques, have allowed a number of key findings in the field of secondary degeneration, repair, regeneration (including insights from peripheral nerve lesion models), metabolic dysfunctions, and pharmacological neuromodulation.

We report on an HIV-negative but immunocompromised patient with disseminated acanthamoebiasis, granulomatous amoebic encephalitis, and underlying miliary tuberculosis and tuberculous meningitis. The patient responded favorably to treatment with miltefosine, an alkylphosphocholine. The patient remained well with no signs of infection 2 years after treatment cessation.

In human immunodeficiency virus treatment adequate virological suppression is warranted, nevertheless for some patients it remains a challenge. We investigated factors associated with low-level viraemia (LLV) and virological failure (VF) under combined antiretroviral therapy (cART).We analysed patients receiving standard regimens between 1st July 2012 and 1st July 2013 with at least one viral load (VL) measurement below the quantification limit (BLQ) in their treatment history. After a minimum of 6 months of unmodified cART, the next single VL measurement within 6 months was analysed. VF was defined as HIV RNA levels ≥ 200 copies/mL and all other quantifiable measurements were classified as LLV. Factors associated with LLV and VF compared to BLQ were identified by logistic regression models.Of 2276 participants, 1972 (86.6%) were BLQ, 222 (9.8%) showed LLV and 82 (3.6%) had VF. A higher risk for LLV and VF was shown in patients with cART interruptions and in patients with boosted PI therapy. The risk for LLV and VF was lower in patients from centres using the Abbott compared to the Roche assay to measure VL. A higher risk for LLV but not for VF was found in patients with a higher VL before cART [for >99.999 copies/mL: aOR (95% CI): 4.19 (2.07-8.49); for 10.000-99.999 copies/mL: aOR (95% CI): 2.52 (1.23-5.19)] and shorter cART duration [for

Metabolic pathways are complex dynamic systems whose response to perturbations and environmental challenges are governed by multiple interdependencies between enzyme properties, reactions rates, and substrate levels. Understanding the dynamics arising from such a network can be greatly enhanced by the construction of a computational model that embodies the properties of the respective system. Such models aim to incorporate mechanistic details of cellular interactions to mimic the temporal behavior of the biochemical reaction system and usually require substantial knowledge of kinetic parameters to allow meaningful conclusions. Several approaches have been suggested to overcome the severe data requirements of kinetic modeling, including the use of approximative kinetics and Monte-Carlo sampling of reaction parameters. In this work, we employ a probabilistic approach to study the response of a complex metabolic system, the central metabolism of the lactic acid bacterium Lactococcus lactis, subject to perturbations and brief periods of starvation. Supplementing existing methodologies, we show that it is possible to acquire a detailed understanding of the control properties of a corresponding metabolic pathway model that is directly based on experimental observations. In particular, we delineate the role of enzymatic regulation to maintain metabolic stability and metabolic recovery after periods of starvation. It is shown that the feedforward activation of the pyruvate kinase by fructose-1,6-bisphosphate qualitatively alters the bifurcation structure of the corresponding pathway model, indicating a crucial role of enzymatic regulation to prevent metabolic collapse for low external concentrations of glucose. We argue that similar probabilistic methodologies will help our understanding of dynamic properties of small-, medium- and large-scale metabolic networks models.

Digestive physiology has played a prominent role in explanations for terrestrial herbivore body size evolution and size-driven diversification and niche differentiation. This is based on the association of increasing body mass (BM) with diets of lower quality, and with putative mechanisms by which a higher BM could translate into a higher digestive efficiency. Such concepts, however, often do not match empirical data. Here, we review concepts and data on terrestrial herbivore BM, diet quality, digestive physiology and metabolism, and in doing so give examples for problems in using allometric analyses and extrapolations. A digestive advantage of larger BM is not corroborated by conceptual or empirical approaches. We suggest that explanatory models should shift from physiological to ecological scenarios based on the association of forage quality and biomass availability, and the association between BM and feeding selectivity. These associations mostly (but not exclusively) allow large herbivores to use low quality forage only, whereas they allow small herbivores the use of any forage they can physically manage. Examples of small herbivores able to subsist on lower quality diets are rare but exist. We speculate that this could be explained by evolutionary adaptations to the ecological opportunity of selective feeding in smaller animals, rather than by a physiologic or metabolic necessity linked to BM. For gigantic herbivores such as sauropod dinosaurs, other factors than digestive physiology appear more promising candidates to explain evolutionary drives towards extreme BM.

A very long neck is a characteristic feature of most sauropod dinosaurs. In the genus Mamenchisaurus, neck length is extreme, greater than 40 percent of total body length. However, the posture, utilization, and selective advantage of very long necks in sauropods are still controversial. An excellently preserved skeleton of Mamenchisaurus youngi, including a complete neck, provides an opportunity for a comprehensive biomechanical analysis of neck posture and mobility. The biomechanical evidence indicates that Mamenchisaurus youngi had a nearly straight, near horizontal neck posture and browsed at low or medium heights. The results differ from the findings for some other sauropod species, like Euhelopus, Diplodocus, and Giraffatitan (Brachiosaurus) that had been analyzed in previous studies with similar methods. The selective advantage of extreme neck length in sauropods is likely advantageous for different feeding strategies.