This report analyzes 36 cases of bacteremia or catheter-related infection caused by Roseomonas species, a group of pink, slimy, waterborne, gram-negative coccobacilli. The causative species included ...the newly described Roseomonas mucosa (22 cases 61%) and Roseomonas gilardii subspecies rosea (8 cases 22%) and known species R. gilardii subspecies gilardii (5 cases 14%) and Roseomonas genomospecies 4 (1 case 3%). Twenty-nine (81%) of the cases were symptomatic, with fever being the most common symptom (in 27 75% of the cases). Twenty (56%) of the infections were monomicrobic. Six cases (17%) involved persistent catheter colonization, and 5 of these cases required removal of the catheter to clear the infection. All infections resolved, most with empirical antibiotic treatment. A summary of the antibiotic susceptibility pattern of these strains and other reported series show that Roseomonas species are consistently susceptible to amikacin and imipenem and frequently susceptible to ciprofloxacin and ticarcillin, but essentially nonsusceptible to ceftazidime and cefepime. This result may guide future therapy for infections due to Roseomonas species.
Mixed synthetic oligonucleotides encoding sequences conserved among tyrosine-specific protein kinases were used to probe the genome of the budding yeast Saccharomyces cerevisiae. Two genes with ...homology to protein kinases were isolated and characterized by DNA sequence analysis. These genes, designated KIN1 and KIN2, are closely related to each other. Among previously characterized protein kinases, the products of KIN1 and KIN2 are most closely related to the bovine cAMP-dependent protein kinase (30% amino acid identities) and the protein encoded by the v-src oncogene (27% and 25% identities with KIN1 and KIN2, respectively) within their putative kinase domains. KIN1 and KIN2 are transcribed into 3.5-kilobase mRNAs that contain uninterrupted open reading frames encoding polypeptides of 117 kDa and 126 kDa, respectively. The predicted proteins are unusual in two respects: (i) their catalytic domains are carried near the N termini of relatively large proteins, in contrast to the majority of characterized protein kinases, and (ii) these catalytic domains are structural mosaics, with some features characteristic of tyrosine-specific protein kinases and other elements that are distinctive of serine/threonine-specific enzymes.
Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1. To identify ...additional susceptibility genes, we performed a genome-wide association study in 750 individuals with PDB (cases) without SQSTM1 mutations and 1,002 controls and identified three candidate disease loci, which were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (P = 5.38 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.
Estuaries worldwide have evolved over the past few centuries under development activities like dredging and shoreline reclamation, which commonly lead to increased channel depths and reduced ...intertidal areas. The Coos Estuary offers a useful example of how these changes, common to diverse global estuaries, have altered tidal and salt dynamics, with implications for estuarine habitats. In the past 150 years, the primary navigation channel has been deepened from ~ 6.7 to 11 m, generating a 12% decrease in estuary area and 21% increase in volume. To evaluate the present and future impacts on the Coos and similar estuaries, a hydrodynamic model was implemented using a detailed bathymetric dataset compiled from multiple data sources including agency charts, water-penetrating lidar, and single-beam-sonar small-vessel surveys. The model was then re-run using grids constructed from 1865 survey data and a future proposed dredging plan. Changes in the hypsometry from 1865 to present have driven a 33% increase in tidal amplitude, an 18% increase in salinity intrusion length, a doubling of the subtidal salt flux, and an increase in ebb dominance of currents. A proposed channel-depth increase from 11 to 14 m is predicted to generate a negligible change in tidal range and a small increase in the salinity intrusion length. These results highlight the utility of curating high-resolution bathymetric datasets for coastal management applications through modeling. The historical and modern models quantify how local bathymetric modifications can significantly alter tidal and salinity regimes and provide context for estuarine response to global climate-change drivers.
Hypoglycemia-related emergency department (ED) or hospital use among patients with type 2 diabetes (T2D) is clinically significant and possibly preventable.
To develop and validate a tool to ...categorize risk of hypoglycemic-related utilization in patients with T2D.
Using recursive partitioning with a split-sample design, we created a classification tree based on potential predictors of hypoglycemia-related ED or hospital use. The resulting model was transcribed into a tool for practical application and tested in 1 internal and 2 fully independent, external samples. Development and internal testing was conducted in a split sample of 206 435 patients with T2D from Kaiser Permanente Northern California (KPNC), an integrated health care system. The tool was externally tested in 1 335 966 Veterans Health Administration and 14 972 Group Health Cooperative patients with T2D.
Based on a literature review, we identified 156 candidate predictor variables (prebaseline exposures) using data collected from electronic medical records.
Hypoglycemia-related ED or hospital use during 12 months of follow-up.
The derivation sample (n = 165 148) had a mean (SD) age of 63.9 (13.0) years and included 78 576 (47.6%) women. The crude annual rate of at least 1 hypoglycemia-related ED or hospital encounter in the KPNC derivation sample was 0.49%. The resulting hypoglycemia risk stratification tool required 6 patient-specific inputs: number of prior episodes of hypoglycemia-related utilization, insulin use, sulfonylurea use, prior year ED use, chronic kidney disease stage, and age. We categorized the predicted 12-month risk of any hypoglycemia-related utilization as high (>5%), intermediate (1%-5%), or low (<1%). In the internal validation sample, 2.0%, 10.7%, and 87.3% were categorized as high, intermediate, and low risk, respectively, with observed 12-month hypoglycemia-related utilization rates of 6.7%, 1.4%, and 0.2%, respectively. There was good discrimination in the internal validation KPNC sample (C statistic = 0.83) and both external validation samples (Veterans Health Administration: C statistic = 0.81; Group Health Cooperative: C statistic = 0.79).
This hypoglycemia risk stratification tool categorizes the 12-month risk of hypoglycemia-related utilization in patients with T2D using only 6 inputs. This tool could facilitate targeted population management interventions, potentially reducing hypoglycemia risk and improving patient safety and quality of life.
Synthetic radionuclides, such as the transuranic actinides plutonium, americium, and curium, present severe health threats as contaminants, and understanding the scope of the biochemical interactions ...involved in actinide transport is instrumental in managing human contamination. Here we show that siderocalin, a mammalian siderophore-binding protein from the lipocalin family, specifically binds lanthanide and actinide complexes through molecular recognition of the ligands chelating the metal ions. Using crystallography, we structurally characterized the resulting siderocalin–transuranic actinide complexes, providing unprecedented insights into the biological coordination of heavy radioelements. In controlled in vitro assays, we found that intracellular plutonium uptake can occur through siderocalin-mediated endocytosis. We also demonstrated that siderocalin can act as a synergistic antenna to sensitize the luminescence of trivalent lanthanide and actinide ions in ternary protein–ligand complexes, dramatically increasing the brightness and efficiency of intramolecular energy transfer processes that give rise to metal luminescence. Our results identify siderocalin as a potential player in the biological trafficking offelements, but through a secondary ligand-based metal sequestration mechanism. Beyond elucidating contamination pathways, this work is a starting point for the design of two-stage biomimetic platforms for photoluminescence, separation, and transport applications.
Abstract
Accessory genes are variably present among members of a species and are a reservoir of adaptive functions. In bacteria, differences in gene distributions among individuals largely result ...from mobile elements that acquire and disperse accessory genes as cargo. In contrast, the impact of cargo-carrying elements on eukaryotic evolution remains largely unknown. Here, we show that variation in genome content within multiple fungal species is facilitated by Starships, a newly discovered group of massive mobile elements that are 110 kb long on average, share conserved components, and carry diverse arrays of accessory genes. We identified hundreds of Starship-like regions across every major class of filamentous Ascomycetes, including 28 distinct Starships that range from 27 to 393 kb and last shared a common ancestor ca. 400 Ma. Using new long-read assemblies of the plant pathogen Macrophomina phaseolina, we characterize four additional Starships whose activities contribute to standing variation in genome structure and content. One of these elements, Voyager, inserts into 5S rDNA and contains a candidate virulence factor whose increasing copy number has contrasting associations with pathogenic and saprophytic growth, suggesting Voyager’s activity underlies an ecological trade-off. We propose that Starships are eukaryotic analogs of bacterial integrative and conjugative elements based on parallels between their conserved components and may therefore represent the first dedicated agents of active gene transfer in eukaryotes. Our results suggest that Starships have shaped the content and structure of fungal genomes for millions of years and reveal a new concerted route for evolution throughout an entire eukaryotic phylum.
Pain is a complex phenomenon that involves more than a simple physical response to external stimuli. In maternal-fetal surgical procedures, fetal analgesia is used primarily to blunt fetal autonomic ...responses and minimize fetal movement. The purpose of this Consult is to review the literature on what is known about the potential for fetal awareness of pain and to discuss the indications for and the risk-benefit calculus involved in the use of fetal anesthesia and analgesia. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we suggest that fetal paralytic agents be considered in the setting of intrauterine transfusion, if needed, for the purpose of decreasing fetal movement (GRADE 2C); (2) although the fetus is unable to experience pain at the gestational age when procedures are typically performed, we suggest that opioid analgesia should be administered to the fetus during invasive fetal surgical procedures to attenuate acute autonomic responses that may be deleterious, avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C); and (3) due to maternal risk and a lack of evidence supporting benefit to the fetus, we recommend against the administration of fetal analgesia at the time of pregnancy termination (GRADE 1C).
Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually ...in the long bones during early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21.2-21.3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.
Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of ...valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis.
In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and
F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score.
A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s 2.93-3.82 m/s; aortic valve calcium score, 1152 AU 655-2065 AU) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 0.18-0.33 µg/L to 0.11 µg/L 0.08-0.17 µg/L) and alendronic acid (0.20 0.14-0.28 µg/L to 0.09 µg/L 0.08-0.13 µg/L) but was unchanged with placebo (0.23 0.17-0.30 µg/L to 0.26 µg/L 0.16-0.31 µg/L). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 198-804 AU versus 354 AU 76-675 AU; P=0.41) or alendronic acid and placebo (326 138-813 AU versus 354 AU 76-675 AU;
=0.49). Similarly, there were no differences in change in peak aortic jet velocity or
F-sodium fluoride aortic valve uptake.
Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.
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