Eosinophilic Syndromes Associated With Daptomycin Use: Re-exposure Hypersensitivity Pneumonitis and Prior Peripheral Eosinophilia.

Background: Daptomycin pulmonary eosinophilia (DPE) has been well described in case reports and reporting from the Food and Drug Administration. We report 3 eosinophilic syndromes associated with daptomycin use. Methods: This is a retrospective review of all patients who received daptomycin (inpatient or outpatient) from 2010 to 2020 at the Veterans Affairs Portland Healthcare System. Patients who developed DPE while receiving daptomycin were evaluated to determine risk factors. Data collected included daptomycin dose and duration, body mass index, creatinine clearance, and peripheral eosinophilia. Results: Of 330 patients who received daptomycin, 81.5% developed a peripheral eosinophilia, with 109 (33%) developing peripheral eosinophilia ≥5%. Fifty-one (16%) met criteria for DPE. Primary DPE occurred in 38 of the 51 patients with a median 26 days of treatment, and 49% had peripheral eosinophilia ≥5%. Re-exposure DPE occurred in the other 13 patients and occurred a median of 3 days after initiation of daptomycin. The presence of an elevated peripheral eosinophilia of ≥5% during daptomycin usage was significantly associated with primary (odds ratio [OR], 2.23; 95% CI, 1.2-4.09; P = .008) and re-exposure DPE (OR, 12; 95% CI, 1.6-103; P = .003). All patients recovered after withdrawal of daptomycin without complications. Conclusions: There are 3 daptomycin eosinophilic syndromes: peripheral eosinophilia, primary DPE occurring about 4 weeks into therapy, and re-exposure DPE. Elevated peripheral eosinophilia ≥5% was a risk factor for both primary and re-exposure DPE, but still identified about half the cases. Peripheral eosinophilia should be carefully monitored during daptomycin treatment, and clinicians should be aware that prior eosinophilia may predict an acute pulmonary reaction upon daptomycin re-exposure.

The influence of posture variation on electromyographic signals in females obtained during maximum voluntary isometric contractions: A shoulder example.

Surface electromyography (sEMG) is commonly used to estimate muscle demands in occupational tasks. To allow for comparisons, sEMG amplitude is normalized to muscle specific maximum voluntary contractions (MVCs) performed in a standardized set of postures. However, maximal sEMG amplitude in shoulder muscles is highly dependent on arm posture and therefore, normalizing task related muscular activity to standard MVCs may lead to misinterpretation of task specific muscular demands. Therefore, the purpose of this study was to investigate differences in commonly monitored shoulder muscles using normalized sEMG amplitude between maximal exertions at different hand locations and across force exertion directions relative to standard MVCs. sEMG was recorded from the middle deltoid, pectoralis major sternal head, infraspinatus, latissimus dorsi, and upper trapezius. Participants completed standardized muscle-specific MVCs and two maximal exertions in 5 hand locations (low left, low right, high left, high right, and central) in each of the four force directions (push, pull, up, and down). Peak sEMG was analyzed in the direction(s) that elicited the highest signal for each muscle. All muscles differed by location (p < 0.05). Latissimus dorsi had the greatest activation during pulls (32-135% MVC); upper trapezius and middle deltoid while exerting upwards (73-103% and 42-78% MVC, respectively); infraspinatus while pushing (38-79% MVC); and pectoralis major activation was the highest during downwards exertions (48-84% MVC). Normalization of location specific maximal exertions to standard muscle specific MVCs underestimated maximal activity across 90% of the tasks in all shoulder muscles tested, except for latissimus dorsi where amplitudes were overestimated in low right hand location. Normalization of location specific muscle activity to standard muscle specific MVCs often underestimates muscle activity in task performance and is cautioned against if the goal is to accurately estimate muscle demands.

Computational methods for predicting 3D genomic organization from high-resolution chromosome conformation capture data.

The advent of high-resolution chromosome conformation capture assays (such as 5C, Hi-C and Pore-C) has allowed for unprecedented sequence-level investigations into the structure-function relationship of the genome. In order to comprehensively understand this relationship, computational tools are required that utilize data generated from these assays to predict 3D genome organization (the 3D genome reconstruction problem). Many computational tools have been developed that answer this need, but a comprehensive comparison of their underlying algorithmic approaches has not been conducted. This manuscript provides a comprehensive review of the existing computational tools (from November 2006 to September 2019, inclusive) that can be used to predict 3D genome organizations from high-resolution chromosome conformation capture data. Overall, existing tools were found to use a relatively small set of algorithms from one or more of the following categories: dimensionality reduction, graph/network theory, maximum likelihood estimation (MLE) and statistical modeling. Solutions in each category are far from maturity, and the breadth and depth of various algorithmic categories have not been fully explored. While the tools for predicting 3D structure for a genomic region or single chromosome are diverse, there is a general lack of algorithmic diversity among computational tools for predicting the complete 3D genome organization from high-resolution chromosome conformation capture data.

Improving fluoroquinolone use in the outpatient setting using a patient safety initiative.

We analyzed the impact of a fluoroquinolone patient safety initiative on the weekly fluoroquinolone prescription rate in Veterans Affairs community-based outpatient clinics. We observed a significant initial but unsustained reduction. Such an initiative can function as an antimicrobial stewardship intervention; however, strategies to promote sustainability should be explored.

GrapHi-C: graph-based visualization of Hi-C datasets.

OBJECTIVES: Hi-C is a proximity-based ligation reaction used to detect regions of the genome that are close in 3D space (or "interacting"). Typically, results from Hi-C experiments (contact maps) are visualized as heatmaps or Circos plots. While informative, these visualizations do not directly represent genomic structure and folding, making the interpretation of the underlying 3D genomic organization obscured. Our objective was to generate a graph-based contact map representation that leads to a more intuitive structural visualization. RESULTS: Normalized contact maps were converted into undirected graphs where each vertex represented a genomic region and each edge represented a detected (intra- and inter-chromosomal) or known (linear) interaction between two regions. Each edge was weighted by the inverse of the linear distance (Hi-C experimental resolution) or the interaction frequency from the contact map. Graphs were generated based on this representation scheme for contact maps from existing fission yeast datasets. Originally, these datasets were used to (1) identify specific principles influencing fission yeast genome organization and (2) uncover changes in fission yeast genome organization during the cell cycle. When compared to the equivalent heatmaps and/or Circos plots, the graph-based visualizations more intuitively depicted the changes in genome organization described in the original studies.

Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine production.

Rapamycin is a well-known inhibitor of the Target of Rapamycin (TOR) signaling cascade; however, the impact of this drug on global genome function and organization in normal primary cells is poorly understood. To explore this impact, we treated primary human foreskin fibroblasts with rapamycin and observed a decrease in cell proliferation without causing cell death. Upon rapamycin treatment chromosomes 18 and 10 were repositioned to a location similar to that of fibroblasts induced into quiescence by serum reduction. Although similar changes in positioning occurred, comparative transcriptome analyses demonstrated significant divergence in gene expression patterns between rapamycin-treated and quiescence-induced fibroblasts. Rapamycin treatment induced the upregulation of cytokine genes, including those from the Interleukin (IL)-6 signaling network, such as IL-8 and the Leukemia Inhibitory Factor (LIF), while quiescent fibroblasts demonstrated up-regulation of genes involved in the complement and coagulation cascade. In addition, genes significantly up-regulated by rapamycin treatment demonstrated increased promoter occupancy of the transcription factor Signal Transducer and Activator of Transcription 5A/B (STAT5A/B). In summary, we demonstrated that the treatment of fibroblasts with rapamycin decreased proliferation, caused chromosome territory repositioning and induced STAT5A/B-mediated changes in gene expression enriched for cytokines.

Detection and molecular characterization of two FAD3 genes controlling linolenic acid content and development of allele-specific markers in yellow mustard (Sinapis alba).

Development of yellow mustard (Sinapis alba L.) with superior quality traits (low erucic and linolenic acid contents, and low glucosinolate content) can make this species as a potential oilseed crop. We have recently isolated three inbred lines Y1127, Y514 and Y1035 with low (3.8%), medium (12.3%) and high (20.8%) linolenic acid (C18∶3) content, respectively, in this species. Inheritance studies detected two fatty acid desaturase 3 (FAD3) gene loci controlling the variation of C18∶3 content. QTL mapping revealed that the two FAD3 gene loci responsible for 73.0% and 23.4% of the total variation and were located on the linkage groups Sal02 and Sal10, respectively. The FAD3 gene on Sal02 was referred to as SalFAD3.LA1 and that on Sal10 as SalFAD3.LA2. The dominant and recessive alleles were designated as LA1 and la1 for SalFAD3.LA1, and LA2 and la2 for SalFAD3.LA2. Cloning and alignment of the coding and genomic DNA sequences revealed that the SalFAD3.LA1 and SalFAD3.LA2 genes each contained 8 exons and 7 introns. LA1 had a coding DNA sequence (CDS) of 1143 bp encoding a polypeptide of 380 amino acids, whereas la1 was a loss-of-function allele due to an insertion of 584 bp in exon 3. Both LA2 and la2 had a CDS of 1152 bp encoding a polypeptide of 383 amino acids. Allele-specific markers for LA1, la1, LA2 and la2 co-segregated with the C18∶3 content in the F2 populations and will be useful for improving fatty acid composition through marker assisted selection in yellow mustard breeding.

Clinical outcomes of a veterans affairs outpatient antimicrobial treatment program.

OBJECTIVES: The outpatient parenteral antibiotic therapy (OPAT) program of the Portland Veterans Affairs Medical Center (PVAMC), which has a self-administration model, is staffed by visiting nurses from a specialist infusion company. This study evaluates the clinical outcomes of these patients. METHODS: This study was a retrospective chart review of 262 patients at PVAMC who had received OPAT between 2007 and 2009. Patients were included only if they received ongoing care at PVAMC. The data collected included conditions and organisms being treated and types and durations of antibiotics used. Clinical cure was defined as documented cure at the end of treatment and 90 days post-OPAT. RESULTS: One hundred ninety patients of 262 were analyzed. The mean age was 63.2 years. Diabetes was the main comorbid factor (17%). The most common indications for OPAT were osteomyelitis (38%), urinary tract infection (23%), and skin and soft tissue infection (12.6%). Mixed bacterial culture (26%) and Staphylococcus aureus (31%) were the most common organisms treated. Vancomycin was the most frequently used antibiotic (26%) followed by ceftriaxone (12%). The median duration of OPAT was 30 days. The rate of clinical cure at end of treatment observed for all infections treated was 78%, which then decreased to 58% at 90 days post-OPAT (P < 0.001). Patients with diabetes and osteomyelitis had an increased risk of relapse at 90 days post-OPAT on multivariate analysis (P = 0.025). CONCLUSIONS: An OPAT program using a self-administration model treating patients who were military veterans had successful outcomes. Patients with diabetes and osteomyelitis had worse clinical outcomes 90 days after the completion of OPAT therapy.

Management of gram-positive coccal bacteremia and hemodialysis.

Gram-positive cocci are the most common cause of bloodstream infections in hemodialysis patients, with Staphylococcus aureus and coagulase-negative staphylococci causing most infections. Management of these infections often is complicated by limited vascular access options, as well as an increasing prevalence of drug-resistant bacteria in hemodialysis centers, including the emergence of strains of methicillin-resistant S aureus with vancomycin heteroresistance and increasing rates of vancomycin-resistant enterococci, both of which have limited antibiotic treatment options. This article describes the management of these infections based on the organism and its susceptibility profile, including catheter management, antibiotic lock therapies, and systemic antibiotic choices. Although coagulase-negative staphylococci bacteremia often may be managed with preservation of the catheter, antibiotic lock therapy, and intravenous antibiotics, this is rarely the case with S aureus bacteremia because of frequent relapse and the risk of complications, including endocarditis. Enterococcal bacteremia requires more individualization of care, but catheters are less likely to be salvaged, especially when vancomycin-resistant Enterococcus is the causative organism. Finally, strong infection control policies in the hemodialysis unit, conversion from catheter to arteriovenous access when possible, and appropriate use of antibiotics are essential factors in the prevention of these bloodstream infections.