Addressing the Inpatient Penicillin Allergy: Implementing a Nurse-Driven Allergy Assessment Tool to Enhance Antimicrobial Stewardship.

Background: In an acute care setting, more than half the inpatient population receives antibiotics. Approximately 10% of the general population reports an allergy to penicillin. It has been replicated in the literature with data that of those who report a penicillin allergy, up to 95% are incorrectly identified. When a patient is admitted to the hospital with a penicillin allergy on their electronic health record, they are at higher risk for adverse events such as a hospital acquired infection, the occurrence of an antibiotic resistant bacteria related to receiving broader therapy and increased healthcare utilization. Purpose: The purpose of this project was to address the over reporting of penicillin allergies by creating a nurse driven protocol consisting of a focused allergy history assessment to help aid with risk stratification, future de-labeling and promotion of antimicrobial stewardship. Methods: This was a quantitative quasi-experimental study utilizing a prospective and retrospective chart review. There was a two-group pre/post intervention in which patients with reported penicillin allergies were examined 3 months prior to intervention and 3 months post implementation of the nurse led allergy de-labeling protocol admitted to four adult Norton Healthcare inpatient hospitals (Norton Hospital Downtown, Norton Brownsboro, Norton Audubon and Norton Women’s and Children). Results: The number of patients from the pre-intervention group (n=8, 0.55%) to the post-intervention group (n=13, 0.88%) who were de-labeled increased by 62.5%. However, a chi-square statistical test was performed and revealed that there was no statistical significance (P = 0.28) in the rate of de-labeling. De-escalation occurred in 3 patients in pre versus 1 patient in post sample. Nursing documentation of patient interactions involving allergies resulted in 10 of the 21 patients de-labeled in the pre- and post-intervention sample, 47.6%. The nurse driven protocol showed 76.9% compliance and had 1131 patient interactions out of 1472 patients admitted with penicillin allergies. Conclusion: Although there was no statistical significance between pre- and post-group samples, with no active intervention it was nonetheless determined to be an improvement. Additionally, multidisciplinary education is needed for the healthcare team to enhance compliance and promote de-labeling . In addition, developing education for the patient when allergies are de-labeled and removed from the electronic health record. Nonetheless, the nurse driven tool was successful at filling the resource gap and gathering patient data when used correctly showing the potential it has in a multi-modal de-labeling approach within the multidisciplinary team upholding that nurses are essential to antimicrobial stewardship programs and their role within should be expanded

Low-Cost, Commercial Scale Production of Sofosbuvir

Recent advances in antiviral therapeutics have produced highly effective small molecule drugs to treat Hepatitis C, a deadly infection of the liver. Sofosbuvir, a hepatitis C drug developed by Gilead Sciences, is a breakthrough treatment due to its low side effects and high cure rate. However, the cost of treatment is extraordinarily high, priced at $84,000 per treatment in the US. In response to backlash regarding the cost barriers in developing countries, Gilead has reached licensing agreements with generic pharmaceutical companies to produce the drug for markets in low-income countries such as India, Kenya, and Cuba among others. The report describes a cost-effective, commercial scale process design for the production of sofosbuvir. The proposed production facility is designed to deliver 350,000 kg/year of the active pharmaceutical ingredient, enough to treat 10 million patients per year. The production will be completed over one hundred batches, requiring operation of 120 days/year. Assuming an 11-year period of operation, detailed economic analysis suggests that this is a profitable venture with an IRR of 67.7$1.2 billion USD

Controlled Cold Water and Water Slushy Ingestion, and Heat Performance in Subjects of Average Fitness

Fluid ingestion is known to improve exercise performance and could lead to a heat sink effect, if cold enough. While research has been conducted on the influence of hydration in exercise performance, little has been done which consider beverages’ temperature during controlled consumption. PURPOSE: To examine the effect of controlled consumption of water at different temperatures on heat performance in subjects of average fitness. METHODS: Fifteen males, ages 18-29, with no prior heat illness were recruited. Subjects were tested for body composition and peak oxygen consumption (VO2peak) prior to testing. All subjects underwent three experimental trials [cold water (CD=4̊C), water slushy (SL=-1̊C), room temperature water (RM=22̊C)] in a balanced crossover design. Subjects were required to exercise on a cycle ergometer at intensity 70% VO2peak (vigorous exercise) in the heat (34.0±0.6̊C, 41.7±2.7% RH, 3.6 km∙hr∙-1 wind speed) until volitional maximum. Subjects were required to consume a controlled volume (2.5 g∙kgBodyMass-1) of one of the treatments (CD, SL, RM) every 10 minutes each trial. Measurements for maximum exercise time (ExT), pre-/post-core body temperature change (ΔTc), heart rate (HR), mean skin temperature (MTsk), sweat rate (SR), and RPE were recorded. One-way (beverage) or two-way (beverage x time) ANOVA with repeated measures was used (α=0.05). RESULTS: ExT did not differ significantly between treatments (CD=33.8±9.4 min; SL=35.0±9.8 min; RM=31.5±8.6 min) but a trend (p=0.0680) was seen where SL&CD\u3eRM, which was supported by all subjects having their longest bouts during CD (n=10) and SL (n=5) trials. Neither ΔTc (CD=0.69±0.36˚C, SL=0.64±0.43˚C, RM=0.77±0.45˚C), or SR (CD=1545±1109 ml·hr-1; SL=1837±692 ml·hr-1; RM=1891±489 ml·hr-1), differed (p\u3e0.05) between treatments. A main effect for beverage was seen in HR (CD=157±16 bpm; SL=153±18 bpm; RM=160±17 bpm)(p\u3c0.05) where SLsk or RPE (p\u3e0.05). A main effect for time (p\u3c0.05) was see in HR (T20=161±18 bpm\u3eT10=153±16 bpm), MTsk (T20=36.2±0.3˚C\u3eT10=35.9±0.3˚C), and RPE (T20=5.8±2.1 (0-10)\u3eT10=3.3±1.4 (0-10)). A trend towards significant beverage x time interaction was seen for HR (p=0.0900) but treatments did not respond differently over time for MTsk or RPE (p\u3e0.05). HR at volitional maximum differed between treatments (CD=168±20 bpm; SL=165±20 bpm; RM=173±20 bpm)(p\u3c0.05), specifically SLsk or RPE (p\u3e0.05). CONCLUSION: SL appeared to improve performance over RM, but not CD. There may be a point where colder beverage temperature does not yield a greater heat sink effect or, results could have been due to shorter exercise time in subjects of average fitness

Chronic activation of Toll-like receptor 2 induces an ichthyotic skin phenotype

BACKGROUND: Ichthyosis defines a group of chronic conditions that manifest phenotypically as a thick layer of scales and often affects the entire skin. While the gene mutations that lead to ichthyosis are well documented, the actual signalling mechanisms that lead to scaling are poorly characterised, however recent publications suggest that there are common mechanisms active in ichthyotic tissue, and in analogous models of ichthyosis. OBJECTIVE: To determine common mechanisms of hyperkeratosis that may be easily targeted with small molecule inhibitors. METHODS: We combined gene expression analysis of gene-specific shRNA knockdowns in rat epidermal keratinocytes of two genes mutated in autosomal recessive congenital ichthyosis (ARCI), Transglutaminase 1 (TGM1) and arachidonate 12-lipoxygenase, 12R type (ALOX12B), and proteomic analysis of skin scale from ARCI patients.as well as RNAseq data from rat epidermal keratinocytes treated with the Toll-like receptor-2 agonist PAM3CSK. RESULTS: we identified a common activation of the Toll-like receptor (TLR) 2 pathway. Exogenous TLR2 activation led to increased expression of important cornified envelope genes and in organotypic culture caused hyperkeratosis. Conversely, blockade of TLR2 signalling in ichthyosis patient keratinocytes and our shRNA models reduced the expression of keratin 1, a structural protein over-expressed in ichthyosis scale. A time-course of Tlr2 activation in rat epidermal keratinocytes revealed that although there was rapid initial activation of innate immune pathways, this was rapidly superseded by widespread up-regulation of epidermal differentiation related proteins. Both NFκβ phosphorylation and Gata3 up-regulation was associated with this switch and Gata3 overexpression was sufficient to increase Keratin 1 expression. CONCLUSION: Taken together, these data define a dual role for Toll-like receptor 2 activation during epidermal barrier repair, that may be a useful therapeutic modality in treating diseases of epidermal barrier dysfunction

Direct Agroinoculation of Maize Seedlings by Injection with Recombinant Foxtail Mosaic Virus and Sugarcane Mosaic Virus Infectious Clones

Agrobacterium-based inoculation approaches are widely used for introducing viral vectors into plant tissues. This study details a protocol for the injection of maize seedlings near meristematic tissue with Agrobacterium carrying a viral vector. Recombinant foxtail mosaic virus (FoMV) clones engineered for gene silencing and gene expression were used to optimize this method, and its use was expanded to include a recombinant sugarcane mosaic virus (SCMV) engineered for gene expression. Gene fragments or coding sequences of interest are inserted into a modified, infectious viral genome that has been cloned into the binary T-DNA plasmid vector pCAMBIA1380. The resulting plasmid constructs are transformed into Agrobacterium tumefaciens strain GV3101. Maize seedlings as young as 4 days old can be injected near the coleoptilar node with bacteria resuspended in MgSO4 solution. During infection with Agrobacterium, the T-DNA carrying the viral genome is transferred to maize cells, allowing for the transcription of the viral RNA genome. As the recombinant virus replicates and systemically spreads throughout the plant, viral symptoms and phenotypic changes resulting from the silencing of the target genes lesion mimic 22 (les22) or phytoene desaturase (pds) can be observed on the leaves, or expression of green fluorescent protein (GFP) can be detected upon illumination with UV light or fluorescence microscopy. To detect the virus and assess the integrity of the insert simultaneously, RNA is extracted from the leaves of the injected plant and RT-PCR is conducted using primers flanking the multiple cloning site (MCS) carrying the inserted sequence. This protocol has been used effectively in several maize genotypes and can readily be expanded to other viral vectors, thereby offering an accessible tool for viral vector introduction in maize

A pre-docking source for the power-law behavior of spontaneous quantal release: application to the analysis of LTP

In neurons, power-law behavior with different scaling exponents has been reported at many different levels, including fluctuations in membrane potentials, synaptic transmission up to neuronal network dynamics. Unfortunately in most cases the source of this nonlinear feature remains controversial. Here we have analyzed the dynamics of spontaneous quantal release at hippocampal synapses and characterized their power-law behavior. While in control conditions a fractal exponent greater than zero was rarely observed, its value was greatly increased by α-latrotoxin (α-LTX), a potent stimulator of spontaneous release, known to act at the very last step of vesicle fusion. Based on computer modeling, we confirmed that at an increase in fusion probability would unmask a pre-docking phenomenon with 1/f structure, where α estimated from the release series appears to sense the increase in release probability independently from the number of active sites. In the simplest scenario the pre-docking 1/f process could coincide with the Brownian diffusion of synaptic vesicles. Interestingly, when the effect of long-term potentiation (LTP) was tested, a ∼200% long-lasting increase in quantal frequency was accompanied by a significant increase in the scaling exponent. The similarity between the action of LTP and of α-LTX suggests an increased contribution of high release probability sites following the induction of LTP. In conclusion, our results indicate that the source of the synaptic powerlaw behavior arises before synaptic vesicles dock to the active zone and that the fractal exponent α is capable of sensing a change in release probability independently from the number of active sites or synapses. © 2015 Lamanna, Signorini, Cerutti and Malgaroli

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice.

Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age-related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24-30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age-related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF

Pulse‐labeling studies of carbon cycling in arctic tundra ecosystems: Contribution of photosynthates to soil organic matter

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95486/1/gbc827.pd