Trends in Incidence of Carbapenem-Resistant Enterobacterales in 7 US Sites, 2016─2020.

Background: We described changes in 2016─2020 carbapenem-resistant Enterobacterales (CRE) incidence rates in 7 US sites that conduct population-based CRE surveillance. Methods: An incident CRE case was defined as the first isolation of Escherichia coli, Klebsiella spp., or Enterobacter spp. resistant to ≥1 carbapenem from a sterile site or urine in a surveillance area resident in a 30-day period. We reviewed medical records and classified cases as hospital-onset (HO), healthcare-associated community-onset (HACO), or community-associated (CA) CRE based on healthcare exposures and location of disease onset. We calculated incidence rates using census data. We used Poisson mixed effects regression models to perform 2016─2020 trend analyses, adjusting for sex, race/ethnicity, and age. We compared adjusted incidence rates between 2016 and subsequent years using incidence rate ratios (RRs) and 95% confidence intervals (CIs). Results: Of 4996 CRE cases, 62% were HACO, 21% CA, and 14% HO. The crude CRE incidence rate per 100 000 was 7.51 in 2016 and 6.08 in 2020 and was highest for HACO, followed by CA and HO. From 2016 to 2020, the adjusted overall CRE incidence rate decreased by 24% (RR, 0.76 [95% CI, .70-.83]). Significant decreases in incidence rates in 2020 were seen for HACO (RR, 0.75 [95% CI, .67-.84]) and CA (0.75 [.61-.92]) but not for HO CRE. Conclusions: Adjusted CRE incidence rates declined from 2016 to 2020, but changes over time varied by epidemiologic class. Continued surveillance and effective control strategies are needed to prevent CRE in all settings.

Distinct Origins and Transmission Pathways of blaKPC Enterobacterales across Three U.S. States.

Carbapenem-resistant Enterobacterales (CRE) are among the most concerning antibiotic resistance threats due to high rates of multidrug resistance, transmissibility in health care settings, and high mortality rates. We evaluated the potential for regional genomic surveillance to track the spread of blaKPC-carrying CRE (KPC-CRE) by using isolate collections from health care facilities in three U.S. states. Clinical isolates were collected from Connecticut (2017 to 2018), Minnesota (2012 to 2018), and Tennessee (2016 to 2017) through the U.S. Centers for Disease Control and Prevention's Multi-site Gram-negative Surveillance Initiative (MuGSI) and additional surveillance. KPC-CRE isolates were whole-genome sequenced, yielding 255 isolates from 214 patients across 96 facilities. Case report data on patient comorbidities, facility exposures, and interfacility patient transfer were extracted. We observed that in Connecticut, most KPC-CRE isolates showed evidence of importation from outside the state, with limited local transmission. In Minnesota, cases were mainly from sporadic importation and transmission of blaKPC-carrying Klebsiella pneumoniae ST258, and clonal expansion of blaKPC-carrying Enterobacter hormaechei ST171, primarily at a single focal facility and its satellite facilities. In Tennessee, we observed transmission of diverse strains of blaKPC-carrying Enterobacter and Klesbiella, with evidence that most derived from the local acquisition of blaKPC plasmids circulating in an interconnected regional health care network. Thus, the underlying processes driving KPC-CRE burden can differ substantially across regions and can be discerned through regional genomic surveillance. This study provides proof of concept that integrating genomic data with information on interfacility patient transfers can provide insights into locations and drivers of regional KPC-CRE burden that can enable targeted interventions.

Increasing seat belt use in the United States by promoting and requiring more effective seat belt reminder systems.

OBJECTIVE: Federal Motor Vehicle Safety Standard (FMVSS) 208 requires every passenger vehicle to provide an auditory signal lasting 4 to 8 seconds and a visual display lasting 60 seconds when the driver is unbelted at ignition. This requirement does not increase seat belt use. This paper summarizes the latest research on using vehicle technology to increase seat belt use and existing safety standards worldwide to support the strengthening of FMVSS 208. METHOD: Studies of seat belt reminders and interlocks published in peer-reviewed journals, conference proceedings, or as technical reports were identified in online databases and reviewed along with current requirements worldwide. Results from past research were used to estimate the front- and rear-seat daytime belt use rate and the annual number of lives that could be saved by a persistent audible reminder at each seating position. RESULTS: Most motor vehicle occupants routinely buckle up. Those that do not typically forget, are going a short distance, or find belts uncomfortable. Seat belt reminders can remind or motivate occupants to buckle up. Enhanced reminders that exceed FMVSS 208 increase belt use by 6 percentage points. Reminders also can increase rear belt use, and although required throughout the world, are not required by FMVSS 208. More persistent reminders, like those required around the world, with a continuous, long-lasting audible signal increase belt use by 30% among drivers who do not routinely buckle up. If every vehicle in the U.S. had such a reminder at each seating position, then it was estimated that the daytime belt use rate in the U.S. would increase about 3 percentage points from 90.3% to 93.2% in the front row and by about 6 percentage points from 80% to 85.9% in the rear row. It was estimated that the increase in belt use from a continuous, long-lasting audible reminder could potentially save about 1,600 lives each year.Seat belt interlocks can increase belt use, but acceptance is a stumbling block. Public outcry ensued after interlocks were required in 1973, and public sentiment remains negative. Opinions toward front and rear reminders are more favorable. Furthermore, past research suggests interlocks may be no more effective for increasing seat belt use than persistent audible reminders. The effect of interlocks on rear belt use have not been explored. CONCLUSION: Persistent seat belt reminder systems that last at least 90 seconds can potentially save hundreds of U.S. motorists each year. Robust empirical evidence, successful exemplars from organizations throughout the world, and a clear public health benefit exists for strengthening FMVSS 208 to require more persistent audible reminders at every seating position.

Reduced graphene oxide influences morphology and thermal properties of silk/cellulose biocomposites.

In recent decades, research into biomaterials such as silk or cellulose has rapidly expanded due to their abundance, low cost, and tunable morphological as well as physicochemical properties. Cellulose is appealing due to its crystalline and amorphous polymorphs while silk is attractive due to its tunable secondary structure formations which is made up of flexible protein fibers. When these two biomacromolecules are mixed, their properties can be modified by changing their material composition and fabrication methodology, e.g., solvent type, coagulation agent, and temperature. Reduced graphene oxide (rGO) can be used to increase molecular interactions and stabilization of natural polymers. In this study, we sought to determine how small amounts of rGO affect the carbohydrate crystallinity and protein secondary structure formation as well as physicochemical properties and how they affect overall ionic conductivity of cellulose-silk composites. Properties of fabricated silk and cellulose composites with and without rGO were investigated using Fourier Transform Infrared Spectroscopy, Scanning Electron Microscopy, X-Ray Scattering, Differential Scanning Calorimetry, Dielectric Relaxation Spectroscopy, and Thermogravimetric Analysis. Our results show that addition of rGO influenced morphological and thermal properties of cellulose-silk biocomposites, specifically through cellulose crystallinity and silk ß-sheet content which further impacted ionic conductivity.

Polymersome Poration and Rupture Mediated by Plasmonic Nanoparticles in Response to Single-Pulse Irradiation.

The self-assembly of amphiphilic diblock copolymers into polymeric vesicles, commonly known as polymersomes, results in a versatile system for a variety of applications including drug delivery and microreactors. In this study, we show that the incorporation of hydrophobic plasmonic nanoparticles within the polymersome membrane facilitates light-stimulated release of vesicle encapsulants. This work seeks to achieve tunable, triggered release with non-invasive, spatiotemporal control using single-pulse irradiation. Gold nanoparticles (AuNPs) are incorporated as photosensitizers into the hydrophobic membrane of micron-scale polymersomes and the cargo release profile is controlled by varying the pulse energy and nanoparticle concentration. We have demonstrated the ability to achieve immediate vesicle rupture as well as vesicle poration resulting in temporal cargo diffusion. Additionally, changing the pulse duration, from femtosecond to nanosecond, provides mechanistic insight into the photothermal and photomechanical contributors that govern membrane disruption in this polymer-nanoparticle hybrid system.

The Impact of Composition and Morphology on Ionic Conductivity of Silk/Cellulose Bio-Composites Fabricated from Ionic Liquid and Varying Percentages of Coagulation Agents.

Blended biocomposites created from the electrostatic and hydrophobic interactions between polysaccharides and structural proteins exhibit useful and unique properties. However, engineering these biopolymers into applicable forms is challenging due to the coupling of the material's physicochemical properties to its morphology, and the undertaking that comes with controlling this. In this particular study, numerous properties of the Bombyx mori silk and microcrystalline cellulose biocomposites blended using ionic liquid and regenerated with various coagulation agents were investigated. Specifically, the relationship between the composition of polysaccharide-protein bio-electrolyte membranes and the resulting morphology and ionic conductivity is explored using numerous characterization techniques, including scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray scattering, atomic force microscopy (AFM) based nanoindentation, and dielectric relaxation spectroscopy (DRS). The results revealed that when silk is the dominating component in the biocomposite, the ionic conductivity is higher, which also correlates with higher ß-sheet content. However, when cellulose becomes the dominating component in the biocomposite, this relationship is not observed; instead, cellulose semicrystallinity and mechanical properties dominate the ionic conduction.

Nanoscale Wetting and Energy Transmission at Solid/Liquid Interfaces.

Understanding the effects and limitations of solid/liquid interfaces on energy transport is crucial to applications ranging from nanoscale thermal engineering to chemical synthesis. Until now, the majority of experimental evidence regarding solid/liquid interactions has been limited to macroscale observations and experiments. The lack of experimental works exploring nanoscale solid/liquid interactions has been accentuated as the body of knowledge from theory and simulations at these scales has exploded in recent years. In this study, we expand on current nanoscale thermal measurement techniques in order to more fully understand solid/liquid interfacial energy transport. We use thermal ablation threshold measurements on thick Au films in various liquids as a metric to describe thermal transport at the Au/liquid interface. Furthermore, using ultrafast pump-probe experiments, we gain insight into this transport through picosecond ultrasonic coupling at solid/liquid interfaces with known macroscopic observations. We find significant variations in both the ablation threshold and the damping of the acoustic modes within the Au films depending on nanoscopic interactions at the solid/liquid interface rather than typical macroscale metrics such as acoustic mismatch, measured contact angle, and work of adhesion.

Small molecule inhibitors of anthrax edema factor.

Anthrax is a highly lethal disease caused by the Gram-(+) bacteria Bacillus anthracis. Edema toxin (ET) is a major contributor to the pathogenesis of disease in humans exposed to B. anthracis. ET is a bipartite toxin composed of two proteins secreted by the vegetative bacteria, edema factor (EF) and protective antigen (PA). Our work towards identifying a small molecule inhibitor of anthrax edema factor is the subject of this letter. First we demonstrate that the small molecule probe 5'-Fluorosulfonylbenzoyl 5'-adenosine (FSBA) reacts irreversibly with EF and blocks enzymatic activity. We then show that the adenosine portion of FSBA can be replaced to provide more drug-like molecules which are up to 1000-fold more potent against EF relative to FSBA, display low cross reactivity when tested against a panel of kinases, and are nanomolar inhibitors of EF in a cell-based assay of cAMP production.

Dynamics of high frequency brain activity.

Evidence suggests that electroencephalographic (EEG) activity extends far beyond the traditional frequency range. Much of the prior study of >120 Hz EEG is in epileptic brains. In the current work, we measured EEG activity in the range of 200 to 2000 Hz, in the brains of healthy, spontaneously behaving rats. Both arrhythmic (1/f-type) and rhythmic (band) activities were identified and their properties shown to depend on EEG-defined stage of sleep/wakefulness. The inverse power law exponent of 1/f-type noise is shown to decrease from 3.08 in REM and 2.58 in NonREM to a value of 1.99 in the Waking state. Such a trend represents a transition from long- to short-term memory processes when examined in terms of the corresponding Hurst index. In addition, treating the 1/f-type activity as baseline noise reveals the presence of two, newly identified, high frequency EEG bands. The first band (ψ) is centered between 260-280 Hz; the second, and stronger, band is a broad peak in the 400-500 Hz range (termed ω). Both of these peaks display lognormal distributions. The functional significance of these frequency bands is supported by the variation in the strength of the peaks with EEG-defined sleep/wakefulness.

Production of Metal Nanoparticles by Pulsed Laser-ablation in Liquids: A Tool for Studying the Antibacterial Properties of Nanoparticles.

The emergence of multidrug-resistant bacteria is a global clinical concern leading some to speculate about our return to a "pre-antibiotics" era of medicine. In addition to efforts to identify novel small-molecule antimicrobial drugs, there has been great interest in the use of metal nanoparticles as coatings for medical devices, wound dressings, and consumer packaging, due to their antimicrobial properties. The wide variety of methods available for nanoparticle synthesis results in a broad spectrum of chemical and physical properties which can affect antibacterial efficacy. This manuscript describes the pulsed laser-ablation in liquids (PLAL) method to create nanoparticles. This approach allows for the fine tuning of nanoparticle size, composition, and stability using post-irradiation methods as well as the addition of surfactants or volume excluders. By controlling particle size and composition, a large range of physical and chemical properties of metal nanoparticles can be explored which may contribute to their antimicrobial efficacy thereby opening new avenues for antibacterial development.

Swine Farming Is a Risk Factor for Infection With and High Prevalence of Carriage of Multidrug-Resistant Staphylococcus aureus.

BACKGROUND: Livestock-associated Staphylococcus aureus (LA-SA) has been documented worldwide. However, much remains unknown about LA-SA colonization and infection, especially in rural environments. METHODS: We conducted a large-scale prospective study of 1342 Iowans, including individuals with livestock contact and a community-based comparison group. Nasal and throat swabs were collected to determine colonization at enrollment, and skin infection swabs over 17 months were assessed for S. aureus. Outcomes included carriage of S. aureus, methicillin-resistant S. aureus (MRSA), tetracycline-resistant S. aureus (TRSA), multidrug-resistant S. aureus (MDRSA), and LA-SA. RESULTS: Of 1342 participants, 351 (26.2%; 95% confidence interval [CI], 23.8%-28.6%) carried S. aureus. MRSA was isolated from 34 (2.5%; 95% CI, 1.8%-3.5%) and LA-SA from 131 (9.8%; 95% CI, 8.3%-11.5%) of the 1342 participants. Individuals with current swine exposure were significantly more likely to carry S. aureus (prevalence ratio [PR], 1.8; 95% CI, 1.4-2.2), TRSA (PR, 8.4; 95% CI, 5.6-12.6), MDRSA (PR, 6.1; 95% CI, 3.8-10.0), and LA-SA (PR, 5.8; 95% CI, 3.9-8.4) than those lacking exposure. Skin infections (n = 103) were reported from 67 individuals, yielding an incidence rate of 6.6 (95% CI, 4.9-8.9) per 1000 person-months. CONCLUSIONS: Current swine workers are 6 times more likely to carry MDRSA than those without current swine exposure. We observed active infections caused by LA-SA. This finding suggests that individuals with livestock contact may have a high prevalence of exposure to, and potentially infection with, antibiotic-resistant S. aureus strains, including LA-SA strains.

Virtual medicinal chemistry: in silico pre-docking functional group transformation for discovery of novel inhibitors of botulinum toxin serotype A light chain.

A novel method for applying high-throughput docking to challenging metalloenzyme targets is described. The method utilizes information-based virtual transformation of library carboxylates to hydroxamic acids prior to docking, followed by compound acquisition, one-pot (two steps) chemical synthesis and in vitro screening. In two experiments targeting the botulinum neurotoxin serotype A metalloprotease light chain, hit rates of 32% and 18% were observed.

Structural characterization of three novel hydroxamate-based zinc chelating inhibitors of the Clostridium botulinum serotype A neurotoxin light chain metalloprotease reveals a compact binding site resulting from 60/70 loop flexibility.

Neurotoxins synthesized by Clostridium botulinum bacteria (BoNT), the etiological agent of human botulism, are extremely toxic proteins making them high-risk agents for bioterrorism. Small molecule inhibitor development has been focused on the light chain zinc-dependent metalloprotease domain of the neurotoxin, an effort that has been hampered by its relatively flexible active site. Developed in concert with structure--activity relationship studies, the X-ray crystal structures of the complex of BoNT serotype A light chain (BoNT/A LC) with three different micromolar-potency hydroxamate-based inhibitors are reported here. Comparison with an unliganded BoNT/A LC structure reveals significant changes in the active site as a result of binding by the unique inhibitor scaffolds. The 60/70 loop at the opening of the active site pocket undergoes the largest conformational change, presumably through an induced-fit mechanism, resulting in the most compact catalytic pocket observed in all known BoNT/A LC structures.

TOB suppresses breast cancer tumorigenesis.

Transducer of ErbB-2 (TOB) is a member of the TOB/Btg gene family. A role for TOB in the suppression of human tumorigenesis has been proposed, based on the observations that TOB-knockout mice spontaneously form tumors and TOB expression is lost in human lung and thyroid cancers. However, the role of TOB in human breast cancer remains unknown. To evaluate the this role, we screened a panel of breast cancer cell lines for TOB expression levels and found that they are inversely correlated with the tumorigenicity and metastatic potential of the cell lines. In addition, we demonstrated for the first time that TOB expression is inversely correlated with breast cancer progression in clinical specimens. These results strongly indicate that the loss of TOB expression plays a role in breast cancer progression. We have also provided the first evidence that TOB functions as a tumor suppressor in breast cancer MCF-7 cells, using gain-of-function and loss-of-function approaches to manipulate TOB expression. Cell-cycle analysis further revealed that TOB can prolong the G1-S phase transition by inducing arrest at G1-S phase. Moreover, upregulation of the cyclin-dependent kinase inhibitor p27 and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-XL were observed in MCF7/TOB transfectants. Conversely, opposite results were observed in shRNA-TOB transfectants. Furthermore, decreased activity of Erk2, AKT, CrkL, PDK1, and Smads were observed in TOB-overexpressing cells. Taken together, these data provide evidence that TOB can function as a tumor suppressor in breast cancer through modulation and regulation of multiple signaling pathways.