Challenges Facing Antimicrobial Stewardship Programs in the Endemic Region for Coccidioidomycosis.

Coccidioidomycosis poses a significant cost and morbidity burden in the United States. Additionally, coccidioidomycosis requires constant decision-making related to prevention, diagnosis, and management. Delays in diagnosis lead to significant consequences, including unnecessary diagnostic workup and antibacterial therapy. Antifungal stewardship considerations regarding empiric, prophylactic, and targeted management of coccidioidomycosis are also complex. In this review, the problems facing antimicrobial stewardship programs (ASPs) in the endemic region for coccidioidomycosis, consequences due to delayed or missed diagnoses of coccidioidomycosis on antibacterial prescribing, and excess antifungal prescribing for prevention and treatment of coccidioidomycosis are elucidated. Finally, our recommendations and research priorities for ASPs in the endemic region for coccidioidomycosis are outlined.

MSG-15: Super-Bioavailability Itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses-A Multicenter, Open-Label, Randomized Comparative Trial.

Background: Invasive fungal disease caused by dimorphic fungi is associated with significant morbidity and mortality. Super-bioavailability itraconazole (SUBA-itra) is a novel antifungal agent with pharmacokinetic advantages over currently available formulations. In this prospective comparative study, we report the outcomes of patients with endemic fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis). Methods: This open-label randomized trial evaluated the efficacy, safety, and pharmacokinetics SUBA-itra compared with conventional itraconazole (c-itra) treatment for endemic fungal infections. An independent data review committee determined responses on treatment days 42 and 180. Results: Eighty-eight patients were enrolled for IFD (SUBA-itra, n = 42; c-itra, n = 46) caused by Histoplasma (n = 51), Blastomyces (n = 18), Coccidioides (n = 13), or Sporothrix (n = 6). On day 42, clinical success was observed with SUBA-itra and c-itra on day 42 (in 69% and 67%, respectively, and on day 180 (in 60% and 65%). Patients treated with SUBA-itra exhibited less drug-level variability at days 7 (P = .03) and 14 (P = .06) of randomized treatment. The concentrations of itraconazole and hydroxyitraconazole were comparable between the 2 medications (P = .77 and P = .80, respectively). There was a trend for fewer adverse events (AEs; 74% vs 87%, respectively; P = .18) and serious AEs (10% vs 26%; P = .06) in the SUBA-itra-treated patients than in those receiving c-itra. Serious treatment-emergent AEs were less common in SUBA-itra-treated patients (12% vs 50%, respectively; P < .001). Conclusions: SUBA-itra was bioequivalent, well tolerated, and efficacious in treating endemic fungi, with a more favorable safety profile than c-itra. Clinical Trials Registration: NCT03572049.

Engineered bacteria titrate hydrogen sulfide and induce concentration-dependent effects on the host in a gut microphysiological system.

Hydrogen sulfide (H2S) is a gaseous microbial metabolite whose role in gut diseases is debated, with contradictory results stemming from experimental difficulties associated with accurate dosing and measuring H2S and the use of model systems that do not accurately represent the human gut environment. Here, we engineer Escherichia coli to titrate H2S across the physiological range in a gut microphysiological system (chip) supportive of the co-culture of microbes and host cells. The chip is engineered to maintain H2S gas tension and enables visualization of co-culture in real time with confocal microscopy. Engineered strains colonize the chip and are metabolically active for 2 days, during which they produce H2S across a 16-fold range and induce changes in host gene expression and metabolism in an H2S-concentration-dependent manner. These results validate a platform for studying the mechanisms underlying microbe-host interactions by enabling experiments that are infeasible with current animal and in vitro models.

Risk for primary cephalosporin resistance in Gram-negative bacteremia.

Objective: This study aimed to examine the clinical risk factors for cephalosporin resistance in patients with Gram-negative bacteremia caused by Escherichia coli (EC), Klebsiella pneumoniae (KP), Enterobacter cloacae (ENC), and Pseudomonas aeruginosa (PS). Methods: This retrospective cohort study included 400 adults with Gram-negative bacteremia. The goal was to review 100 cases involving each species and approximately half resistant and half susceptible to first-line cephalosporins, ceftriaxone (EC or KP), or cefepime (ENC or PS). Logistic regression was used to identify factors predictive of resistance. Results: A total of 378 cases of Gram-negative bacteremia were included in the analysis. Multivariate analysis identified significant risk factors for resistance, including admission from a chronic care hospital, skilled nursing facility, or having a history of infection within the prior 6 months (OR 3.00, P < .0001), requirement for mechanical ventilation (OR 3.76, P < .0001), presence of hemiplegia (OR 3.54, P = .0304), and presence of a connective tissue disease (OR 3.77, P = .0291). Conclusions: Patients without the identified risk factors should be strongly considered for receiving ceftriaxone or cefepime rather than carbapenems and newer broad-spectrum agents.

Engineered bacteria titrate hydrogen sulfide and induce concentration-dependent effects on host in a gut microphysiological system.

Hydrogen sulfide (H2S) is a gaseous microbial metabolite whose role in gut diseases is debated, largely due to the difficulty in controlling its concentration and the use of non-representative model systems in previous work. Here, we engineered E. coli to titrate H2S controllably across the physiological range in a gut microphysiological system (chip) supportive of the co-culture of microbes and host cells. The chip was designed to maintain H2S gas tension and enable visualization of co-culture in real-time with confocal microscopy. Engineered strains colonized the chip and were metabolically active for two days, during which they produced H2S across a sixteen-fold range and induced changes in host gene expression and metabolism in an H2S concentration-dependent manner. These results validate a novel platform for studying the mechanisms underlying microbe-host interactions, by enabling experiments that are infeasible with current animal and in vitro models.

Fighting Back against Antimicrobial Resistance with Comprehensive Policy and Education: A Narrative Review.

Globally, antimicrobial resistance has emerged as a significant threat. A comprehensive plan is required to combat antimicrobial resistance. There have been national and international efforts to address this global health problem, but much work remains. Enhanced funding and regulations to support antimicrobial stewardship policy and program development, reforms to incentivize drug development to treat resistant pathogens, and efforts to strengthen One Health programs are areas for collaboration and innovation. Finally, implementation of educational interventions for trainees encompassing these key areas along with training on policy and leadership development is critical to enable sustainability of these efforts to fight back against antimicrobial resistance.

Individual differences in white and grey matter structure associated with verbal habits of thought.

Modality specific encoding habits account for a significant portion of individual differences reflected in functional activation during cognitive processing. Yet, little is known about how these habits of thought influence long-term structural changes in the brain. Traditionally, habits of thought have been assessed using self-report questionnaires such as the visualizer-verbalizer questionnaire. Here, rather than relying on subjective reports, we measured habits of thought using a novel behavioral task assessing attentional biases toward picture and word stimuli. Hypothesizing that verbal habits of thought are reflected in the structural integrity of white matter tracts and cortical regions of interest, we used diffusion tensor imaging and volumetric analyses to assess this prediction. Using a whole-brain approach, we show that word bias is associated with increased volume in several bilateral language regions, in both white and grey matter parcels. Additionally, connectivity within white matter tracts within an a priori speech production network increased as a function of word bias. These results demonstrate long-term structural and morphological differences associated with verbal habits of thought.

Individual differences in encoded neural representations within cortical speech production network.

When two individuals view the same item, they do not necessarily perceive an item in the same way. If an individual is presented with a stimulus to be recalled later, the information that is encoded is dependent on the features of the stimulus to which one attends. Past studies have shown that, on the group level, verbal and visual information (e.g., words and pictures) are encoded in disparate regions of the brain. However, this account conflates external and internal representational formats, and it also neglects individual differences in attention. In this study, we examined neural and behavioral patterns associated with individual differences in attention to verbal representations-both external and internal. We found that the encoded neural representation of semantic content (meaningful words and pictures) varied as a function of individual differences in verbal attention, independent of the stimulus presentation format. Individuals who demonstrated an attentional bias toward words showed similar multivariate BOLD activity patterns within an a priori speech production network when encoding object names as when encoding pictures of objects. This result indicates that these individuals encode both words and pictures verbally. These effects were not found for non-semantic stimuli (pronounceable non-words and nonsense pictures). Importantly, as expected, no individual differences in neural representation were found in a separate network of regions known to process semantic content independent of format. These results highlight inter-individual divergence and convergence in internal representations of encoded semantic content. SIGNIFICANCE STATEMENT: This study shows how tendencies to attend to word representations is associated with individual differences in encoded neural representations. Individuals who selectively attend to words instead of pictures process semantically meaningful information in language regions of the brain, regardless of whether the information was originally presented as a word or a picture. Though all participants encoded words and pictures similarly in regions that are known to represent domain-general semantic information, only the individuals who were biased towards word representations additionally processed both words and pictures in modality-specific verbal regions. These results demonstrate both the convergence and divergence between individuals that occurs during encoding of meaningful information.

Management of Strongyloides in Solid Organ Transplant Recipients.

Strongyloides stercoralis is a threadworm parasite with the unique capacity to complete its entire life cycle in a human host. Although asymptomatic in normal hosts, S stercoralis infection in solid organ transplant recipients is often severe, disseminated, and fatal. Risk factors for disease acquisition include travel to endemic regions. Antihelminth therapy should be instituted before transplantation for optimal clinical outcomes. Herein we review the epidemiology, biology, immune response, and diagnostic and screening strategies, as well as treatment modalities for S stercoralis in the solid organ transplant population.

Grounded understanding of abstract concepts: The case of STEM learning.

Characterizing the neural implementation of abstract conceptual representations has long been a contentious topic in cognitive science. At the heart of the debate is whether the "sensorimotor" machinery of the brain plays a central role in representing concepts, or whether the involvement of these perceptual and motor regions is merely peripheral or epiphenomenal. The domain of science, technology, engineering, and mathematics (STEM) learning provides an important proving ground for sensorimotor (or grounded) theories of cognition, as concepts in science and engineering courses are often taught through laboratory-based and other hands-on methodologies. In this review of the literature, we examine evidence suggesting that sensorimotor processes strengthen learning associated with the abstract concepts central to STEM pedagogy. After considering how contemporary theories have defined abstraction in the context of semantic knowledge, we propose our own explanation for how body-centered information, as computed in sensorimotor brain regions and visuomotor association cortex, can form a useful foundation upon which to build an understanding of abstract scientific concepts, such as mechanical force. Drawing from theories in cognitive neuroscience, we then explore models elucidating the neural mechanisms involved in grounding intangible concepts, including Hebbian learning, predictive coding, and neuronal recycling. Empirical data on STEM learning through hands-on instruction are considered in light of these neural models. We conclude the review by proposing three distinct ways in which the field of cognitive neuroscience can contribute to STEM learning by bolstering our understanding of how the brain instantiates abstract concepts in an embodied fashion.

Contribution of Embodiment to Solving the Riddle of Infantile Amnesia.

At least since the late nineteenth century, researchers have sought an explanation for infantile amnesia (IA)-the lack of autobiographical memories dating from early childhood-and childhood amnesia (CA), faster forgetting of events up until the age of about seven. Evidence suggests that IA occurs across altricial species, and a number of studies using animal models have converged on the hypothesis that maturation of the hippocampus is an important factor. But why does the hippocampus mature at one time and not another, and how does that maturation relate to memory? Our hypothesis is rooted in theories of embodied cognition, and it provides an explanation both for hippocampal development and the end of IA. Specifically, the onset of locomotion prompts the alignment of hippocampal place cells and grid cells to the environment, which in turn facilitates the ontogeny of long-term episodic memory and the end of IA. That is, because the animal can now reliably discriminate locations, location becomes a stable cue for memories. Furthermore, as the mode of human locomotion shifts from crawling to walking, there is an additional shift in the alignment of the hippocampus that marks the beginning of adult-like episodic memory and the end of CA. Finally, given a reduction in self-locomotion and exploration with aging, the hypothesis suggests a partial explanation for cognitive decline with aging.

Detection of (154)Eu in patients post (153)Sm-EDTMP therapy using a clinical gamma camera.

Enhancements in radiation detection equipment at border crossings and airports resulted in a report to our institution from a Sm-EDTMP therapy patient who was questioned after triggering radiation alarms. Using a clinical SPECT camera in its service mode, gamma-ray spectroscopy was performed on three patients whose Sm-EDTMP injections were given between 4 mo and 2 y prior to this study. The spectra revealed the presence of high-energy photon peaks characteristic of those from Eu. While the presence of Eu in Sm injections is documented in the literature, the implications of its presence are not widely known. The results of this study show that Eu (t1/2 = 8.5 y) remains in the bones in detectable amounts for several years and may create concerning situations for post therapy patients at some security checkpoints. Institutions performing Sm-EDTMP therapy may want to inform their patients of this situation and provide a wallet card.

Different phases of afterdischarge during rapid kindling procedure in mice.

The basic mechanisms of hippocampal networks in epileptogenesis are not entirely understood. To help achieve a better understanding of these mechanisms, we studied the extra-cellular electrically evoked responses in the hippocampi of mice during rapid kindling. Kindling protocol was achieved by stimulating the dorsal right hippocampus six times daily for four days using bipolar electrodes to produce sub-convulsive electrical discharges. Motor responses and analyzed electroencephalographic recordings showed progression from partial complex seizures to generalized seizures associated with different consecutive patterns within the afterdischarges. A spike-wave pattern appeared immediately after stimulation in combination with a poly-spike complex superimposed over the wave (AD1). AD1 was followed by a poly-spike complex (AD2), which was followed by a progressive modification of repetitive spikes (AD3). An ictal depression event was observed at the end of each AD3. Theta oscillations were observed at stage 1-2 of kindling, while beta/gamma oscillations appeared within AD2, associated with stage 4-5 from Racine's score. Benzodiazepine, a GABA (A) agonist (Diazepam) administered at non-sedative doses and only on days 3 and 4 of kindling, limited beta and gamma frequency bands and the progression of seizure severity, suggesting that the failure of GABA (A) agonism mediates the propagation or generalization of seizures. We conclude that different phases of afterdischarge occur during kindling and that high frequencies mediate generalization of seizures.

The Level of Europium-154 Contaminating Samarium-153-EDTMP Activates the Radiation Alarm System at the US Homeland Security Checkpoints.

(153)Sm-EDTMP is a radiopharmaceutical composed of EDTMP (ethylenediamine-tetramethylenephosphonate) and Samarium-153 [1]. (153)Sm-EDTMP has an affinity for skeletal tissue and concentrates in areas with increased bone turnover; thus, it is successfully used in relieving pain related to diffuse bone metastases [1]. The manufacturing process of (153)Sm-EDTMP leads to contamination with (154)Eu (Europium-154) [2]. A previous study only alluded to the retention of (154)Eu in the bones after receiving treatment with (153)Sm-EDTMP [2]. Activation of the alarm at security checkpoints after (153)Sm-EDTMP therapy has not been previously reported. Two out of 15 patients who received (153)Sm-EDTMP at Roger Maris Cancer Center (Fargo, N. Dak., USA) activated the radiation activity sensors while passing through checkpoints; one at a US airport and the other while crossing the American-Canadian border. We assume that the (154)Eu which remained in the patients' bones activated the sensors. METHODS: In order to investigate this hypothesis, we obtained the consent from 3 of our 15 patients who received (153)Sm-EDTMP within the previous 4 months to 2 years, including the patient who had activated the radiation alarm at the airport. The patients were scanned with a handheld detector and a gamma camera for energies from 511 keV to 1.3 MeV. RESULTS: All three patients exhibited identical spectral images, and further analysis showed that the observed spectra are the result of (154)Eu emissions. CONCLUSION: Depending on the detection thresholds and windows used by local and federal authorities, the remaining activity of (154)Eu retained in patients who received (153)Sm-EDTMP could be sufficient enough to increase the count rates above background levels and activate the sensors. At Roger Maris Cancer Center, patients are now informed of the potential consequences of (153)Sm-EDTMP therapy prior to initiating treatment. In addition, patients treated with (153)Sm-EDTMP at Roger Maris Cancer Center receive laminated cards stating the date and the dose of treatment, as well as a statement that the holder may activate the alarm at the security checkpoints.

Detection and measurement of alternative splicing using splicing-sensitive microarrays.

Splicing and alternative splicing are major processes in the interpretation and expression of genetic information for metazoan organisms. The study of splicing is moving from focused attention on the regulatory mechanisms of a selected set of paradigmatic alternative splicing events to questions of global integration of splicing regulation with genome and cell function. For this reason, parallel methods for detecting and measuring alternative splicing are necessary. We have adapted the splicing-sensitive oligonucleotide microarrays used to estimate splicing efficiency in yeast to the study of alternative splicing in vertebrate cells and tissues. We use gene models incorporating knowledge about splicing to design oligonucleotides specific for discriminating alternatively spliced mRNAs from each other. Here we present the main strategies for design, application, and analysis of spotted oligonucleotide arrays for detection and measurement of alternative splicing. We demonstrate these strategies using a two-intron yeast gene that has been altered to produce different amounts of alternatively spliced RNAs, as well as by profiling alternative splicing in NCI 60 cancer cell lines.