CNS Aspergillosis and Cryptococcosis with Cytomegalovirus Pneumonia in a Patient with Chronic Lymphocytic Leukemia Treated with Acalabrutinib.

Bruton's tyrosine kinase inhibitors (BTKis) are the preferred treatment for chronic lymphocytic leukemia (CLL). Despite their therapeutic benefits, these targeted agents have been associated with an increased risk of invasive infections. We describe a 68-year-old male who developed multiple bacterial, fungal and viral infections while on treatment with acalabrutinib. To our knowledge, this is the first reported case of concomitant CNS infections with Cryptococcus neoformans and Aspergillus fumigatus, along with cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) pneumonia while on acalabrutinib. This case adds to the scarce literature of fungal and bacterial infections associated with acalabrutinib, raising the suspicion that infection risk is a medication class effect for BTKis.

No evidence of attentional prioritization for threatening targets in visual search.

Throughout human evolutionary history, snakes have been associated with danger and threat. Research has shown that snakes are prioritized by our attentional system, despite many of us rarely encountering them in our daily lives. We conducted two high-powered, pre-registered experiments (total N = 224) manipulating target prevalence to understand this heightened prioritization of threatening targets. Target prevalence refers to the proportion of trials wherein a target is presented; reductions in prevalence consistently reduce the likelihood that targets will be found. We reasoned that snake targets in visual search should experience weaker effects of low target prevalence compared to non-threatening targets (rabbits) because they should be prioritized by searchers despite appearing rarely. In both experiments, we found evidence of classic prevalence effects but (contrasting prior work) we also found that search for threatening targets was slower and less accurate than for nonthreatening targets. This surprising result is possibly due to methodological issues common in prior studies, including comparatively smaller sample sizes, fewer trials, and a tendency to exclusively examine conditions of relatively high prevalence. Our findings call into question accounts of threat prioritization and suggest that prior attention findings may be constrained to a narrow range of circumstances.

Candidemia in Adult Patients in the ICU: A Reappraisal of Susceptibility Testing and Antifungal Therapy.

OBJECTIVE: To provide updates on the epidemiology and recommendations for management of candidemia in patients with critical illness. DATA SOURCES: A literature search using the PubMed database (inception to March 2023) was conducted using the search terms "invasive candidiasis," "candidemia," "critically ill," "azoles," "echinocandin," "antifungal agents," "rapid diagnostics," "antifungal susceptibility testing," "therapeutic drug monitoring," "antifungal dosing," "persistent candidemia," and "Candida biofilm." STUDY SELECTION/DATA EXTRACTION: Clinical data were limited to those published in the English language. Ongoing trials were identified through ClinicalTrials.gov. DATA SYNTHESIS: A total of 109 articles were reviewed including 25 pharmacokinetic/pharmacodynamic studies and 30 studies including patient data, 13 of which were randomized controlled clinical trials. The remaining 54 articles included fungal surveillance data, in vitro studies, review articles, and survey data. The current 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Management of Candidiasis provides recommendations for selecting empiric and definitive antifungal therapies for candidemia, but data are limited regarding optimized dosing strategies in critically ill patients with dynamic pharmacokinetic changes or persistent candidemia complicated. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Outcomes due to candidemia remain poor despite improved diagnostic platforms, antifungal susceptibility testing, and antifungal therapy selection for candidemia in critically ill patients. Earlier detection and identification of the species causing candidemia combined with recognition of patient-specific factors leading to dosing discrepancies are crucial to improving outcomes in critically ill patients with candidemia. CONCLUSIONS: Treatment of candidemia in critically ill patients must account for the incidence of non-albicans Candida species and trends in antifungal resistance as well as overcome the complex pathophysiologic changes to avoid suboptimal antifungal exposure.

Identification of Regulatory Elements in Primary Sensory Neurons Involved in Trauma-Induced Neuropathic Pain.

Chronic pain is a significant public health issue that is often refractory to existing therapies. Here we use a multiomic approach to identify cis-regulatory elements that show differential chromatin accessibility and reveal transcription factor (TF) binding motifs with functional regulation in the rat dorsal root ganglion (DRG), which contain cell bodies of primary sensory neurons, after nerve injury. We integrated RNA-seq to understand how differential chromatin accessibility after nerve injury may influence gene expression. Using TF protein arrays and chromatin immunoprecipitation-qPCR, we confirmed C/EBPγ binding to a differentially accessible sequence and used RNA-seq to identify processes in which C/EBPγ plays an important role. Our findings offer insights into TF motifs that are associated with chronic pain. These data show how interactions between chromatin landscapes and TF expression patterns may work together to determine gene expression programs in rat DRG neurons after nerve injury.

Impact of Fluoroquinolone Susceptibility Suppression on Discharge Prescribing for Acute Uncomplicated Cystitis.

Background: Fluoroquinolones (FQs) are associated with adverse effects and increasing resistance. However, uncomplicated cystitis remains a frequent reason for FQ use. Selective reporting involves withholding susceptibilities for select antimicrobial agents on microbiology reports, in hopes of dissuading use by providers. The purpose of this study was to investigate the impact of FQ susceptibility suppression on discharge prescribing for hospitalized patients with uncomplicated cystitis. Methods: This retrospective quasi-experimental analysis was conducted among adult patients at a 350-bed academic medical center. Its aim was to compare the incidence of FQ prescribing for cystitis at hospital discharge, one year before and after implementation (1 March 2017-31 March 2019) of a policy to suppress FQ urinary susceptibility results for pansusceptible Klebsiella spp and Escherichia coli. FQ appropriateness and risk factors for FQ use were also examined. Results: There was a relative risk reduction of 39% in discharge FQ prescribing when adjusted for discharge team (adjusted risk ratio, 0.61; 95% CI, .40-.93). Almost all FQ use was inappropriate, largely due to organisms' susceptibility to a guideline-preferred agent (n = 61). In multivariate analysis, odds ratios of discharge FQ prescribing were 0.22 (95% CI, .12-.39) for insured patients, 0.43 (95% CI, .21-.86) for patients with antibiotic allergy, and 57.8 (95% CI, 13.7-244) for those receiving inpatient FQ. Discharge from a medicine team was protective against discharge FQ prescribing. Conclusions: With multidisciplinary inpatient medicine services and avoidance of inpatient FQ use, suppression of FQ susceptibilities on pansusceptible urine isolates for Klebsiella spp and E coli may represent an attractive strategy for antibiotic stewardship at hospital discharge.

Treatment decisions in VRE bacteraemia: a survey of infectious diseases pharmacists.

Background: VRE infections increased in 2020. High-dose daptomycin (≥10 mg/kg) has shown mortality benefit over other regimens, though daptomycin resistance is increasing. Limited data exist on the practice patterns of ID pharmacists for VRE bloodstream infections (VRE BSIs). Objectives: To describe practice patterns for VRE BSI in ID pharmacists. Methods: A 22-question REDCap survey was distributed to ID pharmacist members of the American College of Clinical Pharmacy (ACCP) Infectious Diseases Practice and Research Network (ID PRN) via e-mail listserv. The survey was distributed on 7 April 2022 and remained open for 4 weeks. Results: Sixty-eight pharmacists responded. All pharmacists completed additional training or certification in infectious diseases past their PharmD, and most (70.5%) had been practising for 10 years or less. Pharmacists at academic medical centres (80.0%) were more likely (P = 0.001) to have implemented the updated CLSI breakpoints than pharmacists at other types of institutions (55.2%). Daptomycin was the preferred drug for VRE BSI (92.6%), with 10 mg/kg (72.1%) being the preferred dose. Adjusted body weight was the most common weight (61.2%) used for obese patients. Fourteen days (76.1%) was the most common treatment duration for VRE BSI. Pharmacists defined persistent VRE BSI as 5 days (68.7%) after first blood culture. Conclusions: ID pharmacists overwhelmingly selected high-dose daptomycin for VRE BSI. There were variations in practice and response rate when selecting combination therapy, managing persistent bacteraemia, and treating patients with high daptomycin MICs or previous exposure to daptomycin.

Comparison of dosing strategies in obese patients prescribed intravenous acyclovir and evaluation of rate of acute kidney injury.

INTRODUCTION: There is limited guidance on the most appropriate dosing strategy for intravenous (IV) acyclovir in obese patients. The manufacturer's labelling suggests using ideal body weight (IBW); however, previous pharmacokinetic studies of obese patients have shown more rapid systemic clearance and lower area under the curve and peak concentrations compared with patients with a body mass index (BMI) < 30 kg/m2. Although pharmacokinetic data suggest that plasma concentrations of acyclovir are best predicted when using adjusted body weight (AdjBW) doses, there is concern about higher rates of acute kidney injury (AKI). METHODS: This was a retrospective cohort review of adult patients with a BMI ≥ 30 kg/m2 prescribed IV acyclovir ≥ 48 hours between 1 January 2014 and 31 August 2021 at a 511-bed academic medical centre. The primary objective was to compare AdjBW with IBW dosing in obese patients who had been prescribed IV acyclovir and to determine whether AdjBW dosing results in higher rates of AKI. RESULTS: Ninety-four patients were included: 61 were in the IBW cohort and 33 were in the AdjBW cohort. The median BMI [IQR] for all patients was 34.7 kg/m2 [31.8-40.6]. Patients in the AdjBW cohort received a significantly higher median acyclovir dose of 800 mg/dose [IQR 700-850] compared with 600 mg/dose [IQR 500-700] for the IBW cohort (P ≤ 0.0001). No patients dosed using AdjBW developed AKI compared with eight (13.1%) in the IBW group. CONCLUSION: In this study, 8.5% of all obese patients receiving acyclovir developed AKI. Further studies are needed to confirm dosing recommendations.

Therapeutic Options for Adult Patients With Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Narrative Review.

OBJECTIVE: To compare the efficacy of antimicrobial therapies used in the management of persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. DATA SOURCES: A literature search using the PubMed database (inception to December 2022) was conducted using the search terms "Staphylococcus aureus bacteremia," "methicillin-susceptible Staphylococcus aureus bacteremia," "persistent methicillin-susceptible Staphylococcus aureus bacteremia," and "refractory methicillin-susceptible Staphylococcus aureus bacteremia ." In addition, therapeutic agents which could be used as treatment for MSSA including "nafcillin," "oxacillin," "cefazolin," "ceftaroline," "gentamicin," "rifampin," and "daptomycin" were also combined with the aforementioned search terms to capture data using these agents. STUDY SELECTION/DATA EXTRACTION: Clinical data were limited to those published in the English language. Articles and abstracts were considered for inclusion in addition to ongoing trials identified through ClinicalTrials.gov. DATA SYNTHESIS: A total of 78 articles were reviewed including 17 in vitro or animal model studies and 39 studies including patient data. The remaining 22 articles included guidelines, review articles, and editorials. Recent data evaluating use of dual ß-lactam regimens for persistent MSSA bacteremia were limited to 8 case reports or case series. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: At present, there is little guidance on how to best manage patients with persistent MSSA bacteremia. This narrative review collates the available data to assist clinicians in selecting the best possible antimicrobial regimen when facing this clinical conundrum. CONCLUSIONS: Modification of antimicrobial therapy, in conjunction with source control and infectious diseases consultation, may all be necessary to sterilize blood cultures in patients with persistent MSSA bacteremia.

Impact of a Pharmacist-Managed Outpatient Parenteral Antimicrobial Therapy (OPAT) Service on Cost Savings and Clinical Outcomes at an Academic Medical Center.

Background: Outpatient antimicrobial therapy (OPAT) is managed by a variety of teams, but primarily through an infectious disease clinic. At our medical center, OPAT monitoring is performed telephonically by pharmacists through a collaborative practice agreement under the supervision of an infectious disease physician. The effect of telephonic monitoring of OPAT by pharmacists on patient outcomes is unknown. Methods: This retrospective cohort study was conducted between July 2017 and July 2018 at a 350-bed academic medical center and included adult patients discharged home on IV antibiotics or oral linezolid. The experimental group comprised patients discharged with a consultation for the OPAT management program, whereas the control group comprised patients discharged home without a consultation. The primary outcome was 30-day readmission. Results: In total, 399 patients were included: 243 patients in the OPAT management program group and 156 patients in the control group. The 30-day readmission rates were similar in each cohort (20% vs 19%; P = .8193); however, the 30-day readmission rates were lower in the OPAT management program for patients discharged on vancomycin (19.4% vs 39.1%; P = .004). Conclusions: We did not find a difference in 30-day readmissions between patients receiving pharmacy-driven OPAT management services and those who did not. Patients receiving vancomycin via OPAT had lower 30-day readmissions when included in the pharmacist-driven OPAT management program. Institutions with limited resources may consider reserving OPAT management services for patients receiving antimicrobials that require pharmacokinetic dosing and/or close monitoring.

Variation Among Infectious Diseases Pharmacists for the Treatment of Staphylococcus aureus Bacteremia.

Introduction: Staphylococcus aureus bacteremia (SAB) remains complex, in that optimal treatment for patients, including complicated or persistent infection, remains unclear. Two recent surveys have demonstrated practice variations in SAB among infectious diseases (ID) physicians. Objectives: The purpose of this survey was to examine practice variations in SAB among ID pharmacists. Methods: A thirty-five-question survey was electronically distributed to the American College of Clinical Pharmacy (ACCP) Infectious Diseases Practice and Research Network (IDPRN) in Fall 2019 to determine differences in SAB management. Data were analyzed utilizing Pearson's Chi-Square or Fisher's Exact Test. Results: A total of 106 ID pharmacists responded. Only 28% of pharmacists practiced at hospitals with mandatory ID consultation for SAB. A majority (75%) had rapid diagnostic technology (RDT) for identifying SABSI, but 32% of those facilities with RDT did not notify pharmacy with results. Anti-staphylococcal penicillins were preferred for MSSA blood stream infections (BSI) in patients with central nervous system infection and endocarditis, whereas cefazolin was favored for other MSSA BSI. For persistent MRSA BSI, 34% selected daptomycin alone while 38% elected to combine daptomycin and ceftaroline. Pharmacists at hospitals less than 500 beds were more likely to use daptomycin, while those at larger hospitals were more likely to use daptomycin and ceftaroline for persistent MRSA BSI (P < .05). Conclusions: A survey of ID pharmacists showed variation in the management of SABs, as well as the definition and treatment of persistent SAB. Mandatory ID consultation and RDT use to improve SAB management have not been optimized.

The Oddity Detection in Diverse Scenes (ODDS) database: Validated real-world scenes for studying anomaly detection.

Many applied screening tasks (e.g., medical image or baggage screening) involve challenging searches for which standard laboratory search is rarely equivalent. For example, whereas laboratory search frequently requires observers to look for precisely defined targets among isolated, non-overlapping images randomly arrayed on clean backgrounds, medical images present unspecified targets in noisy, yet spatially regular scenes. Those unspecified targets are typically oddities, elements that do not belong. To develop a closer laboratory analogue to this, we created a database of scenes containing subtle, ill-specified "oddity" targets. These scenes have similar perceptual densities and spatial regularities to those found in expert search tasks, and each includes 16 variants of the unedited scene wherein an oddity (a subtle deformation of the scene) is hidden. In Experiment 1, eight volunteers searched thousands of scene variants for an oddity. Regardless of their search accuracy, they were then shown the highlighted anomaly and rated its subtlety. Subtlety ratings reliably predicted search performance (accuracy and response times) and did so better than image statistics. In Experiment 2, we conducted a conceptual replication in which a larger group of naïve searchers scanned subsets of the scene variants. Prior subtlety ratings reliably predicted search outcomes. Whereas medical image targets are difficult for naïve searchers to detect, our database contains thousands of interior and exterior scenes that vary in difficulty, but are nevertheless searchable by novices. In this way, the stimuli will be useful for studying visual search as it typically occurs in expert domains: Ill-specified search for anomalies in noisy displays.

Keeping Up With the Literature: New Solutions for an Old Problem.

Pharmacists utilize medical literature to provide evidence-based care to patients. However, staying up to date with current literature can be challenging, especially with the increasing number of publications produced in a growing number of journals. While evaluating literature is a standard in pharmacy education and training, the specific skill of keeping up with the literature is often not included. We explore the following 5 strategies to help pharmacists stay up to date with the literature: medical journals, social media, podcasts, teaching/precepting, and continuing education/board certification. Pharmacists are encouraged to evaluate which tactics fit best into their practice and incorporate them into their workflow, as well as routinely reflect on the system they create and continue to modify as needed.

Social Network and Behavioral Synchrony Influences On Maternal and Infant Cortisol Response.

This study examined the contributions of mothers' social network stability and mother-infant behavioral synchrony on cortisol response in infants and their mothers during separation. The quality and stability of mothers' social network system and mother-infant bond have both been shown to affect infant neuroendocrine response. Yet, no studies have directly addressed how these two forms of social relationships might differentially affect infants' and mothers' neuroendocrine responses during separation. First-time mothers (N = 133) and their 3-month-old infants participated in the study. Maternal social network stability, mother-infant behavioral synchrony, and mother and infant cortisol response during an infant challenge task were assessed. Behavioral synchrony accounted for significant variance in infants' cortisol response, and after adjusting for synchrony, mothers' network stability measures did not explain variance in infant cortisol. Social network stability, but not synchrony, accounted for significant variance in mothers' cortisol response. These results demonstrate that, when mothers and infants experience brief separation, the quality of their bond is associated with a lower stress response for infants; but for mothers, it is the longevity of her social relationships outside of the mother-infant relationship context that is associated with her lower stress response.

Evaluation of Ceftazidime Use in the Neonatal Intensive Care Unit and Association With Cephalosporin-Resistant Gram-Negative Bacteria.

BACKGROUND: Cefotaxime shortage in 2015 led to increased ceftazidime use in the neonatal intensive care unit (NICU). OBJECTIVE: The purpose was to explore whether ceftazidime increases risk for development of resistant gram-negative organisms. METHODS: Retrospective evaluation of NICU patients with cultures positive for Escherichia coli, Pseudomonas aeruginosa, Klebsiella species, or Stenotrophomonas maltophilia between January1, 2015 and August 31, 2020. Isolates were excluded if obtained from same patient and source within 90 days or if patient ≤7 days of life or admitted from a referring hospital. Data collection included demographics and clinical parameters, and culture/susceptibility data. The primary objective was comparison of pathogens and clinical parameters in those with and without third-generation cephalosporin resistance. The secondary objectives included a comparison between those with and without ceftazidime exposure and identification of factors associated with resistance. Comparisons were made using χ2, Fisher exact tests, or Wilcoxon tests. A logistic regression was used to identify risk factors for resistance. RESULTS: Overall, 349 isolates, representing 215 patients, were included. The most common source was endotracheal (n = 192, 55.0%) and pathogens were E coli (31.8%) and P aeruginosa (29.2%). Overall, 12.3% (n = 43) were resistant and these were obtained after longer parenteral nutrition (PN), central line access, and antibiotic days versus susceptible isolates. Higher resistance was noted after ceftazidime exposure versus no exposure, 19.1% versus 6.6%. Each day of ceftazidime was associated with 13% greater odds of P aeruginosa resistance (adjusted odds ratio: 1.13 [95% confidence interval: 1.03-1.23]). CONCLUSION AND RELEVANCE: Ceftazidime duration was associated with increased risk for P aeruginosa resistance. Additional studies are needed to confirm these findings.

Cellular Uptake of Gold Nanorods in Breast Cancer Cell Lines.

Nanosized materials have been proposed for a wide range of biomedical applications, given their unique characteristics. However, how these nanomaterials interact with cells and tissues, as well as how they bio-distribute in organisms, is still under investigation. Differences such as the nanoparticle size, shape, and surface chemistry affect the basic mechanisms of cellular uptake and responses, which, in turn, affects the nanoparticles' applicability for biomedical applications. Thus, it is vital to determine how a specific nanoparticle interacts with cells of interest before extensive in vivo applications are performed. Here, we delineate the uptake mechanism and localization of gold nanorods in SKBR-3 and MCF-7 breast cancer cell lines. Our results show both differences and similarities in the nanorod-cell interactions of the two cell lines. We accurately quantified the cellular uptake of gold nanorods in SKBR-3 and MCF-7 using inductively coupled plasma mass spectrometry (ICP-MS). We found that both cell types use macropinocytosis to internalize bare nanorods that aggregate and associate with the cell membrane. In addition, we were able to qualitatively track and show intracellular nanoparticle localization using transmission electron microscopy. The results of this study will be invaluable for the successful development of novel and "smart" nanodrugs based on gold nano-structural delivery vehicles, which heavily depend on their complex interactions with single cells.

CCAAT enhancer binding protein gamma (C/EBP-γ): An understudied transcription factor.

The CCAAT enhancer binding protein (C/EBP) family of transcription factors are important transcriptional mediators of a wide range of physiologic processes. C/EBP-γ is the shortest C/EBP protein and lacks a canonical activation domain for the recruitment of transcriptional machinery. Despite its ubiquitous expression and ability to dimerize with other C/EBP proteins, C/EBP-γ has been studied far less than other C/EBP proteins, and, to our knowledge, no review of its functions has been written. This review seeks to integrate the current knowledge about C/EBP-γ and its physiologic roles, especially in cell proliferation, the integrated stress response, oncogenesis, hematopoietic and nervous system development, and metabolism, as well as to identify areas for future research.

Neuropsychological correlates of evocative multimodal speech: The combined roles of fearful prosody, visuospatial attention, cortisol response, and anxiety.

Past research reveals left-hemisphere dominance for linguistic processing and right-hemisphere dominance for emotional prosody processing during auditory language comprehension, a pattern also found in visuospatial attention studies where listeners are presented with a view of the talker's face. Is this lateralization pattern for visuospatial attention and language processing upheld when listeners are experiencing a stress response? To investigate this question, participants completed the Trier Social Stress Test (TSST) between administrations of a visuospatial attention and language comprehension dual-task paradigm. Subjective anxiety, cardiovascular, and saliva cortisol measures were taken before and after the TSST. Higher language comprehension scores in the post-TSST neutral prosody condition were associated with lower cortisol responses, differences in blood pressure, and less subjective anxiety. In this challenging task, visuospatial attention was most focused at the mouth region, both prior to and after stress induction. Greater visuospatial attention on the left side of the face image, compared to the right side, indicated greater right hemisphere activation. In the Fear, but not the Neutral, prosody condition, greater cortisol response was associated with greater visuospatial attention to the left side of the face image. Results are placed into theoretical context, and can be applied to situations where stressed listeners must interpret emotionally evocative language.