A cluster of three extrapulmonary Mycobacterium abscessus infections linked to well-maintained water-based heater-cooler devices.

BACKGROUND: Various water-based heater-cooler devices (HCDs) have been implicated in nontuberculous mycobacteria outbreaks. Ongoing rigorous surveillance for healthcare-associated M. abscessus (HA-Mab) put in place following a prior institutional outbreak of M. abscessus alerted investigators to a cluster of 3 extrapulmonary M. abscessus infections among patients who had undergone cardiothoracic surgery. METHODS: Investigators convened a multidisciplinary team and launched a comprehensive investigation to identify potential sources of M. abscessus in the healthcare setting. Adherence to tap water avoidance protocols during patient care and HCD cleaning, disinfection, and maintenance practices were reviewed. Relevant environmental samples were obtained. Patient and environmental M. abscessus isolates were compared using multilocus-sequence typing and pulsed-field gel electrophoresis. Smoke testing was performed to evaluate the potential for aerosol generation and dispersion during HCD use. The entire HCD fleet was replaced to mitigate continued transmission. RESULTS: Clinical presentations of case patients and epidemiologic data supported intraoperative acquisition. M. abscessus was isolated from HCDs used on patients and molecular comparison with patient isolates demonstrated clonality. Smoke testing simulated aerosolization of M. abscessus from HCDs during device operation. Because the HCD fleet was replaced, no additional extrapulmonary HA-Mab infections due to the unique clone identified in this cluster have been detected. CONCLUSIONS: Despite adhering to HCD cleaning and disinfection strategies beyond manufacturer instructions for use, HCDs became colonized with and ultimately transmitted M. abscessus to 3 patients. Design modifications to better contain aerosols or filter exhaust during device operation are needed to prevent NTM transmission events from water-based HCDs.

An Enhanced Strategy for Daily Disinfection in Acute Care Hospital Rooms: A Randomized Clinical Trial.

Importance: Environmental contamination is a source of transmission between patients, health care practitioners, and other stakeholders in the acute care setting. Objective: To compare the efficacy of an enhanced daily disinfection strategy vs standard disinfection in acute care hospital rooms. Design, Setting, and Participants: This randomized clinical trial (RCT) was conducted in acute care hospital rooms at Duke University Hospital in Durham, North Carolina, from November 2021 to March 2022. Rooms were occupied by patients with contact precautions. Room surfaces (bed rails, overbed table, and in-room sink) were divided into 2 sides (right vs left), allowing each room to serve as its own control. Each side was randomized 1:1 to the intervention group or control group. Interventions: The intervention was a quaternary ammonium, salt-based, 24-hour continuously active germicidal wipe. It was applied in addition to routine disinfection for the intervention group. The control group received no intervention beyond routine disinfection. Main Outcomes and Measures: The primary outcome was the total contamination, measured in colony-forming units (CFUs) on the bed rails, overbed table, and sink on study day 1. The secondary outcomes were the proportion of sample areas with positive test results for clinically important pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and carbapenem-resistant Enterobacteriaceae; the similarity in baseline contamination between sample area sides on study day 0 before application of the intervention, and the proportion of sample areas with removed UV luminescent gel on study day 1. Results: A total of 50 study rooms occupied by 50 unique patients (median [IQR] age, 61 [45-69] years; 26 men [52%]) with contact precautions were enrolled. Of these patients, 41 (82%) were actively receiving antibiotics, 39 (78%) were bedridden, and 28 (56%) had active infections with study-defined clinically important pathogens. On study day 1, the median (IQR) total CFUs for the intervention group was lower than that for the control group (3561 [1292-7602] CFUs vs 5219 [1540-12 364] CFUs; P = .002). On study day 1, the intervention side was less frequently contaminated with patient-associated clinically important pathogens compared with the control side of the room (4 [14%] vs 11 [39%]; P = .04). Conclusions and Relevance: Results of this RCT demonstrated that a quaternary ammonium, salt-based, 24-hour continuously active germicidal wipe decreased the environmental bioburden in acute care hospital rooms compared with routine disinfection. The findings warrant large-scale RCTs to determine whether enhanced daily disinfection strategies can decrease patient acquisition and adverse patient outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT05560321.

Auditory pitch glides influence time-to-contact judgements of visual stimuli.

A common experimental task used to study the accuracy of estimating when a moving object arrives at a designated location is the time-to-contact (TTC) task. The previous studies have shown evidence that sound motion cues influence TTC estimates of a visual moving object. However, the extent to which sound can influence TTC of visual targets still remains unclear. Some studies on the crossmodal correspondence between pitch and speed suggest that descending pitch sounds are associated with faster speeds compared to ascending pitch sounds due to an internal model of gravity. Other studies have shown an opposite pitch-speed mapping (i.e., ascending pitch associated with faster speeds) and no influence of gravity heuristics. Here, we explored whether auditory pitch glides, a continuous pure tone sound either ascending or descending in pitch, influence TTC estimates of a vertically moving visual target and if any observed effects are consistent with a gravity-centered or gravity-unrelated pitch-speed mapping. Subjects estimated when a disc moving either upward or downward at a constant speed reached a visual landmark after the disc disappeared behind an occluder under three conditions: with an accompanying ascending pitch glide, with a descending pitch glide, or with no sound. Overall, subjects underestimated TTC with ascending pitch glides and overestimated TTC with descending pitch glides, compared to the no-sound condition. These biases in TTC were consistent in both disc motion directions. These results suggest that subjects adopted a gravity-unrelated pitch-speed mapping where ascending pitch is associated with faster speeds and descending pitch associated with slower speeds.

BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer.

BET bromodomain inhibitors block prostate cancer cell growth at least in part through c-Myc and androgen receptor (AR) suppression. However, little is known about other transcriptional regulators whose suppression contributes to BET bromodomain inhibitor anti-tumor activity. Moreover, the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency is increasing, is also unknown. Herein, we demonstrate that BET bromodomain inhibition blocks growth of a diverse set of CRPC cell models, including those that are AR-independent or in which c-Myc is not suppressed. To identify transcriptional regulators whose suppression accounts for these effects, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1 and then performed RNA-sequencing followed by Master Regulator computational analysis. This approach identified several previously unappreciated transcriptional regulators that are highly expressed in CRPC and whose suppression, via both transcriptional or post-translational mechanisms, contributes to the anti-tumor activity of BET bromodomain inhibitors.

Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer.

The BET bromodomain protein BRD4 is a chromatin reader that regulates transcription, including in cancer. In prostate cancer, specifically, the anti-tumor activity of BET bromodomain inhibition has been principally linked to suppression of androgen receptor (AR) function. MYC is a well-described BRD4 target gene in multiple cancer types, and prior work demonstrates that MYC plays an important role in promoting prostate cancer cell survival. Importantly, several BET bromodomain clinical trials are ongoing, including in prostate cancer. However, there is limited information about pharmacodynamic markers of response or mediators of de novo resistance. Using a panel of prostate cancer cell lines, we demonstrated that MYC suppression-rather than AR suppression-is a key determinant of BET bromodomain inhibitor sensitivity. Importantly, we determined that BRD4 was dispensable for MYC expression in the most resistant cell lines and that MYC RNAi + BET bromodomain inhibition led to additive anti-tumor activity in the most resistant cell lines. Our findings demonstrate that MYC suppression is an important pharmacodynamic marker of BET bromodomain inhibitor response and suggest that targeting MYC may be a promising therapeutic strategy to overcome de novo BET bromodomain inhibitor resistance in prostate cancer.

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.

Organizational Learning in a Cardiac Intensive Care Unit: A Learning History.

INTRODUCTION: Providing high-quality care to every patient is challenging, particularly in critical care units (CCUs). However, this standard can be achieved through organizational learning. Unfortunately, the process of organizational learning in CCUs is not well understood. OBJECTIVE: The objective of this study is to describe the developmental progression of a cardiac intensive care unit (CICU) to reach its current state of reliably excellent clinical performance. METHODS: The method selected for this study was a learning history. A total of 43 individuals with experience working on the CICU participated in small group interviews. Participants included nurses, surgeons, unit clerks, administrators, nursing assistants, a pharmacist, a respiratory therapist, and an administrative assistant. Relevant artifacts, including unit performance data, were also gathered to complement interview data. RESULTS: The CICU progressed through 4 distinct developmental stages to reach its current state. The CICU's early development involved establishing psychological safety on the unit, which prepared the unit for increased accountability, improved performance, and the pursuit of reliability. DISCUSSION/CONCLUSION: The findings validate the relationship between psychological safety and organizational learning, offer insight into how CCUs become high-reliability organizations, and provide clinical leaders with guidance for achieving high reliability in their organizations. The findings also help validate the American Association of Critical-Care Nurses position that a healthy work environment is essential to achieving clinical excellence. Critical care unit teams should use these findings as a framework for collective reflection and planning to achieve their desired future. Further research is needed to validate the applicability of these findings and to continue building the evidence base for organizational learning in hospital units.

Integrative molecular network analysis identifies emergent enzalutamide resistance mechanisms in prostate cancer.

Recent work demonstrates that castration-resistant prostate cancer (CRPC) tumors harbor countless genomic aberrations that control many hallmarks of cancer. While some specific mutations in CRPC may be actionable, many others are not. We hypothesized that genomic aberrations in cancer may operate in concert to promote drug resistance and tumor progression, and that organization of these genomic aberrations into therapeutically targetable pathways may improve our ability to treat CRPC. To identify the molecular underpinnings of enzalutamide-resistant CRPC, we performed transcriptional and copy number profiling studies using paired enzalutamide-sensitive and resistant LNCaP prostate cancer cell lines. Gene networks associated with enzalutamide resistance were revealed by performing an integrative genomic analysis with the PAthway Representation and Analysis by Direct Reference on Graphical Models (PARADIGM) tool. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with MEK, EGFR, RAS, and NFKB. Functional validation studies of 64 genes identified 10 candidate genes whose suppression led to greater effects on cell viability in enzalutamide-resistant cells as compared to sensitive parental cells. Examination of a patient cohort demonstrated that several of our functionally-validated gene hits are deregulated in metastatic CRPC tumor samples, suggesting that they may be clinically relevant therapeutic targets for patients with enzalutamide-resistant CRPC. Altogether, our approach demonstrates the potential of integrative genomic analyses to clarify determinants of drug resistance and rational co-targeting strategies to overcome resistance.

Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor.

Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) - the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation.

Src and STAT3 inhibitors synergize to promote tumor inhibition in renal cell carcinoma.

The intracytoplasmic tyrosine kinase Src serves both as a conduit and a regulator for multiple processes required for the proliferation and survival cancer cells. In some cancers, Src engages with receptor tyrosine kinases to mediate downstream signaling and in other cancers, it regulates gene expression. Src therefore represents a viable oncologic target. However, clinical responses to Src inhibitors, such as dasatinib have been disappointing to date. We identified Stat3 signaling as a potential bypass mechanism that enables renal cell carcinoma (RCC) cells to escape dasatinib treatment. Combined Src-Stat3 inhibition using dasatinib and CYT387 (a JAK/STAT inhibitor) synergistically reduced cell proliferation and increased apoptosis in RCC cells. Moreover, dasatinib and CYT387 combine to suppress YAP1, a transcriptional co-activator that promotes cell proliferation, survival and organ size. Importantly, this combination was well tolerated, and caused marked tumor inhibition in RCC xenografts. These results suggest that combination therapy with inhibitors of Stat3 signaling may be a useful therapeutic approach to increase the efficacy of Src inhibitors.