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Pupillometry is the most used objective tool to assess listening effort but has several disadvantages. The current study explores a new, objective way to assess listening effort through eye movements. Building on cognitive and neurophysiological work, we examine the hypothesis that eye movements decrease when speech listening becomes challenging. In three experiments with human participants from both sexes, we demonstrate, consistent with this hypothesis, that fixation duration increases and spatial gaze dispersion decreases with increasing speech masking. Eye movements decreased during effortful speech listening for different visual scenes (free viewing; object tracking) and speech materials (simple sentences; naturalistic stories). In contrast, pupillometry was insensitive to speech masking during story listening, highlighting the challenges with pupillometric measures for the assessments of listening effort in naturalistic speech-listening paradigms. Our results reveal a critical link between eye movements and cognitive load, and provide the foundation for a novel measure of listening effort applicable in a wide range of contexts.Significance statementAssessment of listening effort is critical for early diagnosis of age-related hearing loss. Pupillometry is most used but has several disadvantages. The current study explores a new, objective way to assess listening effort through eye movements. We examine the hypothesis that eye movements decrease when speech listening becomes effortful. We demonstrate, consistent with this hypothesis, that fixation duration increases and gaze dispersion decreases with increasing speech masking. Eye movements decreased during effortful speech listening for different visual scenes (free viewing; object tracking) and speech materials (sentences; naturalistic stories). Our results reveal a critical link between eye movements and cognitive load, and provide the foundation for a novel measure of listening effort applicable in a wide range of contexts.

Machine Learning is frequently used to predict and classify data. Natural Language Processing (NLP) uses machine learning to classify strings of words. There are many different machine learning models that can be used for NLP, with three main categories being regression, decision tree, and neural net models. Each has their own advantages and drawbacks. After being trained and tested on a set of tweets concerning cyberbullying, Logistic Regression, XGboost, and Long Short-Term Memory (LSTM) were compared in terms of several metrics, including accuracy, recall, precision, and f1-score. Afterwards, the metrics were considered in combination with model runtime and complexity to determine which model was most appropriate for the given dataset and other similar datasets. Logistic Regression was found to lack sufficient complexity to properly classify the data. LSTM had worse metrics than XGboost and had significantly higher complexity and runtime. XGboost performed best, with the highest metrics and relatively short runtime.

Clinically effective CAR-T cell therapy for solid tumors, such as clear cell renal cell carcinoma (ccRCC), will require substantial T cell engineering to increase their specificity and potency. We have developed an Integrated Circuit T cell (ICT) that encodes multiple synthetic “modules” in order to overcome diverse barriers to efficacy in ccRCC; ICT cells are generated via CRISPR-mediated, targeted knock-in of a single large transgene into the novel GS94 safe-harbor locus. Both primary and metastatic sites of ccRCC are highly vascularized, with the majority of tumor cells expressing elevated levels of carbonic anhydrase IX (CA9), suggesting CA9 may be an excellent CAR target. However, CA9 is also expressed in healthy bile ducts and stomach tissue which has led to on-target, off-tumor toxicities in patients treated with constitutive CA9 CAR T cells. To improve the therapeutic index of CA9 CAR T cells, we developed an “AND” logic gated ICT cell that requires the presence of two antigens to trigger tumor cell killing, thereby enhancing tumor specificity. Induction of the CA9 CAR is gated on the expression of PSMA found on the tumor neovasculature of ccRCC. Importantly, PSMA and CA9 are not co-expressed in normal tissues. When the anti-PSMA priming receptor (PrimeRTM) binds PSMA, PrimeRTM engagement triggers proteolytic release of a chimeric, fully human transcription factor that induces expression of a CA9 CAR. We confirmed the feasibility of vascular priming using a transwell assay where ICTs were primed by a PSMA expressing endothelial cell line and then migrated across the transwell membrane to kill CA9 expressing RCC cells. In addition, a dual flank xenograft model was used to show logic gated circuits selectively kill tumors that express both CA9 and PSMA, and not tumors that express CA9 alone. Transforming growth factor beta (TGFb) is an immunosuppressive cytokine known to be highly expressed in ccRCC. To further increase the potency and persistence of the ICT cells an shRNA cassette was developed targeting both FAS and TGFBR2, a receptor required for TGFB signaling in T cells. Addition of FAS/TGFBR2 shRNA enhanced antitumor activity of PSMAxCA9 logic gate expressing T cells during in vitro chronic stimulation assays conducted in the presence of exogenous TGFb. Furthermore, FAS/TGFBR shRNA containing ICTs demonstrated enhanced antitumor activity in multiple xenograft RCC models. Collectively, these results demonstrate that PSMAxCA9 ICT cells can (i) selectively target antigens that cannot be safely targeted by conventional CARs and (ii) overcome multiple suppressive mechanisms in the tumor microenvironment. Citation Format: Angela C. Boroughs, Irene Scarfo, Nickolas Attanasio, Thomas Gardner, Jenessa B. Smith, Jennifer McDevitt, Laura Lim, Nishant Mehta, Suchismita Mohanty, James Zhang, Eric Cui, Vibhavari Sail, Amanda Fearon, Samuel Williams, Stephen Santoro, W. Nicholas Haining, Levi Gray-Rupp. A neovasculature-inducible CA9 CAR resistant to FASL and TGFb mediated suppression for the treatment of ccRCC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4088.

The CLEAR trial demonstrated that a multi-site body decolonization regimen reduced post-discharge infection and hospitalization in methicillin-resistant Staphylococcus aureus (MRSA) carriers. This report describes decolonization efficacy in clearing site-specific MRSA colonization during the trial.We performed a large, multi-center, randomized clinical trial of MRSA decolonization among adult patients after hospital discharge with MRSA infection or colonization. Participants were randomized 1:1 to either MRSA prevention education or education plus decolonization with 4% topical chlorhexidine daily, 0.12% oral chlorhexidine rinse twice daily, and 2% nasal mupirocin twice daily. The intervention was given for five consecutive days twice monthly. Participants were swabbed in the nares, throat, axilla/groin, and wound (if applicable) at baseline, 1, 3, 6, and 9 months after randomization. The primary outcomes of this report are follow-up colonization differences between groups.Among 2,121 participants, 1,058 were randomized to the decolonization group. By one month, MRSA colonization was lower in the decolonization group compared to the education only group (OR = 0.44 [95% Confidence Interval 0.36-0.54, p≤0.001). Similar magnitude of reduction was seen in the nares (OR = 0.34 [0.27-0.42], p 0.001) throat (OR = 0.55 [0.42-0.73], p 0.001), and axilla/groin (OR = 0.57 [0.43-0.75], p 0.001). These differences persisted through month 9 except at the wound site, which had a relatively small sample size. Higher regimen adherence was associated with lower MRSA colonization (p≤0.01).In a randomized clinical trial, a repeated post-discharge decolonization regimen for MRSA carriers reduced MRSA colonization overall and at multiple body sites. Higher treatment adherence was associated with greater reductions in MRSA colonization.

BACKGROUND: Hospitalized patients who are colonized with methicillin-resistant Staphylococcus aureus (MRSA) are at high risk for infection after discharge. METHODS: We conducted a multicenter, randomized, controlled trial of postdischarge hygiene education, as compared with education plus decolonization, in patients colonized with MRSA (carriers). Decolonization involved chlorhexidine mouthwash, baths or showers with chlorhexidine, and nasal mupirocin for 5 days twice per month for 6 months. Participants were followed for 1 year. The primary outcome was MRSA infection as defined according to Centers for Disease Control and Prevention (CDC) criteria. Secondary outcomes included MRSA infection determined on the basis of clinical judgment, infection from any cause, and infection-related hospitalization. All analyses were performed with the use of proportional-hazards models in the per-protocol population (all participants who underwent randomization, met the inclusion criteria, and survived beyond the recruitment hospitalization) and as-treated population (participants stratified according to adherence). RESULTS: In the per-protocol population, MRSA infection occurred in 98 of 1063 participants (9.2%) in the education group and in 67 of 1058 (6.3%) in the decolonization group; 84.8% of the MRSA infections led to hospitalization. Infection from any cause occurred in 23.7% of the participants in the education group and 19.6% of those in the decolonization group; 85.8% of the infections led to hospitalization. The hazard of MRSA infection was significantly lower in the decolonization group than in the education group (hazard ratio, 0.70; 95% confidence interval [CI], 0.52 to 0.96; P=0.03; number needed to treat to prevent one infection, 30; 95% CI, 18 to 230); this lower hazard led to a lower risk of hospitalization due to MRSA infection (hazard ratio, 0.71; 95% CI, 0.51 to 0.99). The decolonization group had lower likelihoods of clinically judged infection from any cause (hazard ratio, 0.83; 95% CI, 0.70 to 0.99) and infection-related hospitalization (hazard ratio, 0.76; 95% CI, 0.62 to 0.93); treatment effects for secondary out-comes should be interpreted with caution owing to a lack of prespecified adjustment for multiple comparisons. In as-treated analyses, participants in the decolonization group who adhered fully to the regimen had 44% fewer MRSA infections than the education group (hazard ratio, 0.56; 95% CI, 0.36 to 0.86) and had 40% fewer infections from any cause (hazard ratio, 0.60; 95% CI, 0.46 to 0.78). Side effects (all mild) occurred in 4.2% of the participants. CONCLUSIONS: Postdischarge MRSA decolonization with chlorhexidine and mupirocin led to a 30% lower risk of MRSA infection than education alone. (Funded by the AHRQ Healthcare-Associated Infections Program and others; ClinicalTrials.gov number, NCT01209234.)

Objective.Screening for methicillin-resistantStaphylococcus aureus(MRSA) in high-risk patients is a legislative mandate in 9 US states and has been adopted by many hospitals. Definitions of high risk differ among hospitals and state laws. A systematic evaluation of factors associated with colonization is lacking. We performed a systematic review of the literature to assess factors associated with MRSA colonization at hospital admission.Design.We searched MEDLINE from 1966 to 2012 for articles comparing MRSA colonized and noncolonized patients on hospital or intensive care unit (ICU) admission. Data were extracted using a standardized instrument. Meta-analyses were performed to identify factors associated with MRSA colonization.Results.We reviewed 4,381 abstracts; 29 articles met inclusion criteria (n= 76,913 patients). MRSA colonization at hospital admission was associated with recent prior hospitalization (odds ratio [OR], 2.4 [95% confidence interval (CI), 1.3–4.7];PP< .01), and history of exposure to healthcare-associated pathogens (MRSA carriage: OR, 8.0 [95% CI, 4.2–15.1];Clostridium difficileinfection: OR, 3.4 [95% CI, 2.2–5.3]; vancomycin-resistantEnterococcicarriage: OR, 3.1 [95% CI, 2.5–4.0];P< .01 for all). Select comorbidities were associated with MRSA colonization (congestive heart failure, diabetes, pulmonary disease, immunosuppression, and renal failure;P< .01 for all), while others were not (human immunodeficiency virus, cirrhosis, and malignancy). ICU admission was not associated with an increased risk of MRSA colonization (OR, 1.1 [95% CI, 0.6–1.8];P= .87).Conclusions.MRSA colonization on hospital admission was associated with healthcare contact, previous healthcare-associated pathogens, and select comorbid conditions. ICU admission was not associated with MRSA colonization, although this is commonly used in state mandates for MRSA screening. Infection prevention programs utilizing targeted MRSA screening may consider our results to define patients likely to have MRSA colonization.

Both targeted decolonization and universal decolonization of patients in intensive care units (ICUs) are candidate strategies to prevent health care-associated infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA).We conducted a pragmatic, cluster-randomized trial. Hospitals were randomly assigned to one of three strategies, with all adult ICUs in a given hospital assigned to the same strategy. Group 1 implemented MRSA screening and isolation; group 2, targeted decolonization (i.e., screening, isolation, and decolonization of MRSA carriers); and group 3, universal decolonization (i.e., no screening, and decolonization of all patients). Proportional-hazards models were used to assess differences in infection reductions across the study groups, with clustering according to hospital.A total of 43 hospitals (including 74 ICUs and 74,256 patients during the intervention period) underwent randomization. In the intervention period versus the baseline period, modeled hazard ratios for MRSA clinical isolates were 0.92 for screening and isolation (crude rate, 3.2 vs. 3.4 isolates per 1000 days), 0.75 for targeted decolonization (3.2 vs. 4.3 isolates per 1000 days), and 0.63 for universal decolonization (2.1 vs. 3.4 isolates per 1000 days) (P=0.01 for test of all groups being equal). In the intervention versus baseline periods, hazard ratios for bloodstream infection with any pathogen in the three groups were 0.99 (crude rate, 4.1 vs. 4.2 infections per 1000 days), 0.78 (3.7 vs. 4.8 infections per 1000 days), and 0.56 (3.6 vs. 6.1 infections per 1000 days), respectively (P0.001 for test of all groups being equal). Universal decolonization resulted in a significantly greater reduction in the rate of all bloodstream infections than either targeted decolonization or screening and isolation. One bloodstream infection was prevented per 54 patients who underwent decolonization. The reductions in rates of MRSA bloodstream infection were similar to those of all bloodstream infections, but the difference was not significant. Adverse events, which occurred in 7 patients, were mild and related to chlorhexidine.In routine ICU practice, universal decolonization was more effective than targeted decolonization or screening and isolation in reducing rates of MRSA clinical isolates and bloodstream infection from any pathogen. (Funded by the Agency for Healthcare Research and the Centers for Disease Control and Prevention; REDUCE MRSA ClinicalTrials.gov number, NCT00980980).

Background.Central line-associated bloodstream infection (CLABSI) is a national target for mandatory reporting and a Centers for Medicare and Medicaid Services target for value-based purchasing. Differences in chart review versus claims-based metrics used by national agencies and groups raise concerns about the validity of these measures.Objective.Evaluate consistency and reasons for discordance among chart review and claims-based CLABSI events.Methods.We conducted 2 multicenter retrospective cohort studies within 6 academic institutions. A total of 150 consecutive patients were identified with CLABSI on the basis of National Healthcare Safety Network (NHSN) criteria (NHSN cohort), and an additional 150 consecutive patients were identified with CLABSI on the basis of claims codes (claims cohort). Ail events had full-text medical record reviews and were identified as concordant or discordant with the other metric.Results.In the NHSN cohort, there were 152 CLABSIs among 150 patients, and 73.0% of these cases were discordant with claims data. Common reasons for the lack of associated claims codes included coding omission and lack of physician documentation of bacteremia cause. In the claims cohort, there were 150 CLABSIs among 150 patients, and 65.3% of these cases were discordant with NHSN criteria. Common reasons for the lack of NHSN reporting were identification of non-CLABSI with bacteremia meeting Centers for Disease Control and Prevention (CDC) criteria for an alternative infection source.Conclusion.Substantial discordance between NHSN and claims-based CLABSI indicators persists. Compared with standardized CDC chart review criteria, claims data often had both coding omissions and misclassification of non-CLABSI infections as CLABSI. Additionally, claims did not identify any additional CLABSIs for CDC reporting. NHSN criteria are a more consistent interhospital standard for CLABSI reporting.

A recent trial showed that universal decolonization in adult intensive care units (ICUs) resulted in greater reductions in all bloodstream infections and clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) than either targeted decolonization or screening and isolation. Since regional health-care facilities are highly interconnected through patient-sharing, focusing on individual ICUs may miss the broader impact of decolonization. Using our Regional Healthcare Ecosystem Analyst simulation model of all health-care facilities in Orange County, California, we evaluated the impact of chlorhexidine baths and mupirocin on all ICU admissions when universal decolonization was implemented for 25%, 50%, 75%, and 100% of ICU beds countywide (compared with screening and contact precautions). Direct benefits were substantial in ICUs implementing decolonization (a median 60% relative reduction in MRSA prevalence). When 100% of countywide ICU beds were decolonized, there were spillover effects in general wards, long-term acute-care facilities, and nursing homes resulting in median 8.0%, 3.0%, and 1.9% relative MRSA reductions at 1 year, respectively. MRSA prevalence decreased by a relative 3.2% countywide, with similar effects for methicillin-susceptible S. aureus. We showed that a large proportion of decolonization's benefits are missed when accounting only for ICU impact. Approximately 70% of the countywide cases of MRSA carriage averted after 1 year of universal ICU decolonization were outside the ICU.

Maintenance of genomic integrity in embryonic cells is pivotal to proper embryogenesis, organogenesis and to the continuity of species. Cultured mouse embryonic stem cells (mESCs), a model for early embryonic cells, differ from cultured somatic cells in their capacity to remodel chromatin, in their repertoire of DNA repair enzymes, and in the regulation of cell cycle checkpoints. Using 129XC3HF1 mESCs heterozygous for Aprt, we characterized loss of Aprt heterozygosity after exposure to ionizing radiation. We report here that the frequency of loss of heterozygosity mutants in mESCs can be induced several hundred-fold by exposure to 5 to 10 Gy of x-rays. This induction is 50 to 100-fold higher than the induction reported for mouse adult or embryonic fibroblasts. The primary mechanism underlying the elevated loss of heterozygosity after irradiation is mitotic recombination, with lesser contributions from deletions and gene conversions that span Aprt. Aprt point mutations and epigenetic inactivation are very rare in mESCs compared to fibroblasts. Mouse ESCs, therefore, are distinctive in their response to ionizing radiation and studies of differentiated cells may underestimate the mutagenic effects of ionizing radiation on ESC or other stem cells. Our findings are important to understanding the biological effects of ionizing radiation on early development and carcinogenesis.

The natural history and optimal treatment of upper extremity (UE) deep venous thromboses (DVT's) remains uncertain as does the clinical significance of catheter-associated (CA) UE DVT's. We sought to analyze predictors of UE DVT resolution and hypothesized that anticoagulation will be associated with quicker UE DVT clot resolution and that CA UE DVT's whose catheters are removed will resolve more often than non-CA UE DVT's.All patients on the surgical intensive care unit service were prospectively followed from January 2008 to May 2010. A standardized DVT prevention protocol was used and screening bilateral UE and lower extremity duplex examinations were obtained within 48 hours of admission and then weekly. Computed tomography angiography for pulmonary embolism was obtained if clinically indicated. Patients with UE DVT were treated according to attending discretion. Data regarding patient demographics and UE DVT characteristics were recorded: DVT location, catheter association, occlusive status, treatment, and resolution. The primary outcome measure was UE DVT resolution before hospital discharge. Interval decrease in size on the subsequent duplex after UE DVT detection was also noted. UE DVTs without a follow-up duplex were excluded from the final analysis. Univariate and multivariate analyses were used to identify independent predictors of UE DVT resolution.There were 201 UE DVT's in 129 patients; 123 DVTs had a follow-up duplex and were included. Fifty-four percent of UEDVTs improved on the next duplex, 60% resolved before discharge, and 2% embolized. The internal jugular was the most common site (52%) and 72% were nonocclusive. Sixty-four percent were CAUEDVT's and line removal was associated with more frequent improvement on the next duplex (55% vs. 17%, p = 0.047, mid-P exact). Sixty-eight percent of UEDVTs were treated with some form of anticoagulation, but this was not associated with improved UE DVT resolution (61% vs. 60%). Independent predictors of clot resolution were location in the arm (odds ratio = 4.1 compared with the internal jugular, p = 0.031) and time from clot detection until final duplex (odds ratio =1.052 per day, p = 0.032).A majority of UE DVT's are CA, more than half resolve before discharge, and 2% embolize. Anticoagulation does not appear to affect outcomes, but line removal does result in a quicker decrease in clot size.

In a retrospective cohort study of 1,140 patients harboring methicillin-resistant Staphylococcus aureus , the nasal burden was low in 31%, category 1+ to 2+ in 54%, and category 3+ to 4+ in 15%. There was a significant trend in infection risk with increasing nasal burden ( P = 0.007). In multivariate models, high nasal burden remained significantly associated with invasive infection.

We surveyed infection prevention programs in 16 hospitals for hospital-associated methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, extended-spectrum β-lactamase, and multidrug-resistant Acinetobacter acquisition, as well as hospital-associated MRSA bacteremia and Clostridium difficile infection based on defining events as occurring >2 days versus >3 days after admission. The former resulted in significantly higher median rates, ranging from 6.76% to 45.07% higherInfect Control Hosp Epidemiol 2014;35(11):1417–1420

We surveyed administrators at 13 nursing homes in Orange County, CA, on their likelihood to admit methicillin-resistant Staphylococcus aureus (MRSA) carriers and assessed applicant characteristics associated with rejection. In multivariate models, denial of admission was associated with MRSA carriage (odds ratio, 2.7; P =.02) and receiving lower ratings for overall suitability for admission (odds ratio, 5.9; P

Objective.Methicillin-resistantStaphylococcus aureus(MRSA) is a common cause of healthcare-associated infections. Recent legislative mandates require nares screening for MRSA at hospital and intensive care unit (ICU) admission in many states. However, MRSA colonization at extranasal sites is increasingly recognized. We conducted a systematic review of the literature to identify the yield of extranasal testing for MRSA.Design.We searched MEDLINE from January 1966 through January 2012 for articles comparing nasal and extranasal screening for MRSA colonization. Studies were categorized by population tested, specifically those admitted to ICUs and those admitted to hospitals with a high prevalence (6% or greater) or low prevalence (less than 6%) of MRSA carriers. Data were extracted using a standardized instrument.Results.We reviewed 4,381 abstracts and 735 articles. Twenty-three articles met the criteria for analysis (n= 39,479 patients). Extranasal MRSA screening increased the yield by approximately one-third over nares alone. The yield was similar at ICU admission (weighted average, 33%; range, 9%–69%) and hospital admission in high-prevalence (weighted average, 37%; range, 9%–86%) and low-prevalence (weighted average, 50%; range, 0%–150%) populations. For comparisons between individual extranasal sites, testing the oropharynx increased MRSA detection by 21% over nares alone; rectum, by 20%; wounds, by 17%; and axilla, by 7%.Conclusions.Extranasal MRSA screening at hospital or ICU admission in adults will increase MRSA detection by one-third compared with nares screening alone. Findings were consistent among subpopulations examined. Extranasal testing may be a valuable strategy for outbreak control or in settings of persistent disease, particularly when combined with decolonization or enhanced infection prevention protocols.

Background: Alcohol screening and brief intervention (SBI) is used to decrease alcohol consumption, health care costs, and injury recidivism in trauma patients. Despite SBI being mandated for trauma centers, various concerns have led many centers to conduct SBI only on patients with a detectable blood alcohol concentration (BAC). We sought to determine the predictive nature of BAC on hazardous drinking behavior. Study Design: Adult trauma patients were included if they received an SBI before discharge. SBI was administered using a computerized alcohol screening and intervention (CASI) system with the Alcohol Use Disorder Identification Test (AUDIT). Data regarding demographics, injuries, and BAC were prospectively collected. Multivariate analyses were performed to identify independent predictors of hazardous drinking behavior. Results: Data were complete for 1,340 patients, with a mean age of 43 years (SD 20 years). Sixty-eight percent were male, 33% had detectable BAC, and 19% had hazardous drinking behavior. Multivariate analysis identified age (odds ratio [OR] 0.97 per year), male sex (OR 3.1), BAC (OR 1.009 per mg/dL), detectable BAC (OR 3.9), and legal intoxication (OR 7.8) as independent predictors of hazardous drinking behavior. Asian/Pacific Islander ethnicity was a significant negative predictor (OR 0.53) compared with white. Thirty-eight percent of patients with hazardous drinking behavior had no detectable BAC. Conclusions: Younger age, male sex, and higher BAC are early predictors of hazardous drinking behavior in adult trauma patients. Asian/Pacific Islander patients are half as likely to report hazardous drinking behavior compared with white patients. More than one-third of patients with hazardous drinking behavior do not have detectable BAC on admission and are not receiving interventions in centers that screen solely based on BAC. © 2012 American College of Surgeons.