Figure S5 shows pharmacodynamic effect of enozertinib on EGFR Protein

Antimicrobial resistance (AMR) in Escherichia coli (E.coli) poses a significant global threat to public health due to increasing resistance against antibiotics. This study explored a novel combination therapy by investigating the synergistic potential of three distinct antibiotics to combat AMR in E. coli isolates. Multi drug resistant (MDR), extensive drug resistant (XDR), and pan drug resistant (PDR) E. coli isolates were confirmed using the automated system Vitek followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Dual and triple combinations of meropenem, ceftazidime, and polymyxin B were evaluated using a checkerboard assay and were further corroborated using field emission scanning electron microscopy (FE-SEM). Checkerboard assays demonstrated significant bactericidal activity up to 24 h for all MDR, XDR, and PDR isolates treated with combinations of meropenem + polymyxin B; ceftazidime + polymyxin B and meropenem + ceftazidime + polymyxin B. Notably, few of the XDR and PDR isolates showed no bacterial growth for up to 96 h with meropenem + polymyxin B; ceftazidime + polymyxin B; and meropenem + ceftazidime + polymyxin B combinations. FE-SEM images supported these findings, revealing significant plasmolysis with meropenem + polymyxin B; ceftazidime + polymyxin B; and meropenem + ceftazidime + polymyxin B treatments compared to the control. Dual and triple combination regimens were found to be effective for treating MDR, XDR, and PDR isolates. The present study suggested a promising strategy in in vitro conditions, but its effectiveness still requires further in vivo validation considering pharmacokinetics/pharmacodynamics (PK-PD) modeling and dynamic dosing regimens.

BACKGROUND:Musculoskeletal symptoms, stress, and burnout contribute to nurse attrition. This study builds on previous research about physical strain in nurses by exploring the relationship between musculoskeletal symptoms and two occupational psychological factors: job-related stress and burnout. METHODS:This cross-sectional, observational study utilized an online survey to assess musculoskeletal symptoms (Nordic Musculoskeletal Questionnaire), job-related stress (Job Content Questionnaire), and burnout (Oldenburg Burnout Inventory). The survey also included questions about sociodemographics, work information, COVID-19-related stress level, and likelihood of leaving current position. A logistic regression model assessed musculoskeletal symptoms for associations with Job Content Questionnaire and Oldenburg Burnout Inventory scores while controlling for personal and work-related factors. FINDINGS:Fifty-three percent of nurses in the sample (N = 173) indicated limited functional activity due to musculoskeletal symptoms. High overall burnout approached a significant association with limited function (OR = 1.13, 95% CI [0.995, 1.28], p = .06). The odds of having limited function were 15.32 times higher (OR = 15.32, 95% CI [3.10, 75.82], p = .01) in nurses who were very likely to leave their job in the next year.Conclusions/Applications to Practice:Limited function due to musculoskeletal symptoms was significantly associated with nurse attrition and approached a significant association with high burnout. Nurse attrition is costly to healthcare organizations and compromises patient safety. Future interventions aimed at musculoskeletal health and attrition in nurses should reduce job-related stress and burnout, in addition to reducing physical strain.

Supplementary Table 3. Key Tumor Characteristics (AR Resistance Variants, AVPC Molecular Features, and GR Status) of Patients in Dose Expansion

Supplementary Table 2.ctDNA Data for 29 and cfRNA Data for 26 Patients in Dose

AbstractPurpose:Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist.Patients and Methods:Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D).Results:A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65–38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation.Conclusions:Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.

OBJECTIVE:This scoping review synthesizes and summarizes the evidence on racial and ethnic disparities in outcomes after physical therapist treatment. METHODS:Four databases from 2001 through 2021 were searched for articles reporting physical therapy outcomes across racial and ethnic groups. The Arksey and O'Malley methodological framework was adapted for this scoping review. Two reviewers screened the abstracts, and 5 reviewers screened full texts for inclusion. Five reviewers extracted information including study design, diagnoses, setting, outcomes reported, the domains the outcomes measured, and racial and ethnic groups included. To identify disparities, summarized differences in outcomes (better, worse, no difference) for each racial and ethnic group compared to White patients were calculated. RESULTS:Of 1511 abstracts screened, 65 met inclusion criteria, 57 of which were observational designs. All 65 articles included non-Hispanic White patients as the reference group. A majority of the physical therapy outcomes reported by race were for Black patients and/or Hispanic or Latino patients, whereas outcomes for Asian, American Indian, Alaskan Native, and/or Native Hawaiians or Pacific Islander patients were reported infrequently. Most articles reported disparities in health outcomes for patients in the inpatient rehabilitation setting (n = 48) and for adults (n = 59) with neurologic diagnoses (n = 36). Compared to White patients, worse outcomes were reported more frequently for all marginalized racial and ethnic groups after physical therapy, with the exception of marginalized groups having the same or better outcomes for successful post-rehabilitation community discharge. CONCLUSION:Gaps remain in understanding outcome disparities beyond older adult and neurologic populations as well as for musculoskeletal diagnoses frequently treated by physical therapists. IMPACT:The presence of racial and ethnic disparities in physical therapy outcomes should motivate physical therapists to understand the mechanisms underlying disparities and focus on social and structural drivers of health inequity in their clinical decision-making.

The COVID-19 pandemic and recent incidents of social injustice exposed the systemic racism and discrimination in health care and clinical research that perpetuate systemic inequities. This perspective utilizes the acronym JEDI (justice, equity, diversity, and inclusion) as a vision for addressing inequities in physical therapy research. The need to go beyond diversity and focus on inclusion, equity, and justice is emphasized to achieve transformation within physical therapy research. The prevailing research paradigms are examined, acknowledging that research can perpetuate inequities and reinforcing the importance of integrating JEDI principles into the research process. The underrepresentation of diverse researchers in physical therapy is discussed, as well as the barriers faced by underrepresented researchers and research participants. Funding disparities are also highlighted, emphasizing the need for JEDI principles in research funding practices. How other health professions' associations are addressing JEDI in research is also explored. The authors propose a framework for action, utilizing the concepts of the socioecological model to identify gaps in JEDI within physical therapy research at different levels of influence and conclude by emphasizing the importance of justice in dismantling inequitable systems and urge the physical therapy research community to become JEDI warriors to bring about transformative change. Impact. By championing cultures that value justice, equity, diversity, and inclusion, individuals within the physical therapy research community have the potential to ignite a powerful transformation in society. The authors envision a future where JEDI warriors emerge, embracing the spirit of "Do or do not. There is no try," to forge a research community that is inclusive for all.1 Drawing inspiration from this mindset, this perspective seeks to empower individuals to harness the force of a JEDI warrior, fostering cultures that value justice, embrace inclusive methodologies, and ensure equitable access to resources and opportunities for researchers and participants.

Supplementary Table 1. Representativeness of Study Participants

Abstract First generation inhibitors of PRC2 (Polycomb Repressive Complex 2) targeting EZH2 (Enhancer of Zeste Homolog 2) achieved clinical proof-of-concept in follicular lymphoma and epithelioid sarcoma, and emerging clinical data recently revealed promising activity in prostate cancer in combination with AR pathway inhibitors (ARPIs). Here we describe the discovery and development of a second generation PRC2 inhibitor, ORIC-944, a potent, selective, allosteric inhibitor of PRC2 that binds the EED (Embryonic Ectoderm Development) subunit within the complex. Co-crystallization of previously disclosed triazolopyrimidine-based compounds demonstrated binding to EED in the histone H3K27me3 binding pocket, adopting a Lys211-in conformation. We evaluated the apo structure of EED and hypothesized that the Lys211-in conformation may be energetically unfavorable. Using structure-based drug design we pursued a strategy for differentiation of SAR and physicochemical properties by progressing from an early 2-substituted imidazopyrimidine that targets the cryptic pocket with a Lys211-out conformation. Key optimization criteria focused on metabolic stability and solubility, and resulted in the discovery of ORIC-944, an orally bioavailable inhibitor of PRC2 with best-in-class properties. Single agent tumor growth inhibition was observed for ORIC-944 in prostate cancer xenograft models. ORIC-944 also improved ARPI antitumor activity in preclinical combination studies and demonstrated in vitro synergy. Characterization of ORIC-944 revealed superiority to first generation clinical PRC2 inhibitors across a variety of preclinical assessments including potency, solubility, CYP inhibition/induction, PK and oral bioavailability. Together, the preclinical results indicate the desired properties were achieved in ORIC-944 to meet a superior target candidate profile, and the ongoing phase 1b trial (NCT05413421) demonstrates a clinical half-life of approximately 20 hours consistent with once daily dosing and a potential best-in-class profile. Citation Format: Matthew A. Marx, Aaron C. Burns, Nidhi Arora, Thomas P. Bobinski, David M. Briere, Andrew Calinisan, Robin J. Gunn, John M. Ketcham, David Lawson, Matthew Lee, Peter Olson, Christopher R. Smith, Niranjan Sudhakar, James G. Christensen, Chelsea X. Chen, Natalie Yuen, Livia Ulicna, Frank Duong, Christophe Colas, Anjana Ramnath, Ron Xu, Edna Chow Maneval, Pratik S. Multani, Rupal Patel, Archana Kumar, Anneleen Daemen, Anthony Romero, Melissa R. Junttila, Lori S. Friedman. Discovery of ORIC-944, a novel inhibitor of PRC2 with best-in-class properties for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND04.

INTRODUCTION:This study describes the development, content validity, and reliability of the Physical Therapy Social Determinants of Health Scale (PT-SDHS), in Doctor of Physical Therapy (DPT) students. REVIEW OF LITERATURE:Addressing inequities stemming from the social determinants of health (SDOH) is critical for providing effective clinical care and improving population health. Currently, no tool exists to assess DPT students' education or competence with SDOH. SUBJECTS:Recruited domain experts were licensed health professionals, had a peer-reviewed publication on SDOH, and had at least 3 years of experience with SDOH. A convenience sample of DPT students was also recruited from multiple cohorts at 2 universities in multiple geographic locations. METHODS:The Association for Medical Education in Europe best practices for developing questionnaires for educational research guided development of the PT-SDHS. Eight experts established content validity through item- and scale-content validity index measures and modified Kappa statistics. Qualitative data determined clarity and comprehensiveness. Construct validity and scale reliability were determined using exploratory factor analysis and Cronbach's alpha. RESULTS:The PT-SDHS showed high item content validity (range: 0.86-1) and scale content validity (S-CVI/UA = 0.83; S-CVI/Ave = 0.98). After expert validation, the PT-SDHS consisted of 30 items with 5 ordinal answer choices. Factor analysis of 254 DPT student responses revealed 4 content domains with a factor loading greater than 0.4. Two items did not load onto any of the factors, and 2 items were cross-loaded onto multiple factors, so they were removed, leaving a scale of 26 items. Cronbach's alpha ranged from 0.74 (satisfactory) to 0.96 (excellent) across the 4 factors. DISCUSSION AND CONCLUSION:The PT-SDHS is the first psychometrically valid and reliable instrument related to educating DPT students on 4 SDOH domains: Knowledge, Attitudes, Personal Barriers, and Beliefs About Others. This tool could aid development and assessment of SDOH educational interventions for health care students.

The current study explored the intelligibility and acceptability ratings of dysarthric speakers with African American English (AAE) and General American English (GAE) dialects by listeners who identify as GAE or AAE speakers, as well as listener ability to identify dialect in dysarthric speech. Eighty-six listeners rated the intelligibility and acceptability of sentences extracted from a passage read by speakers with dysarthria. Samples were used from the Atlanta Motor Speech Disorders Corpus and ratings were collected via self-report. The listeners identified speaker dialect in a forced-choice format. Listeners self-reported their dialect and exposure to AAE. AAE dialect was accurately identified in 63.43% of the the opportunities; GAE dialect was accurately identified in 70.35% of the opportunities. Listeners identifying as AAE speakers rated GAE speech as more acceptable, whereas, listeners identifying as GAE speakers rated AAE speech as more acceptable. Neither group of listeners demonstrated a difference in intelligibility ratings. Exposure to AAE had no effect on intelligibility or acceptability ratings. Listeners can identify dialect (AAE and GAE) with a better than chance degree of accuracy. One's dialect may have an effect on intelligibility and acceptability ratings. Exposure to a dialect did not affect listener ratings of intelligibility or acceptability.

Objective. Chronic musculoskeletal pain (CMP) poses a considerable threat to physical, mental, and financial health worldwide. Beyond physical difficulties, CMP has a pronounced impact on pain behaviors and cognitive function. The purpose of this scoping review was to examine the relationship between pain catastrophizing (PC) and cognitive function in CMP, identify gaps in the literature, and provide future directions for research on the topic. Methods. Search strings were entered in the following databases: PubMed, CINAHL, Nursing and Allied Health, Ovid Emcare, PsycInfo, and Scopus. Data from the included articles were extracted thematically based on diagnostic classification and included author(s), year of publication, country, aim, sample, methods, intervention (if applicable), and key findings. Results. 30 articles were included after screening. The studied populations included patients with fibromyalgia, chronic low back pain, and CMP. Two studies were designed to assess the relationship between PC and cognition as the primary aim. The included studies demonstrated variable evidence regarding the relationship between PC and cognition. Only four studies included clinically relevant PC populations (i.e., Pain Catastrophizing Scale score >30), and all found significant correlations. Conclusion. Although evidence exists for the relationship between cognitive function and PC, there is a lack of rigorous research to indicate the strength of this relationship and the specific cognitive functions affected. The literature lacks appropriate populations needed to investigate clinically relevant PC and is limited by heterogeneous neuropsychological test batteries. Future research should include populations demonstrating the behaviors being studied, intentional analysis of outcomes, and appropriate cognitive tests.

Figure S1, Figure S2, Figure S3, Figure S4, Table S1, Table S2, Table S3

Supplementary Figure 1. In vitro characterization of RET inhibitory activity of RXDX-105 in HBEC3KT-RET cells; Supplementary Figure 2. In vivo efficacy of RXDX-105 in a xenograft model of HBEC3KT-RET harboring CCDC6-RET fusion.

College is a transitional period when many individuals gain independence. During this period of exploration, substance use behaviors tend to increase and healthy behaviors decrease. Furthermore, there are often increased feelings of stress and mental health disorders. This period is difficult in the presence of academic pressure and financial strain but is made more difficult when combined with food and housing insecurity. However, most faculty are unaware of the prevalence of these stressors - particularly at major, flagship universities that are often seen as drawing higher SES students. PURPOSE: To describe the occurrence of various forms of stress (academic, financial, etc.) and substance usage among pre-health profession college students. METHODS: An online Qualtrics-based survey was completed by 96 (F = 71) undergraduate university students (20.5 yrs). The survey included: demographic information; food and housing insecurity; the National College Health Risk Behavior Survey (NCHRBS); the State-Trait Anxiety Inventory (STAI); and the Perceived Stress Scale (PSS). Participants received course credit. Descriptive statistics, correlations, and one-way ANOVAs were calculated using R. RESULTS: Participants were primarily Kinesiology and Health majors. A majority (86%) were in their 2nd and 3rd yrs. Approximately 43% reported food insecurity and 14% reported housing insecurity. Furthermore, 58% reported using substances (e.g., alcohol, cigarettes, marijuana, etc.) in the past 7 days. The mean score on the STAI 16.05 ± 4.95, and PSS 16.55 ± 6.16 were moderately high. There was a negative correlation between stress and GPA (r = -0.22, p < 0.05) and positive correlations between food insecurity and anxiety (r = 0.27, p < 0.05) and between binge drinking and food insecurity (r = 0.33, p < 0.05). There was a significant group difference in STAI scores between participants who are and are not food insecure (F1, 94 = 7.595, p < 0.05). No other significant results were found regarding substance use, housing insecurity, food insecurity, STAI, or PSS. CONCLUSIONS: The high proportion of food insecurity among these students is quite high and it contributes significantly to anxiety. Educators in health profession fields should be aware of this issue and provide services for remediation.

Purpose: The cost of higher education programs across allied health disciplines have increased substantially in recent years while salaries have remained relatively stagnant. The result of which is an increase in debt burden for graduates of allied health professional programs. One possible intervention to improve the experience of graduates is to improve financial literacy; however, research on the effectiveness of financial literacy education in higher education is scant. Therefore, the purpose of this study was to understand the effectiveness of a financial literacy and career planning seminar in a Doctor of Physical Therapy (DPT) program. Specifically, this study aimed to (1) describe the implementation of a novel career planning and financial literacy workshop as an additional component of a required physical therapy administration course in a DPT program, and to (2) understand the outcomes and effectiveness of the model utilized. Methods: This study included a single cohort pre/post design and between subject analysis. DPT students completed a pre-and post-survey before and after attending a 1-hour asynchronous career planning and financial literacy workshop. The survey included questions to capture students' knowledge and confidence in financial literacy. Results: Overall, 80 DPT students completed the pre survey and 54 DPT students completed the post-survey. The group of 55 participants that completed the post-workshop knowledge portion of the survey (M=87%, SD 220.72) demonstrated significantly better knowledge scores t(124) = 7.44, p < .05 compared to the group of 77 participants that completed the pre-workshop knowledge portion of the survey (M = 67%, SD 282.31). The group of 53 participants that completed the post-workshop confidence portion of the survey (M=35.79%, SD 27.09) demonstrated significantly improved confidence on the post-workshop survey t(130) = 2.75, p < .05 compared to the group of 79 participants that completed the pre-workshop confidence portion of the survey (M = 32.62, SD 64.57). Conclusion: A 1-hour workshop can be effective at improving knowledge and confidence in financial literacy of DPT students, and it can be implemented in existing DPT curricula without considerable time or added credit hours.