Current insights into equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy.

Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disease associated with vitamin E deficiency in the first year of life. It is the second most common cause of spinal ataxia in horses euthanized for neurologic disease. Equine NAD/EDM is characterized by neurologic signs including a symmetric proprioceptive ataxia (> grade 2/5) and a wide-base stance at rest. There are currently no antemortem tests for eNAD/EDM in any breed. Conclusive diagnosis requires postmortem histologic evaluation of the brainstem and spinal cord at necropsy. Research studies on antemortem biomarkers and genetic testing are ongoing. The development of a genetic test for eNAD/EDM would have widespread impact, even if it were breed specific. Currently, the best approach to eNAD/EDM is to focus on preventing cases by providing pregnant mares and foals with access to pasture. Alternatively, dams' diets can be supplemented with high doses of water-soluble RRR-α-tocopherol during the last trimester of gestation, with continued supplementation of foals through the first two years of life. It is important to measure horses' baseline serum vitamin E levels prior to supplementing. While considered generally safe, oversupplementation of vitamin E is possible and can lead to coagulopathies.

Positive Leadership within Breast Imaging: Impact on Burnout, Intent to Leave, and Engagement.

Background High rates of provider burnout and turnover, as well as staffing shortages, are creating crises within radiology departments. Identifying ways to support health care workers, such as the Positively Energizing Leadership program, is important during these ongoing crises. Purpose To identify the relationship between leadership behaviors and workplace climate and health care worker outcomes (ie, burnout, intent to leave, and engagement) and to determine whether the positive leadership program could improve workplace climate and health care worker outcomes. Materials and Methods This prospective study involved two parts. First, a web-based survey was administered to faculty and staff in a breast imaging unit of a large academic medical center in February 2021 to identify relationships between leadership behaviors and workplace climate and health care worker outcomes. Second, a web-based survey was administered in February 2023, following the implementation of a positive leadership program, to determine improvement in engagement and reduction of burnout and intent to leave since 2021. Multiple regression, the Sobel test, Pearson correlation, and the t test were used, with a conservative significance level of P < .001. Results The sample consisted of 88 respondents (response rate, 95%) in 2021 and 85 respondents (response rate, 92%) in 2023. Leadership communication was associated with a positive workplace climate (ß = 0.76, P < .001) and a positive workplace climate was associated with improved engagement (ß = 0.53, P < .001), reduction in burnout (ß = -0.42, P < .001), and reduction in intent to leave (ß = -0.49, P < .001). Following a 2-year positive leadership program, improved perceptions were observed for leadership communication (pretest mean, 4.59 ± 1.51 [SD]; posttest mean, 5.80 ± 1.01; t = 5.97, P < .001), workplace climate (pretest mean, 5.09 ± 1.43; posttest mean, 5.77 ± 1.11; t = 3.35, P < .001), and engagement (pretest mean, 5.27 ± 1.20, posttest mean, 5.68 ± 0.96; t = 2.50, P < .01), with a reduction in burnout (pretest mean, 2.69 ± 0.94; posttest mean, 2.18 ± 0.74; t = 3.50, P < .001) and intent to leave (pretest mean, 3.12 ± 2.23; posttest mean, 2.56 ± 1.84; t = 1.78, P < .05). Conclusion After implementation of a positive leadership program in a radiology department breast imaging unit, burnout and intention to leave decreased among health care workers, while engagement increased. © RSNA, 2024 See also the editorial by Thrall in this issue.

A Focus on Leadership Communication and Feeling Valued to Prevent Burnout and Turnover Among Healthcare Professionals.

OBJECTIVE: The purpose of this study was to examine the relative importance of leadership communication in predicting burnout and intention to stay among faculty and staff while controlling for other factors such as satisfaction with compensation and work-home flexibility. METHODS: This study involved a secondary analysis of data derived from an organizational engagement survey that included 2336 faculty members (75% response rate) and 17,664 staff members (72% response rate). RESULTS: Effective leadership communication was a stronger predictor of burnout and intent to stay than satisfaction with compensation and work-home flexibility. Feeling valued by the organization mediated the relationship between leadership communication and the outcome variables. CONCLUSIONS: Leadership communication provides a low-cost solution to burnout and staff shortages and is primarily effective because it conveys to both faculty and staff that they are valued by the organization.

Application of the Bayesian network theory in clinical trial data: Severity shift in spasticity numeric rating scale in patients with multiple sclerosis.

BACKGROUND: Data digitization expands data collection opportunities, representing both a chance to understand interrelationships between variables and a challenge to identify the most appropriate clinical factors. Applications of causal inference techniques to clinical trial data is becoming very attractive, especially with the intent to provide insights into the relationships between baseline characteristics and outcomes. Graphical representations of model structures and conditional probabilities can be powerful tools to illustrate relationships in a high-dimensional data setting. METHODS: We review and apply Bayesian network theory to a clinical case study, presenting an analytical approach to investigating and visualizing causal relationships. We propose the use of the adherence score to compare data networks' patterns based on different variables' discretization. Data from adult patients with spasticity related to multiple sclerosis (MSS) from two randomized placebo-controlled clinical trials of nabiximols were used as analysis sets. The training and validation sets included 106 (53 treated, 53 placebo) and 155 (76 treated, 79 placebo) participants, respectively. The primary objective was to create a network and estimate the causal dependencies between participants' characteristics, changes in MSS severity as reflected by shifts in the patient-reported numeric rating scale (NRS), and changes in symptoms, functional abilities, and quality of life factors. RESULTS: A causal network was identified between the key factors of assigned treatment, end of study spasticity NRS, and mental health/vitality subscales of the 36-Item Short Form Health Survey questionnaire (4 nodes and 3 edges; adherence score = 93%). In patients with mild spasticity, the impact of nabiximols on mental health or vitality subscales resulted in a probability ratio of 1.63. The decomposed mediation effect of spasticity NRS was observed through a mediation analysis between treatment and mental health (99.4%) or vitality (93.7%) subscales. CONCLUSIONS: The use of innovative methods such as causal networks is highly encouraged to identify dependent relationships among key factors in clinical trial data and drive insights for additional research.

Prospective Clinical Prognostication of Endometrial Carcinomas Based on Next-Generation Sequencing and Immunohistochemistry-Real-World Implementation and Results at a Tertiary Care Center.

Based on findings from The Cancer Genome Atlas and the Proactive Molecular Risk Classifier for Endometrial Cancer algorithm, endometrial carcinoma can now be stratified into 4 prognostically distinct subgroups based on molecular alterations and immunohistochemical (IHC) aberrations. In this study, we describe the de novo adoption and clinical reporting of prognostic subgroup classification based on next-generation sequencing (NGS) and IHC analyses of all endometrial carcinoma resections at a single institution, framed by the Exploration, Preparation, Implementation, and Sustainment model. Results from the first 13 months show 188 tumors underwent analysis by a combination of IHC and a medium-sized (56 analyzed genes) NGS-based assay. All cases were assigned as either POLE (POLE-mutated) (5.3%), mismatch repair deficient (27.7%), no specific molecular profile (45.7%), or p53 abnormal (21.3%) inclusive of multiple-classifier cases. NGS-based analysis revealed additional distinctions among the subgroups, including reduced levels of PI3K pathway activation in the p53 abnormal subgroup, an increased rate of CTNNB1 activating mutation in the no specific molecular profile subgroup, and lower TP53 mutation variant allele frequencies in POLE and mismatch repair deficient subgroups compared with the p53 abnormal subgroup. Overall, we describe the testing protocol, reporting, and results of a combination of NGS and IHC to prospectively prognosticate endometrial carcinomas at a single tertiary care center.

A phase 3b, multicenter, open-label, single-arm study of roxadustat (ASPEN): Operational learnings within United States dialysis organizations.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). ASPEN evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD in US dialysis organizations. METHODS: This open-label, single-arm study (NCT04484857) comprised a 6-week screening period, followed by 24 weeks of treatment (with optional extension ≤1 year) and a 4-week follow-up. Patients aged ≥18 years, receiving chronic dialysis, with hemoglobin (Hb) 9.0-12.0 g/dL if converting from erythropoiesis-stimulating agents (ESAs), or <10.0 g/dL if receiving ESAs for <6 weeks, received oral roxadustat three times weekly in-center. Primary efficacy endpoints included proportion of patients with mean Hb ≥10 g/dL, averaged over weeks 16-24, and mean Hb change from baseline to the average over weeks 16-24. Safety was also assessed. FINDINGS: Overall, 283 patients were enrolled and treated, 282 (99.6%) were included in the full analysis set, and 216 (76.3%) continued into the extension period. Most patients enrolled were from DaVita sites (71%), with the rest from US Renal Care sites (29%). Mean (standard deviation [SD]) baseline Hb was 10.6 (0.7) g/dL. Nearly all patients were prior ESA users (n = 274; 97.2%). The proportion of patients with mean Hb ≥10 g/dL during weeks 16-24 was 83.7% (95% confidence interval 78.9-88.6). Mean (SD) Hb increase from baseline to the average over weeks 16-24 was 0.2 (1.0) g/dL. During the treatment period, 82 (29.0%) patients reported treatment-emergent serious adverse events (TESAEs). The most common TESAEs were COVID-19 pneumonia (n = 10; 3.5%), acute respiratory failure (n = 9; 3.2%), COVID-19 (n = 7; 2.5%), acute myocardial infarction (n = 7; 2.5%), and fluid overload (n = 6, 2.1%). DISCUSSION: Roxadustat was effective in maintaining Hb in patients with anemia of CKD on dialysis in large, community-based dialysis organizations.

Declining rates of opioid/acetaminophen combination product overdose: 2011-2020.

BACKGROUND: During the opioid epidemic, misuse of acetaminophen-opioid products resulted in supratherapeutic acetaminophen ingestions and cases of hepatotoxicity. In 2014, the US Food and Drug Administration (FDA) limited the amount of acetaminophen in combination products to 325 mg, and the US Drug Enforcement Administration (DEA) changed hydrocodone/acetaminophen from schedule III to schedule II. This study assessed whether these federal mandates were associated with changes in acetaminophen-opioid supratherapeutic ingestions. METHODS: We identified emergency department encounters at our institution of patients with a detectable acetaminophen concentration and manually reviewed these charts. RESULTS: We found a decline in acetaminophen-opioid supratherapeutic ingestions after 2014. A downtrend in hydrocodone/acetaminophen ingestions accompanied a relative increase in codeine/acetaminophen ingestions from 2015 onwards. CONCLUSION: This experience at one large safety net hospital suggests a beneficial impact of the FDA ruling in reducing likely unintentional acetaminophen supratherapeutic ingestions, carrying a risk of hepatotoxicity, in the setting of intentional opioid ingestions.

Positive Schemas: Replication, Associations With Negative Schemas, and the Dark Triad.

The purpose of the current study was to replicate the factor structure of the 14 positive schemas identified in the earlier study by Louis et al. (2018). Using confirmatory factor analysis (CFA), and Multi-group CFA, the 14 positive schemas were found to be robust across four new non-clinical English-speaking community samples - USA (n = 396), South Africa (n = 390), Nigeria (n = 364), and India (n = 306). Further, results from CFA, and chi square tests showed that positive and negative schemas were independent but related constructs, and that they do not reflect bipolarity. Using hierarchical regression and Pearson's correlations the negative schemas of Entitlement, Approval Seeking and Mistrust, and the positive schema of Empathic Consideration were found to be associated positively and negatively respectively with Machiavellianism, narcissism, and psychopathy of the Dark Triad scale in all four worldwide samples. Implications of this finding in Schema Therapy treatment were discussed.

From a Culture of Incivility to Virtuousness: A Call to Elevate Workplace Behaviors in Radiology.

Radiology has been identified as a subspecialty with exceptionally high rates of incivility among colleagues. Such behaviors are detrimental to the well-being, productivity, and retention of health care practitioners and to the quality of patient care. Addressing incivility has become imperative given current and anticipated staff shortages, yet research from positive organizational scholarship suggests a greater opportunity to be had. Going forward, we need not only to address incivility but also to build purpose-driven, compassionate, and supportive workplaces.

Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα.

Small molecule inhibitors that target the phosphatidylinositol 3-kinase (PI3K) signaling pathway have received significant interest for the treatment of cancers. The class I isoform PI3Kα is most commonly associated with solid tumors via gene amplification or activating mutations. However, inhibitors demonstrating both PI3K isoform and mutant specificity have remained elusive. Herein, we describe the optimization and characterization of a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors of PI3Kα which also induce the selective degradation of the mutant p110α protein, the catalytic subunit of PI3Kα. Structure-based design informed isoform-specific interactions within the binding site, leading to potent inhibitors with greater than 300-fold selectivity over the other Class I PI3K isoforms. Further optimization of pharmacokinetic properties led to excellent in vivo exposure and efficacy and the identification of clinical candidate GDC-0077 (inavolisib, 32), which is now under evaluation in a Phase III clinical trial as a treatment for patients with PIK3CA-mutant breast cancer.

Adoption of digital tools in the context of the COVID-19 pandemic in the Region of the Americas - the Go.Data experience.

The COVID-19 pandemic has accelerated the growth of digital health tools. Although a number of different tools exist to support field data collection in the context of outbreak response, they have not been sufficient. This prompted the World Health Organization (WHO) to collaborate with the Global Outbreak Alert and Response Network (GOARN) and GOARN partners to develop a comprehensive system, Go.Data. Go.Data, a digital tool for outbreak response has simplified how countries operationalize and monitor case and contact data. Since the start of the pandemic, WHO and GOARN partners have provided support to Go.Data projects in 65 countries and territories, yet the demand by countries to have documented success cases of Go.Data implementations continues to grow. This viewpoint documents the successful Go.Data implementation frameworks in two countries, Argentina and Guatemala and an academic institution, the University of Texas at Austin.

SARS-CoV-2 viral load is associated with risk of transmission to household and community contacts.

BACKGROUND: Factors that lead to successful SARS-CoV-2 transmission are still not well described. We investigated the association between a case's viral load and the risk of transmission to contacts in the context of other exposure-related factors. METHODS: Data were generated through routine testing and contact tracing at a large university. Case viral loads were obtained from cycle threshold values associated with a positive polymerase chain reaction test result from October 1, 2020 to April 15, 2021. Cases were included if they had at least one contact who tested 3-14 days after the exposure. Case-contact pairs were formed by linking index cases with contacts. Chi-square tests were used to evaluate differences in proportions of contacts testing positive. Generalized estimating equation models with a log link were used to evaluate whether viral load and other exposure-related factors were associated with a contact testing positive. RESULTS: Median viral load among the 212 cases included in the study was 5.6 (1.8-10.4) log10 RNA copies per mL of saliva. Among 365 contacts, 70 (19%) tested positive following their exposure; 36 (51%) were exposed to a case that was asymptomatic or pre-symptomatic on the day of exposure. The proportion of contacts that tested positive increased monotonically with index case viral load (12%, 23% and 25% corresponding to < 5, 5-8 and > 8 log10 copies per mL, respectively; X2 = 7.18, df = 2, p = 0.03). Adjusting for cough, time between test and exposure, and physical contact, the risk of transmission to a close contact was significantly associated with viral load (RR = 1.27, 95% CI 1.22-1.32). CONCLUSIONS: Further research is needed to understand whether these relationships persist for newer variants. For those variants whose transmission advantage is mediated through a high viral load, public health measures could be scaled accordingly. Index cases with higher viral loads could be prioritized for contact tracing and recommendations to quarantine contacts could be made according to the likelihood of transmission based on risk factors such as viral load.

Molecular Monitoring of EHV-1 in Silently Infected Performance Horses through Nasal and Environmental Sample Testing.

While the main goal in the management of an EHM outbreak focuses on identifying early clinical disease in order to physically separate infected horses, little effort is placed towards monitoring healthy horses. The assumption that EHV-1 shedding parallels clinical disease is erroneous, as subclinical shedders have been shown to be actively involved in viral spread. In an attempt to document the frequency of EHV-1 shedders and their impact on environmental contamination, we collected nasal swabs from 231 healthy horses and 203 environmental samples for the testing of EHV-1 by qPCR. Six horses and 28 stalls tested qPCR-positive for EHV-1. There was no association in the EHV-1 qPCR-positive status between nasal and stall swabs. While testing nasal secretions of healthy at-risk horses can detect active shedding at a specific time point, the testing of stall swabs allows to assess the temporal EHV-1 shedding status of a horse. The study results highlight the risk of subclinical EHV-1 shedders and stalls occupied by these horses as sources of infection for susceptible horses. The testing of individual stalls for the presence of EHV-1 may be a more practical approach than the collection of individual nasal swabs for the monitoring and early detection of the circulating virus. The results also highlight the need to improve the cleanliness and disinfection of stalls utilized by performance horses during show events.

When and How to Utilize Pudendal Nerve Blocks for Treatment of Pudendal Neuralgia.

Chronic pelvic pain is a common cause of pain in reproductive age women with debilitating consequences for affected women's health and quality of life. Treatment providers must be well versed in all treatment options for these patients, understanding the overlap in the management and treatment of chronic pelvic pain caused by pudendal neuralgia, myofascial pelvic pain, and vulvodynia. Pudendal blocks are a simple and quick procedure that can be performed in the office and often helps improve all the above conditions when used along with other treatment options. We review the anatomy and methodology on when and how to perform pudendal blocks in the office to better inform the general gynecologist on how to implement offering this treatment in the outpatient clinical setting.

Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.

The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development of resistance. We have established prostate cancer models of acquired resistance to the allosteric inhibitor MK-2206 or the ATP-competitive inhibitor ipatasertib following prolonged exposure. While alterations in AKT are associated with acquired resistance to MK-2206, ipatasertib resistance is driven by rewired compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance can be overcome by treatment with ipatasertib, while ipatasertib resistance can be reversed by co-treatment with inhibitors of pathways including PIM signaling. These findings demonstrate that distinct resistance mechanisms arise to the two classes of AKT inhibitors and that combination approaches may reverse resistance to ATP-competitive inhibition.

PIK3CA Mutations Drive Therapeutic Resistance in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

The phosphatidylinositol 3-kinase (PI3K) pathway is an intracellular pathway activated in response to progrowth signaling, such as human epidermal growth factor receptor 2 (HER2) and other kinases. Abnormal activation of PI3K has long been recognized as one of the main oncogenic drivers in breast cancer, including HER2-positive (HER2+) subtype. Somatic activating mutations in the gene encoding PI3K alpha catalytic subunit (PIK3CA) are present in approximately 30% of early-stage HER2+ tumors and drive therapeutic resistance to multiple HER2-targeted agents. Here, we review currently available agents targeting PI3K, discuss their potential role in HER2+ breast cancer, and provide an overview of ongoing trials of PI3K inhibitors in HER2+ disease. Additionally, we review the landscape of PIK3CA mutational testing and highlight the gaps in knowledge that could present potential barriers in the effective application of PI3K inhibitors for treatment of HER2+ breast cancer.

Comparative Effectiveness of mRNA-based BNT162b2 Vaccine versus Adenovirus Vector-Based Ad26.COV2.S Vaccine for the Prevention of COVID-19 among Dialysis Patients.

BACKGROUND: Studies have demonstrated that mRNA-based SARS-CoV-2 vaccines are highly effective among patients on dialysis. Because individual vaccines may be differentially available or acceptable to patients, it is important to understand comparative effectiveness relative to other vaccines, such those on the basis of adenovirus technologies. METHODS: In this retrospective study, we compared the clinical effectiveness of adenovirus vector-based Ad26.COV2.S (Janssen/Johnson & Johnson) to mRNA-based BNT162b2 (Pfizer/BioNTech) in a contemporary cohort of patients on dialysis. Patients who received a first BNT162b2 dose were matched 1:1 to Ad26.COV2.S recipients on the basis of date of first vaccine receipt, US state of residence, site of dialysis care (in-center versus home), history of COVID-19, and propensity score. The primary outcome was the comparative rate of COVID-19 diagnoses starting in the 7th week postvaccination. In a subset of consented patients who received Ad26.COV2.S, blood samples were collected ≥28 days after vaccination and anti-SARS-CoV-2 immunoglobulin G antibodies were measured. RESULTS: A total of 2572 matched pairs of patients qualified for analysis. Cumulative incidence rates of COVID-19 did not differ for BNT162b2 versus Ad26.COV2.S. No differences were observed in peri-COVID-19 hospitalizations and deaths among patients receiving BNT162b2 versus Ad26.COV2.S, who were diagnosed with COVID-19 during the at-risk period. Results were similar when excluding patients with a history of COVID-19, in subgroup analyses restricted to patients who completed the two-dose BNT162b2 regimen, and in patients receiving in-center hemodialysis. SARS-CoV-2 antibodies were detected in 59.4% of 244 patients who received Ad26.COV2.S. CONCLUSIONS: In a large real-world cohort of patients on dialysis, no difference was detected in clinical effectiveness of BNT162b2 and Ad26.COV2.S over the first 6 months postvaccination, despite an inconsistent antibody response to the latter.

Evidence-based pelvic floor disorder care pathways optimize shared decision making between patients and surgeons.

INTRODUCTION AND HYPOTHESIS: Evidence-based care pathways improve care standardization and patient outcomes. We created pelvic organ prolapse (POP) and stress urinary incontinence (SUI) care pathways as decision aids for our multidisciplinary team to use when counseling patients. METHODS: Using a modified Delphi process, an expert team reviewed existing guidelines and literature to reach consensus on pathway definitions and components. RESULTS: Entry to the care pathways occurs via an advanced practice provider visit. Symptom and quality-of-life questionnaires as well as open-ended patient goals are used to guide patient-provider shared decision making. All treatment choices, including surgical and nonsurgical management, are presented to patients by advanced practice providers. Patients electing nonsurgical management follow-up by telehealth (preferred) or in-person visits as determined by the care pathway. Surgeon consultations are scheduled for patients desiring surgery. Surgical patients undergo urodynamics, simple cystometrics or deferred bladder testing according to the urodynamics clinical pathway. Postoperative follow-up includes telehealth visits and minimizes in-person visits for women with uncomplicated postoperative courses. Patients with resolution of symptoms are graduated from clinic and return to their referring physician. The pathways are revised following publication of new compelling evidence. CONCLUSIONS: We developed POP and SUI care pathways to standardize care across a diverse provider group. Advanced practice providers use care pathways with patients as shared decision-making tools for initial evaluation of patients with prolapse and incontinence. These pathways serve as components of value-based care and encourage team members to function independently while utilizing the full scope of their training.