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Brian S Decker,1,2 Kalisha D O'Neill,1,2 Mary A Chambers,1,2 James E Slaven,3 Zhangsheng Yu,3 David R Jones,2,4 Sharon M Moe1,21Division of Nephrology, 2Department of Medicine, 3Department of Biostatistics, 4Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USAAbstract: There is a paucity of studies evaluating the change in liver metabolism in subjects receiving hemodialysis. The purpose of this study was to compare the effect of uremic toxins on hepatic cytochrome P450 (CYP)3A4 and CYP2D6 metabolism before and after a 4-hour hemodialysis session. Midazolam and dextromethorphan were incubated with uremic serum collected from subjects before and after the 4-hour hemodialysis session. Analysis and quantification of the 1'-OH-midazolam and 4-OH-midazolam and dextrorphan metabolites were performed by high-pressure liquid chromatography/mass spectrometry. Statistical analysis using the Student's t-test (paired) was used to compare the amount of metabolite formed. The mean amount of 1'-OH-midazolam, 4-OH-midazolam, and dextrorphan metabolites formed before and after hemodialysis did not significantly differ. There was no significant difference in CYP3A4 and CYP2D6 metabolic activity in uremic serum before and after hemodialysis.Keywords: hemodialysis, uremia, CYP3A4, CYP2D6, metabolism

Introduction: Femoral shaft nonunion negatively affects patient quality of life. Although multiple risk factors have been identified for femoral shaft nonunion after intramedullary nail (IMN) fixation, there is no quantitative model for predicting nonunion., Study Description: The study is a retrospective cohort study of patients with femoral shaft fractures treated at two level one trauma centers who were followed to fracture union or nonunion. Patient, injury, and surgical characteristics were analyzed to create a quantitative model for nonunion risk after intramedullary nailing., Methods: Eight hundred one patients aged 18 years and older with femoral shaft fractures treated with reamed, locked IMNs were identified. Risk factors including demographics, comorbidities, surgical variables, and injury-related characteristics were evaluated. Multivariate analysis was conducted, and several variables were included in a scoring system to predict nonunion risk., Results: The overall nonunion rate was 7.62% (61/801). Multivariate analysis showed significant association among pulmonary injury (odds ratio [OR] = 2.19, P = 0.022), open fracture (OR=2.36, P = 0.02), current smoking (OR=3.05, P < 0.001), postoperative infection (OR=12.1, P = 0.007), AO/OTA fracture pattern type A or B (OR=0.43, P = 0.014), and percent cortical contact obtained intraoperatively ≥25% (OR=0.41, P = 0.021) and nonunion. The scoring system created to quantitatively stratify nonunion risk showed that a score of 3 or more yielded an OR of 6.38 for nonunion (c-statistic = 0.693, P < 0.0001)., Conclusions: Femoral shaft nonunion risk is quantifiable based on several independent injury, patient, and surgical factors. This scoring system is an additional tool for clinical decision making when caring for patients with femoral shaft fractures treated with IMNs., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Objective: A diverse physician workforce ensures equitable care. The holistic review of residency applications is one strategy to enhance physician diversity; however, little is known about current adoption and the factors that facilitate/impede the adoption of holistic recruitment practices (HRPs) by graduate medical education (GME) residency, and fellowship program directors (PDs). To describe the current state and explore, the barriers/facilitators to the adoption of HRPs at our institution., Methods: We disseminated information about HRP within our program between 2021 and 2022. In May 2022, a survey of 73 GME PDs assessed current recruitment practices and self-reported barriers to holistic recruitment. Holistic Recruitment Scores (HRSs) reflecting the adoption of best practices were tabulated for each program and compared to identify predictors of adoption., Results: 73/80 (92%) of PDs completed the survey. Programs whose PDs had higher academic rank, total number of trainees, and female trainees in the past 3 years had higher HRSs. Program size was directly correlated with HRS. Most (93%) PDs felt their current efforts were aligned to increase diversity and 58% felt there were no barriers to the adoption of holistic review. The most reported barriers were lack of time and knowledge/expertise in diversity, equity, and inclusion ( DEI ) , both reported by 16 out of 73 PDs (22%)., Conclusion: While most PDs implemented some HRP, institutional and departmental support of program directors through the commitment of resources (eg, staffing help and subject matter experts/coaches hiring) are crucial to overcome barriers., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI ( 60 Co 1.79 or 1.80 Gy, 0.42-0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B , TNFA , CCL2, IL18 , and CXCL8 , and the inflammasome component NLRP3 . Captopril suppressed radiation-induced IL1B and TNFA . Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

Background: Research from across the United States has shown that rurality is associated with worse melanoma outcomes. In Indiana, nearly a quarter of all residents live in rural counties and an estimated 2180 cases of melanoma will be diagnosed in 2023., Aims: This study examines how geographical location affects the stage of melanoma diagnosis in Indiana, aiming to identify and address rural health disparities to ultimately ensure equitable care., Methods and Results: Demographics and disease characteristics of patients diagnosed with melanoma at Indiana University Health from January 2017 to September 2022 were compared using Students t-tests, Wilcoxon tests, chi-squared or Fisher's exact tests. Patients from rural areas presented with more pathological stage T3 melanomas (15.0% vs. 3.5%, p < 0.001) in contrast to their urban counterparts. Additionally, rural patients presented with fewer clinical stage I melanomas (80.8% vs. 89.3%) and more clinical stage II melanomas (19.2% vs. 8.1%), compared to urban patients, with no stage III (p = 0.028). Concerningly, a significantly higher percentage of the rural group (40.7%) had a personal history of BCC compared to the urban group (22.6%) (p = 0.005) and fewer rural patients (78.0%) compared to urban patients (89.4%) received surgical treatment (p = 0.016)., Conclusion: Patients from rural counties in Indiana have higher pathological and clinical stage melanoma at diagnosis compared to patients from urban counties. Additionally fewer rural patients receive surgical treatment and may be at higher risk of developing subsequent melanomas., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Social isolation is a global public health threat. Veterans are particularly at risk for social isolation due to high rates of comorbid physical and mental health problems. Yet, effective interventions are limited., Objectives: Our primary objective was to assess the feasibility and acceptability of CONNECTED, a novel, transdiagnostic intervention to reduce social isolation that includes individual and group components and is delivered by peers via telehealth. Secondary objectives were to identify appropriate outcome measures and explore preliminary intervention effects., Methods: This was a two-phase study. In Phase 1, to evaluate study feasibility, we surveyed 200 veterans to assess prevalence of social isolation and their interest in social connectedness interventions. In Phase 2, we employed a mixed-methods, pre-post study design in which we piloted CONNECTED with 19 veterans through 2 successive cohorts to further assess feasibility, to evaluate acceptability, and to explore preliminary effectiveness. Quantitative analyses involved descriptive and bivariate analyses as well as multivariate modeling. Qualitative interviews were analyzed using thematic analysis., Results: For Phase 1, 39% of veterans surveyed were socially isolated. Participants who were ≤ 55 years old, caregivers, and those who experienced unmet social needs were more likely to report social isolation. Over 61% expressed interest in VA programs to reduce social isolation. For Phase 2, the pilot intervention, recruitment rate was 88% and the enrollment rate was 86%. Retention rates for the two cohorts were 80% and 50%, respectively, and satisfaction rates among intervention completers were 100%. Results also showed statistically significant improvements in social isolation (+ 5.91, SD = 4.99; p = .0028), social support (+ 0.74, SD = 1.09; p = .03), anxiety (-3.92, SD = 3.73; p = .003), and depression (-3.83, SD = 3.13; p = .001). Results for the other measures were not statistically significant., Conclusion: CONNECTED is a feasible and acceptable intervention and is likely to be an effective tool to intervene on social isolation among veterans., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The COVID-19 pandemic created complex challenges regarding the timing and appropriateness of do-not-attempt cardiopulmonary resuscitation (DNACPR) and/or Do Not Intubate (DNI) code status orders. This paper sought to determine differences in utilization of DNACPR and/or DNI orders during different time periods of the COVID-19 pandemic, including prevalence, predictors, timing, and outcomes associated with having a documented DNACPR and/or DNI order in hospitalized patients with COVID-19., Methods: A cohort study of hospitalized patients with COVID-19 at two hospitals located in the Midwest. DNACPR code status orders including, DNI orders, demographics, labs, COVID-19 treatments, clinical interventions during hospitalization, and outcome measures including mortality, discharge disposition, and hospice utilization were collected. Patients were divided into two time periods (early and late) by timing of hospitalization during the first wave of the pandemic (March-October 2020)., Results: Among 1375 hospitalized patients with COVID-19, 19% ( n  = 258) of all patients had a documented DNACPR and/or DNI order. In multivariable analysis, age (older) p  =< 0.01, OR 1.12 and hospitalization early in the pandemic p  = 0.01, OR 2.08, were associated with having a DNACPR order. Median day from DNACPR order to death varied between cohorts p  => 0.01 (early cohort 5 days versus late cohort 2 days). In-hospital mortality did not differ between cohorts among patients with DNACPR orders, p  = 0.80., Conclusions: There was a higher prevalence of DNACPR and/or DNI orders and these orders were written earlier in the hospital course for patients hospitalized early in the pandemic versus later despite similarities in clinical characteristics and medical interventions. Changes in clinical care between cohorts may be due to fear of resource shortages and changes in knowledge about COVID-19., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Lung cancer is the leading cause of cancer death for both men and women in the United States. The National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography (LDCT) screening can reduce lung cancer mortality among high-risk individuals, but uptake of lung screening remains low. Social media platforms have the potential to reach a large number of people, including those who are at high risk for lung cancer but who may not be aware of or have access to lung screening., Methods: This paper discusses the protocol for a randomized controlled trial (RCT) that leverages FBTA to reach screening-eligible individuals in the community at large and intervene with a public-facing, tailored health communication intervention (LungTalk) to increase awareness of, and knowledge about, lung screening., Discussion: This study will provide important information to inform the ability to refine implementation processes for national population efforts to scale a public-facing health communication focused intervention using social media to increase screening uptake of appropriate, high-risk individuals., Trial Registration: The trial is registered at clinicaltrials.gov (#NCT05824273)., (© 2023. The Author(s).)

Objectives: The objective of this study was to assess the impact of an emergency department (ED) deprescribing intervention for geriatric adults. We hypothesized that pharmacist-led medication reconciliation for at-risk aging patients would increase the 60-day case rate of primary care provider (PCP) deprescribing of potentially inappropriate medications (PIMs)., Methods: This was a retrospective, before-and-after intervention pilot study conducted at an urban Veterans Affairs ED. In November 2020, a protocol utilizing pharmacists to perform medication reconciliations for patients 75 years or older who screened positive using an Identification of Seniors at Risk tool at triage was implemented. Reconciliations focused on identifying PIMs and providing deprescribing recommendations to patients' PCPs. A preintervention group was collected between October 2019 and October 2020, and a postintervention group was collected between February 2021 to February 2022. The primary outcome compared case rates of PIM deprescribing in the preintervention group to the postintervention group. Secondary outcomes include per-medication PIM deprescribing rate, 30-day PCP follow-up visits, 7- and 30-day ED visits, 7- and 30-day hospitalizations, and 60-day mortality., Results: A total of 149 patients were analyzed in each group. Both groups were similar in age and sex, with an average age of 82 years and 98% male. The case rate of PIM deprescribing at 60 days was 11.1% preintervention compared to 57.1% postintervention (p < 0.001). Preintervention, 91% of PIMs remained unchanged at 60 days compared to 49% (p < 0.05) postintervention. Regardless of PIM identification, the 30-day primary care follow-up rate increased postintervention: 31.5% and 55.7% (p < 0.0001), respectively. There was no improvement in 7- or 30-day subsequent ED visits, hospitalization, or mortality., Conclusions: Pharmacist-led medication reconciliation in high-risk geriatric patients was associated with an increase both in the rate of PIM deprescribing and in post-ED primary care engagement., (© 2023 Society for Academic Emergency Medicine.)

Objectives: Frailty is a clinical syndrome characterized by decreased physiologic reserve that diminishes the ability to respond to stressors such as acute illness. Veterans Health Administration (VA) emergency departments (ED) are the primary venue of care for Veterans with acute illness and represent key sites for frailty recognition. As questionnaire-based frailty instruments can be cumbersome to implement in the ED, we examined two administratively derived frailty scores for use among VA ED patients., Methods: This national retrospective cohort study included all VA ED visits (2017-2020). We evaluated two administratively derived scores: the Care Assessment Needs (CAN) score and the VA Frailty Index (VA-FI). We categorized all ED visits across four frailty groups and examined associations with outcomes of 30-day and 90-day hospitalization and 30-day, 90-day, and 1-year mortality. We used logistic regression to assess the model performance of the CAN score and the VA-FI., Results: The cohort included 9,213,571 ED visits. With the CAN score, 28.7% of the cohort were classified as severely frail; by VA-FI, 13.2% were severely frail. All outcome rates increased with progressive frailty (p-values for all comparisons < 0.001). For example, for 1-year mortality based on the CAN score frailty was determined as: robust, 1.4%; prefrail, 3.4%; moderately frail, 7.0%; and severely frail, 20.2%. Similarly, for 90-day hospitalization based on VA-FI, frailty was determined as prefrail, 8.3%; mildly frail, 15.3%; moderately frail, 29.5%; and severely frail, 55.4%. The c-statistics for CAN score models were higher than for VA-FI models across all outcomes (e.g., 1-year mortality, 0.721 vs. 0.659)., Conclusions: Frailty was common among VA ED patients. Increased frailty, whether measured by CAN score or VA-FI, was strongly associated with hospitalization and mortality and both can be used in the ED to identify Veterans at high risk for adverse outcomes. Having an effective automatic score in VA EDs to identify frail Veterans may allow for better targeting of scarce resources., (© 2023 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Most people with cystic fibrosis (CF) are diagnosed following abnormal newborn screening (NBS), which begins with measurement of immunoreactive trypsinogen (IRT) values. A case report found low concentrations of IRT in an infant with CF exposed to the CF transmembrane conductance regulator (CFTR) modulator, elexacaftor-tezacaftor-ivacaftor (ETI), in utero. However, IRT values in infants born to mothers taking ETI have not been systematically assessed. We hypothesized that ETI-exposed infants have lower IRT values than newborns with CF, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID), or CF carriers. IRT values were collected from infants born in Indiana between 1 January 2020, and 2 June 2022, with ≥1 CFTR mutation. IRT values were compared to infants born to mothers with CF taking ETI followed at our institution. Compared to infants identified with CF ( n = 51), CRMS/CFSPID ( n = 21), and CF carriers ( n = 489), ETI-exposed infants ( n = 19) had lower IRT values ( p < 0.001). Infants with normal NBS results for CF had similar median (interquartile range) IRT values, 22.5 (16.8, 30.6) ng/mL, as ETI-exposed infants, 18.9 (15.2, 26.5). IRT values from ETI-exposed infants were lower than for infants with abnormal NBS for CF. We recommend that NBS programs consider performing CFTR variant analysis for all ETI-exposed infants.

Low dose-rate radiation exposure can occur in medical imaging, as background from environmental or industrial radiation, and is a hazard of space travel. In contrast with high dose-rate radiation exposure that can induce acute life-threatening syndromes, chronic low-dose radiation is associated with Chronic Radiation Syndrome (CRS), which can alter environmental sensitivity. Secondary effects of chronic low dose-rate radiation exposure include circulatory, digestive, cardiovascular, and neurological diseases, as well as cancer. Here, we investigated 1-2 Gy, 0.66 cGy/h, 60 Co radiation effects on primary human mesenchymal stem cells (hMSC). There was no significant induction of apoptosis or DNA damage, and cells continued to proliferate. Gene ontology (GO) analysis of transcriptome changes revealed alterations in pathways related to cellular metabolism (cholesterol, fatty acid, and glucose metabolism), extracellular matrix modification and cell adhesion/migration, and regulation of vasoconstriction and inflammation. Interestingly, there was increased hypoxia signaling and increased activation of pathways regulated by iron deficiency, but Nrf2 and related genes were reduced. The data were validated in hMSC and human lung microvascular endothelial cells using targeted qPCR and Western blotting. Notably absent in the GO analysis were alteration pathways for DNA damage response, cell cycle inhibition, senescence, and pro-inflammatory response that we previously observed for high dose-rate radiation exposure. Our findings suggest that cellular gene transcription response to low dose-rate ionizing radiation is fundamentally different compared to high-dose-rate exposure. We hypothesize that cellular response to hypoxia and iron deficiency are driving processes, upstream of the other pathway regulation.

Background: Little is known about the consistency of initial NIHSS scores between neurologists and RNs in clinical practice., Methods: A cohort study of patients with a code stroke was conducted at an urban academic Primary Stroke Center in the Midwest between January 1, 2018, and December 31, 2019 to determine consistency in National Institutes of Health Stroke Scale Scores (NIHSS) between neurologists and registered nurses (RNs)., Results: Among the 438 patients included in this study 65.3% ( n = 286) of neurologist-RN NIHSS scoring pairs had congruent scores. One-in-three, (34.7%, n = 152) of neurologist-RN NIHSS scoring pairs had a clinically meaningful scoring difference of two points or greater. Higher NIHSS ( p ≤ 0.01) and aphasia ( p ≤ 0.01) were each associated with incongruent scoring between neurologist and emergency room RN pairs., Conclusions: One-in-three initial NIHSS assessed by both a neurologist and RN had a clinically meaningful score difference between providers. More severe stroke, as indicated by a higher NIHSS was associated with scoring inconsistency between neurologist-RN pairs. Subjective scoring measures, especially those involving a patient having aphasia, was associated with greater score incongruency. Score differences may be attributed to differences in NIHSS training requirements between neurologists and RNs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Comer, Templeton, Glidden, Bartlett, D'Cruz, Nemati, Zabel and Slaven.)

Background: In-hospital resuscitation events have complex and enduring effects on clinicians, with implications for job satisfaction, performance, and burnout. Ethically ambiguous cases are associated with increased moral distress. We aim to quantitatively describe the multidisciplinary resuscitation experience., Methods: Multidisciplinary in-hospital healthcare professionals at an adult academic health center in the Midwestern United States completed surveys one and six weeks after a resuscitation event. Surveys included demographic data, task load (NASA-TLX), overall and moral distress, anxiety, depression, and spiritual peace. Spearman's rank correlation was computed to assess task load and distress., Results: During the 5-month study period, the study included 12 resuscitation events across six inpatient units. Of 82 in-hospital healthcare professionals eligible for recruitment, 44 (53.7%) completed the one-week post-resuscitation event survey. Of those, 37 (84.1%) completed the six-week survey. Highest median task load burden at one week was seen for temporal demand, effort, and mental demand. Median moral distress scores were low, while "at peace" median scores tended to be high. There were no significant non-zero changes in task load or distress scores from weeks 1-6. Mental demand ( r  = 0.545, p  < 0.001), physical demand ( r  = 0.464, p  = 0.005), performance ( r  = -0.539, p  < 0.001), and frustration ( r  = 0.545, p  < 0.001) significantly correlated with overall distress. Performance ( r  = -0.371, p  = 0.028) and frustration ( r  = 0.480, p  = 0.004) also significantly correlated with moral distress., Conclusions: In-hospital healthcare professionals' experiences of resuscitation events are varied and complex. Aspects of task load burden including mental and physical demand, performance, and frustration contribute to overall and moral distress, deserving greater attention in clinical contexts., (© 2022 The Author(s).)

Background: Infants with cystic fibrosis (CF) develop structural lung disease early in life, and viral infections are associated with progressive lung disease. We hypothesized that the presence of respiratory viruses would be associated with structural lung disease on computed tomography (CT) of the chest in infants with CF., Methods: Infants with CF were enrolled before 4 months of age. Multiplex PCR assays were performed on nasal swabs to detect respiratory viruses during routine visits and when symptomatic. Participants underwent CT imaging at approximately 12 months of age. Associations between Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) CT scores and respiratory viruses and symptoms were assessed with Spearman correlation coefficients., Results: Sixty infants were included for analysis. Human rhinovirus was the most common virus detected, on 28% of tested nasal swabs and in 85% of participants. The median (IQR) extent of lung fields that was healthy based on PRAGMA-CF was 98.7 (0.8)%. There were no associations between PRAGMA-CF and age at first virus, or detection of any virus, including rhinovirus, respiratory syncytial virus, or parainfluenza. The extent of airway wall thickening was associated with ever having wheezed (ρ = 0.31, p = 0.02) and number of encounters with cough (ρ = 0.25, p = 0.0495)., Conclusions: Infants with CF had minimal structural lung disease. We did not find an association between respiratory viruses and CT abnormalities. Wheezing and frequency of cough were associated with early structural changes., (Copyright © 2022. Published by Elsevier B.V.)

Importance: Medication management and cognitive behavioral therapy (CBT) are commonly used treatments for chronic low back pain (CLBP). However, little evidence is available comparing the effectiveness of these approaches., Objective: To compare collaborative care medication optimization vs CBT on pain intensity, interference, and other pain-related outcomes., Design, Setting, and Participants: The Care Management for the Effective Use of Opioids (CAMEO) trial was a 12-month, comparative effectiveness randomized clinical trial with blinded outcome assessment. Recruitment of veterans with CLBP prescribed long-term opioids occurred at 7 Veterans Affairs primary care clinics from September 1, 2011, to December 31, 2014, and follow-up was completed December 31, 2015. Analyses were based on intention to treat in all randomized participants and were performed from March 22, 2015, to November 1, 2021., Interventions: Patients were randomized to receive either collaborative care with nurse care manager-delivered medication optimization (MED group) (n = 131) or psychologist-delivered CBT (CBT group) (n = 130) for 6 months, with check-in visits at 9 months and final outcome assessment at 12 months., Main Outcomes and Measures: The primary outcome was change in Brief Pain Inventory (BPI) total score, a composite of the pain intensity and interference subscales at 6 (treatment completion) and 12 (follow-up completion) months. Scores on the BPI range from 0 to 10, with higher scores representing greater pain impact and a 30% improvement considered a clinically meaningful treatment response. Secondary outcomes included pain-related disability, pain catastrophizing, self-reported substance misuse, health-related quality of life, depression, and anxiety., Results: A total of 261 patients (241 [92.3%] men; mean [SD] age, 57.9 [9.5] years) were randomized and included in the analysis. Baseline mean (SD) BPI scores in the MED and CBT groups were 6.45 (1.79) and 6.49 (1.67), respectively. Improvements in BPI scores were significantly greater in the MED group at 12 months (between-group difference, -0.54 [95% CI, -1.18 to -0.31]; P = .04) but not at 6 months (between-group difference, -0.46 [95% CI, -0.94 to 0.11]; P = .07). Secondary outcomes did not differ significantly between treatment groups., Conclusions and Relevance: In this randomized clinical trial among US veterans with CLBP who were prescribed long-term opioid therapy, collaborative care medication optimization was modestly more effective than CBT in reducing pain impact during the 12-month study. However, this difference may not be clinically meaningful or generalize to nonveteran populations., Trial Registration: ClinicalTrials.gov Identifier: NCT01236521.

Purpose: Previous studies have shown that black patients are more likely to prefer life-sustaining treatments such as cardiopulmonary resuscitation at end-of-life (EOL) compared to non-Hispanic white patients. Given prior racial disparities in health care, distrust has been proposed to explain these preferences. As many hospitalized older adults require surrogates to make medical decisions, we explored surrogates' code status preferences and the role of trust in these decisions., Methods: We conducted secondary analyses of an observational study of patient/surrogate dyads admitted to three hospitals in a Midwest metropolitan area. Distrust was assessed using the Revised Health Care System Distrust Scale. A single item asked the surrogate which code status they thought was best for the patient, full code or do not resuscitate., Results: We enrolled 350 patient/surrogate dyads (101 black; 249 white). In bivariate analysis, higher proportion of black surrogates preferred full code (62.4% vs. 38.3%, p =0.0001). After adjusting for trust and sociodemographic and psychological covariates, race was still significantly associated with preference for full code (adjusted odds ratio=2.13; 95% confidence interval: 1.16-3.92; p =0.0153). Surrogate race was not associated with distrust in bivariate or multivariable analysis, adjusting for sociodemographic and psychological covariates ( p =0.3049)., Conclusion: Although black race was associated with preferences for full code status, we observed no association between race and distrust. Differences in code status preference may be due to other factors related to race and culture. To ensure that patients are receiving EOL care that is consistent with their values, more work is needed to understand the cultural complexities behind EOL care preferences., Competing Interests: No competing financial interests exist., (© Sang Yoon Na et al., 2022; Published by Mary Ann Liebert, Inc.)

Exposure to ionizing radiation can occur during medical treatments, from naturally occurring sources in the environment, or as the result of a nuclear accident or thermonuclear war. The severity of cellular damage from ionizing radiation exposure is dependent upon a number of factors including the absorbed radiation dose of the exposure (energy absorbed per unit mass of the exposure), dose rate, area and volume of tissue exposed, type of radiation (e.g., X-rays, high-energy gamma rays, protons, or neutrons) and linear energy transfer. While the dose, the dose rate, and dose distribution in tissue are aspects of a radiation exposure that can be varied experimentally or in medical treatments, the LET and eV are inherent characteristics of the type of radiation. High-LET radiation deposits a higher concentration of energy in a shorter distance when traversing tissue compared with low-LET radiation. The different biological effects of high and low LET with similar energies have been documented in vivo in animal models and in cultured cells. High-LET results in intense macromolecular damage and more cell death. Findings indicate that while both low- and high-LET radiation activate non-homologous end-joining DNA repair activity, efficient repair of high-LET radiation requires the homologous recombination repair pathway. Low- and high-LET radiation activate p53 transcription factor activity in most cells, but high LET activates NF-kB transcription factor at lower radiation doses than low-LET radiation. Here we review the development, uses, and current understanding of the cellular effects of low- and high-LET radiation exposure.

Background: Chronic neck pain (CNP) is prevalent, and it reduces functional status and quality of life and is associated with deleterious psychological outcomes in affected individuals. Despite the desirability of massage and its demonstrated effectiveness in CNP treatment, multiple accessibility barriers exist. Caregiver-applied massage has demonstrated feasibility in various populations but has not been examined in Veterans with CNP or compared in parallel to therapist-delivered massage., Objective: This manuscript described the original study design, lessons learned, and resultant design modifications for the Trial Outcomes for Massage: Care Ally-Assisted Versus Therapist-Treated (TOMCATT) study., Methods: TOMCATT began as a 3-arm, randomized controlled trial of 2 massage delivery approaches for Veterans with CNP with measures collected at baseline, 1 and 3 months after intervention, and 6 months (follow-up). Arm I, care ally-assisted massage, consisted of an in-person, 3.5-hour training workshop, an instructional DVD, a printed treatment manual, and three 30-minute at-home care ally-assisted massage sessions weekly for 3 months. Arm II, therapist-treated massage, consisted of two 60-minute sessions tailored to individual pain experiences and treatments per week for 3 months. The treatments followed a standardized Swedish massage approach. Arm III consisted of wait-list control., Results: Retention and engagement challenges in the first 30 months were significant in the care ally-assisted massage study arm (63% attrition between randomization and treatment initiation) and prompted modification to a 2-arm trial, that is, removing arm I., Conclusions: The modified TOMCATT study successfully launched and exceeded recruitment goals 2.5 months before the necessary COVID-19 pause and is expected to be completed by early 2023., Trial Registration: ClinicalTrials.gov NCT03100539; https://clinicaltrials.gov/ct2/show/NCT03100539., International Registered Report Identifier (irrid): DERR1-10.2196/38950., (©Niki Munk, Joanne K Daggy, Erica Evans, Matthew Kline, James E Slaven, Brian Laws, Trevor Foote, Marianne S Matthias, Matthew J Bair. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 27.09.2022.)

Background: Chronic pain and access to care are identified as critical needs of the Veterans Health Administration. Music imagery and music listening interventions have shown promise as effective nonpharmacological options for pain management. However, most studies have focused on acute pain, passive music experiences, and in-person delivery., Objective: In this study, we aimed to examine the feasibility and acceptability of 2 music interventions delivered through telehealth for chronic musculoskeletal pain, trial design, and theoretical model before conducting a fully powered efficacy or comparative effectiveness trial., Methods: FAMILIA (Feasibility and Acceptability of Music Imagery and Listening Interventions for Analgesia) is a 3-arm, parallel group, pilot trial. A total of 60 veterans will be randomized to one of the three conditions: music imagery, music listening, or usual care. Aim 1 is to test the feasibility and acceptability of a multicomponent, interactive music imagery intervention (8-weekly, individual sessions) and a single-component, minimally interactive music learning intervention (independent music listening). Feasibility metrics related to recruitment, retention, engagement, and completion of the treatment protocol and questionnaires will be assessed. Up to 20 qualitative interviews will be conducted to assess veteran experiences with both interventions, including perceived benefits, acceptability, barriers, and facilitators. Interview transcripts will be coded and analyzed for emergent themes. Aim 2 is to explore the effects of music imagery and music listening versus usual care on pain and associated patient-centered outcomes. These outcomes and potential mediators will be explored through changes from baseline to follow-up assessments at 1, 3, and 4 months. Descriptive statistics will be used to describe outcomes; this pilot study is not powered to detect differences in outcomes., Results: Recruitment for FAMILIA began in March 2022, and as of July 2022, 16 participants have been enrolled. We anticipate that enrollment will be completed by May 2023. We expect that music imagery and music listening will prove acceptable to veterans and that feasibility benchmarks will be reached. We hypothesize that music imagery and music listening will be more effective than usual care on pain and related outcomes., Conclusions: FAMILIA addresses four limitations in music intervention research for chronic pain: limited studies in veterans, evaluation of a multicomponent music intervention, methodological rigor, and internet-based delivery. Findings from FAMILIA will inform a fully powered trial to identify putative mechanisms and test efficacy., Trial Registration: ClinicalTrials.gov NCT05426941; https://tinyurl.com/3jdhx28u., International Registered Report Identifier (irrid): DERR1-10.2196/38788., (©Kristin M Story, Dawn M Bravata, Sheri L Robb, Sally Wasmuth, James E Slaven, Leah Whitmire, Barry Barker, Tetla Menen, Matthew J Bair. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 22.09.2022.)

Total body irradiation (TBI) can result in death associated with hematopoietic insufficiency. Although radiation causes apoptosis of white blood cells, red blood cells (RBC) undergo hemolysis due to hemoglobin denaturation. RBC lysis post-irradiation results in the release of iron into the plasma, producing a secondary toxic event. We investigated radiation-induced iron in the spleens of mice following TBI and the effects of the radiation mitigator captopril. RBC and hematocrit were reduced ~7 days (nadir ~14 days) post-TBI. Prussian blue staining revealed increased splenic Fe 3+ and altered expression of iron binding and transport proteins, determined by qPCR, western blotting, and immunohistochemistry. Captopril did not affect iron deposition in the spleen or modulate iron-binding proteins. Caspase-3 was activated after ~7-14 days, indicating apoptosis had occurred. We also identified markers of iron-dependent apoptosis known as ferroptosis. The p21/Waf1 accelerated senescence marker was not upregulated. Macrophage inflammation is an effect of TBI. We investigated the effects of radiation and Fe 3+ on the J774A.1 murine macrophage cell line. Radiation induced p21/Waf1 and ferritin, but not caspase-3, after ~24 h. Radiation ± iron upregulated several markers of pro-inflammatory M1 polarization; radiation with iron also upregulated a marker of anti-inflammatory M2 polarization. Our data indicate that following TBI, iron accumulates in the spleen where it regulates iron-binding proteins and triggers apoptosis and possible ferroptosis.

Background: Mental health care disparities are persistent and have increased in recent years. Compared with their White counterparts, members of racially and ethnically minoritized groups have less access to mental health care. Minoritized groups also have lower engagement in mental health treatment and are more likely to experience ineffective patient-provider communication, which contribute to negative mental health care experiences and poor mental health outcomes. Interventions that embrace recovery-oriented practices to support patient engagement and empower patients to participate in their mental health care and treatment decisions may help reduce mental health care disparities. Designed to achieve this goal, the Proactive, Recovery-Oriented Treatment Navigation to Engage Racially Diverse Veterans in Mental Healthcare (PARTNER-MH) is a peer-led patient navigation intervention that aims to engage minoritized patients in mental health treatment, support them to play a greater role in their care, and facilitate their participation in shared treatment decision-making., Objective: The primary aim of this study is to assess the feasibility and acceptability of PARTNER-MH delivered to patients over 6 months. The second aim is to evaluate the preliminary effects of PARTNER-MH on patient activation, patient engagement, and shared decision-making. The third aim is to examine patient-perceived barriers to and facilitators of engagement in PARTNER-MH as well as contextual factors that may inhibit or promote the integration, sustainability, and scalability of PARTNER-MH using the Consolidated Framework for Implementation Research., Methods: This pilot study evaluates the feasibility and acceptability of PARTNER-MH in a Veterans Health Administration (VHA) mental health setting using a mixed methods, randomized controlled trial study design. PARTNER-MH is tested under real-world conditions using certified VHA peer specialists (peers) selected through usual VHA hiring practices and assigned to the mental health service line. Peers provide PARTNER-MH and usual peer support services. The study compares the impact of PARTNER-MH versus a wait-list control group on patient activation, patient engagement, and shared decision-making as well as other patient-level outcomes. PARTNER-MH also examines organizational factors that could impact its future implementation in VHA settings., Results: Participants (N=50) were Veterans who were mostly male (n=31, 62%) and self-identified as non-Hispanic (n=44, 88%) and Black (n=35, 70%) with a median age of 45 to 54 years. Most had at least some college education, and 32% (16/50) had completed ≥4 years of college. Randomization produced comparable groups in terms of characteristics and outcome measures at baseline, except for sex., Conclusions: Rather than simply documenting health disparities among vulnerable populations, PARTNER-MH offers opportunities to evaluate a tailored, culturally sensitive, system-based intervention to improve patient engagement and patient-provider communication in mental health care for racially and ethnically minoritized individuals., Trial Registration: ClinicalTrials.gov NCT04515771; https://clinicaltrials.gov/ct2/show/NCT04515771., International Registered Report Identifier (irrid): DERR1-10.2196/37712., (©Johanne Eliacin, Diana J Burgess, Angela L Rollins, Scott Patterson, Teresa Damush, Matthew J Bair, Michelle P Salyers, Michele Spoont, James E Slaven, Caitlin O'Connor, Kiara Walker, Denise S Zou, Emily Austin, John Akins, James Miller, Matthew Chinman, Marianne S Matthias. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 06.09.2022.)

Background: Fibromyalgia is a common pain condition that often leads to significant disability. Unfortunately, the effectiveness of most medications for fibromyalgia is limited, and there is a need for alternative, non-pharmacological therapies. Yoga and aerobic exercise are both evidence-based non-pharmacological treatments for fibromyalgia. However, no prior studies have directly compared the effectiveness of yoga vs. exercise., Objective: This article describes the study design and recruitment outcomes of the Pain Outcomes comparing Yoga vs. Structured Exercise (POYSE) Trial, a two-arm randomized comparative effectiveness trial., Methods: Veterans with fibromyalgia, defined by the 2010 American College of Rheumatology diagnostic criteria, who also experienced at least moderate pain severity were enrolled. The participants were randomized to a 12-week yoga-based or a structured exercise program (SEP) and will undergo comprehensive outcome assessments at baseline, 1, 3, 6, and 9 months by interviewers blinded to treatment assignment. The primary outcome will be the overall severity of fibromyalgia as measured by the total Fibromyalgia Impact Questionnaire-Revised. Secondary outcomes included depression, anxiety, health-related quality of life, pain beliefs, fatigue, sleep, and self-efficacy., Results: A total of 2,671 recruitment letters were sent to potential participants with fibromyalgia. Of the potential participants, 623 (23.3%) were able to be contacted by telephone and had their eligibility assessed. Three hundred seventy-one of those interviewed were found to be eligible (59.6%) and 256 (69.0%) agreed to participate and were randomized to the YOGA ( n = 129) or the SEP ( n = 127) arm of the trial., Conclusions: Clinicians are faced with numerous challenges in treating patients with fibromyalgia. The interventions being tested in the POYSE trial have the potential to provide primary care and other care settings with new treatment options for clinicians while simultaneously providing a much needed relief for patients suffering from fibromyalgia., Trial Registration: Funded by VA Rehabilitation Research and Development (D1100-R); Trial registration: ClinicalTrials.gov, NCT01797263., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Allsop, Schmid, Miller, Slaven, Daggy, Froman, Kline, Sargent, French, Ang, Van Puymbroeck, Schalk and Bair.)

Background: Despite reliable evidence-based research supporting the COVID-19 vaccines, population-wide confidence and trust remain limited. We sought to expand prior knowledge about COVID-19 vaccine perceptions, while determining which population groups are at greatest risk for not getting a vaccine., Methods: Study participants in the U.S. (79% female, median age group 46-60 years) were recruited through an online Qualtrics survey distributed as a Facebook advertisement from 3/19/21-4/30/21. We assumed that every participant is at risk of COVID-19 infection and should be able to get the vaccine with proper access. Bivariate and multivariable models were performed. Collinearity between variables was assessed., Results: A total of 2,626 responses were generated and 2,259 were included in data analysis. According to our multivariate model analysis, vaccines were perceived as safe by those who had or planned to obtain full vaccination (adjusted odds ratio (aOR) (95% confidence interval) = 40.0 (19.0, 84.2); p< 0.0001) and those who indicated trust in science (aOR = 10.5 (5.1, 21.8); p< 0.0001); vaccines were perceived as not safe by those who self-identified as Republicans vs. self-identified Democrats (aOR = 0.2 (0.1, 0.5); p = 0.0020) and those with high school or lower education (aOR = 0.2 (0.1, 0.4); p = 0.0007). Similarly, according to our multivariate model analysis, the following groups were most likely to reject vaccination based on belief in vaccinations: those with lower income (aOR = 0.8 (0.6, 0.9); p = 0.0106), those who do not know anyone who had been vaccinated (aOR = 0.1 (0.1, 0.4); p< 0.0001), those who are unwilling to get vaccinated even if family and friends had done so (aOR = 0.1 (<0.1, 0.2); p< 0.0001), those who did not trust science (aOR < 0.1 (<0.1, 0.1); p< 0.0001), those who believe that vaccination was unnecessary if others had already been vaccinated (aOR = 2.8 (1.5, 5.1); p = 0.0007), and those who indicate refusal to vaccinate to help others (aOR = 0.1 (0.1, 0.2); p< 0.0001). An alpha of p<0.05 was used for all tests., Conclusion: Level of education and partisanship, but not race/ethnicity, were the most likely factors associated with vaccine hesitancy or likelihood to vaccinate. Also, low vaccination rates among underrepresented minorities may be due to distrust for healthcare industries. Population sub-groups less likely to be vaccinated and/or receptive to vaccines should be targeted for vaccine education and incentives., Competing Interests: The authors have declared that no competing interests exist.

Background: Proactively monitoring infliximab levels is an emerging area of interest in pediatric Crohn's disease. There are only limited data on therapeutic drug monitoring for children with Crohn's disease. The goal of our study was to determine the utility of therapeutic drug monitoring in achieving clinical remission in a cohort of pediatric Crohn's disease patients receiving infliximab., Methods: This prospective single-center study enrolled 37 patients with Crohn's disease at the start of infliximab infusions and monitored trough levels at 6-month intervals for 18 months. Each participant was matched to a historic control for the modified pediatric Crohn's disease activity index (mPCDAI) at baseline, age and sex. The primary outcome was an mPCDAI score of ≤7.5 at 6, 12 and 18 months. A multivariate logistic regression analysis was performed., Results: Data were available for all 37 cases at 6 and 12 months and for 34 cases at 18 months. Demographics and disease characteristics were similar between groups. All 34 cases demonstrated clinical remission at 18 months (100% vs. 88%, P=0.114). Univariate and multivariate analyses did not show statistical significance. Dose intensification was seen more often in the cases at 18 months., Conclusion: All of our moderate-to-severe pediatric Crohn's disease patients who received prospective therapeutic drug monitoring of infliximab were in clinical remission at follow up, but this was not statistically significantly different from the 88% clinical remission rate of the control group., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Background: Hydrocolloid dressings (HCD) are helpful in chronic wound care, but research is limited in acute postoperative wounds. HCD can potentially be incorporated into a simplified wound care regimen after excisional surgeries., Objective: To examine whether a one-time HCD application after dermatologic surgery results in greater patient satisfaction and improved postoperative outcomes compared with conventional daily dressings (CDD)., Methods: We examined patients who underwent Mohs or standard surgical excision with linear closure followed by HCD. The patients additionally had a history of excisional surgery with CDD in the past 5 years. A modified version of the validated Bluebelle Wound Healing Questionnaire was administered., Results: The survey response rate was 74.4% (64/86). Compared with CDD, HCD rated higher in comfort, convenience, scar appearance, and simplicity of wound care instructions ( P  < .0001). Nearly all patients (96.8%) preferred HCD over CDD., Limitations: Variability in time from prior dermatologic surgery may introduce recall bias. Prior surgeries involving CDD were sometimes performed by a different surgeon, which could introduce other confounding factors., Conclusions: A simplified wound care regimen involving HCD can potentially lead to increased comfort, convenience, simplicity, and a subjective improvement in scar appearance, though additional studies are needed., Competing Interests: None disclosed.

The vascular system is sensitive to radiation injury, and vascular damage is believed to play a key role in delayed tissue injury such as pulmonary fibrosis. However, the response of endothelial cells to radiation is not completely understood. We examined the response of primary human lung microvascular endothelial cells (HLMVEC) to 10 Gy (1.15 Gy/min) X-irradiation. HLMVEC underwent senescence (80-85%) with no significant necrosis or apoptosis. Targeted RT-qPCR showed increased expression of genes CDKN1A and MDM2 (10-120 min). Western blotting showed upregulation of p2/waf1, MDM2, ATM, and Akt phosphorylation (15 min-72 h). Low levels of apoptosis at 24-72 h were identified using nuclear morphology. To identify novel pathway regulation, RNA-seq was performed on mRNA using time points from 2 to 24 h post-irradiation. Gene ontology and pathway analysis revealed increased cell cycle inhibition, DNA damage response, pro- and anti- apoptosis, and pro-senescence gene expression. Based on published literature on inflammation and endothelial-to-mesenchymal transition (EndMT) pathway genes, we identified increased expression of pro-inflammatory genes and EndMT-associated genes by 24 h. Together our data reveal a time course of integrated gene expression and protein activation leading from early DNA damage response and cell cycle arrest to senescence, pro-inflammatory gene expression, and endothelial-to-mesenchymal transition., (© 2021. The Author(s).)

Our laboratory has demonstrated that captopril, an angiotensin converting enzyme inhibitor, mitigates hematopoietic injury following total body irradiation in mice. Improved survival in mice is correlated with improved recovery of mature blood cells and bone marrow, reduction of radiation-induced inflammation, and suppression of radiation coagulopathy. Here we investigated the effects of captopril treatment against radiation injuries in the Göttingen mini pig model of Hematopoietic-Acute Radiation Syndrome (H-ARS). Minipigs were given captopril orally (0.96 mg/kg) twice daily for 12 days following total body irradiation (60Co 1.79 Gy, 0.42-0.48 Gy/min). Blood was drawn over a time course following irradiation, and tissue samples were collected at euthanasia (32-35 days post-irradiation). We observed improved survival with captopril treatment, with survival rates of 62.5% in vehicle treated and 87.5% in captopril treated group. Additionally, captopril significantly improved recovery of peripheral blood mononuclear cells, and a trend toward improvement in recovery of red blood cells and platelets. Captopril significantly reduced radiation-induced expression of cytokines erythropoietin and granulocyte-macrophage colony-stimulating factor and suppressed radiation-induced acute-phase inflammatory response cytokine serum amyloid protein A. Using quantitative-RT-PCR to monitor bone marrow recovery, we observed significant suppression of radiation-induced expression of redox stress genes and improved hematopoietic cytokine expression. Our findings suggest that captopril activities in the Göttingen minipig model of hematopoietic-acute radiation syndrome reflect findings in the murine model., Competing Interests: KOG is currently employed by Leidos Biomedical Research Inc. KOG was not employed by Leidos Biomedical Research Inc at the time this study was conducted. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To examine screening strategies for identifying problematic sleep in a diverse sample of infants., Methods: Parents of infants (5-19 months; N = 3,271) presenting for a primary care visit responded to five screening items and the Infant Sleep Questionnaire (ISQ), a validated measure of problematic infant sleep. If parents responded affirmatively to any screening item, primary care providers received a prompt to evaluate. For each of the screening questions, we examined differences in item endorsement and criterion related validity with the ISQ. Using conceptual composites of night waking and sleep difficulty, prevalence, criterion-related validity, and concurrent demographic correlates were analyzed., Results: Infants were primarily of Black race (50.1%) or Hispanic ethnicity (31.7%), with the majority (63.3%) living in economically distressed communities. Rates of problematic sleep ranged from 7.4%, for a single item assessing parental perception of an infant having a sleep problem, to 74.0%, for a single item assessing night wakings requiring adult intervention. Items assessing sleep difficulty had high (95.0-97.8%) agreement with the ISQ in identifying infants without problematic sleep, but low agreement (24.9-34.0%) in identifying those with problematic sleep. The opposite was true for items assessing night waking, which identified 91.0-94.6% of those with sleep problems but only 31.8-46.9% of those without., Conclusions: Screening strategies for identifying problematic infant sleep yielded highly variable prevalence rates and associated factors, depending on whether the strategy emphasized parent-perceived sleep difficulty or night wakings. The strategy that is most appropriate will depend on the system's goals., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To understand clinicians' perspectives on dialysis care of undocumented immigrants. Methods: A 21-item Internet-based survey using Survey Monkey ® was sent to 765 physicians and nurses at a safety-net hospital located in Indianapolis, IN. Moral distress thermometer score was used to assess moral distress (MD). Participants were asked to rate their MD regarding five ethically challenging clinical situations: (1) frail patients with multiple comorbidities and poor quality of life, (2) patients with dementia, (3) a noncompliant patient with frequent emergency room (ER) visits, (4) violent patients with potential harm to others, and (5) undocumented immigrants receiving emergent dialysis only. Key Results: There were 299 of 775 participants (38.5% response rate) who completed the survey; 49.5% were physicians. Nearly half (48%) reported severe MD and 33% reported none to mild. In adjusted ordered logistic regression, females had significantly higher odds of MD (odds ratio [OR]=2.12, CI 1.03-4.33), and nurses had lower MD than fellows/residents (OR=0.14, CI 0.03-0.63). Over 70% of respondents attributed their distress to suffering of patients due to inadequate dialysis and tension between what is considered ethical and the law allows or forbids; 78% believed the patients' quality of life to be worse than those who receive routine hemodialysis. Among nephrologists, caring for these patients led to MD levels like that of dealing with a violent dialysis patient. Conclusions: Emergent-only dialysis causes significant MD in clinicians. Legal and fiscal policies need to be balanced with the ethical and moral commitments of providers for ensuring standard of care to all., Competing Interests: No competing financial interests exist., (© Areeba Jawed et al., 2021; Published by Mary Ann Liebert, Inc.)

Rationale: Little is known on the use of noninvasive ventilation (NIPPV) in pediatric hematopoietic cell transplant (HCT) patients., Objective: We sought to describe the landscape of NIPPV use and to identify risk factors for failure to inform future investigation or quality improvement., Methods: This is a multicenter, retrospective observational cohort of 153 consecutive children post-HCT requiring NIPPV from 2010-2016., Results: 97 (63%) failed NIPPV. Factors associated with failure on univariate analysis included: longer oxygen use prior to NIPPV (p=0.04), vasoactive agent use (p<0.001), and higher respiratory rate at multiple hours of NIPPV use (1hr p=0.02, 2hr p=0.04, 4hr p=0.008, 8hr p=0.002). Using respiratory rate at 4 hours a multivariable model was constructed. This model demonstrated high ability to discriminate NIPPV failure (AUC=0.794) with the following results: respiratory rate >40 at 4 hours [aOR=6.3 9(95% CI: 2.4, 16.4), p<0.001] and vasoactive use [aOR=4.9 (95% CI: 1.9, 13.1), p=0.001]. Of note, 11 patients had a cardiac arrest during intubation (11%) and 3 others arrested prior to intubation. These 14 patients were closer to HCT [14 days (IQR:4, 73) vs 54 (IQR:21,117), p<0.01] and there was a trend toward beginning NIPPV outside of the PICU and arrest during/prior to intubation (p=0.056)., Conclusions: In this cohort respiratory rate at 4 hours and vasoactive use are independent risk factors of NIPPV failure. An objective model to predict which children may benefit from a trial of NIPPV, may also inform the timing of both NIPPV initiation and uncomplicated intubation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rowan, Fitzgerald, Agulnik, Zinter, Sharron, Slaven, Kreml, Bajwa, Mahadeo, Moffet, Tarquinio and Steiner.)

Objective: The primary objective was to evaluate the efficacy of a weekly palliative care-guided, case-based discussion of high-risk infants on Neonatal Intensive Care Unit (NICU) physician (MD) and Advanced Practice Provider (APP) perceptions of pediatric palliative care (PPC). Study Design: The study setting was a level IV academic NICU in a United States midwestern children's hospital. A pre/post design was used to evaluate the effects of a weekly palliative care-guided, case-based discussion of high-risk infants on neonatology providers' (MD and APP) perspectives of palliative and end-of-life care in the NICU using a previously published survey instrument. Surveys were completed at baseline and after 12 months of implementation. Data was analyzed with a Wilcoxon Signed Rank test with significance set at p  < 0.05. Results: Thirty-one providers (13 APPs and 18 MDs) completed both pre- and post-intervention surveys. Post-intervention, providers were more likely to endorse that they "are comfortable with PPC", "feel comfortable teaching PPC to trainees", "feel confident handling end-of-life care", "have time to discuss PPC", and "were satisfied with the transition to end-of-life care for their most recent patient". They also were more likely to report, "families' perception of burden is relevant when making ethical decisions", that "parents are involved in decisions regarding palliative care", and that their "institution is supportive of palliative care." ( p -values < 0.05 for all). Conclusion: NICU provider perceptions of palliative care can be improved through the implementation of a case-based interdisciplinary conference that emphasizes palliative care domains in the context of Neonatal ICU care., Competing Interests: No competing financial interests exist., (© Jayme D. Allen et al., 2021; Published by Mary Ann Liebert, Inc.)

Background: High-flow nasal cannula (HFNC) therapy is a respiratory modality that has been adopted to support pediatric patients with bronchiolitis. There is no standardized protocol for initiation, escalation, or weaning of HFNC in the pediatric ICU. The aim of this respiratory therapist (RT)-driven quality improvement management protocol was to decrease duration of HFNC., Methods: An RT-driven HFNC management protocol based on an objective respiratory score was implemented in 2017 at a quaternary care children's hospital. Subjects included children less than 2 y old admitted to the pediatric ICU with bronchiolitis. All subjects needing HFNC were scored and placed within the protocol as appropriate for age, then weaned or escalated per the scoring tool. Comparison to a pre-intervention control group was performed. Average HFNC duration per subject was used as the primary outcome measure. Protocol compliance was used as a process measure. Noninvasive ventilation use, intubation rate, and 30-d pediatric ICU readmission rate were used as balancing measures. RT satisfaction with HFNC management before and after protocol implementation were measured., Results: Protocol compliance was sustainable and above the goal of 80% after 4 months of protocol implementation. HFNC duration decreased from 2.5 d to 2 days for each subject during planning and then to 1.8 d after protocol implementation. Length of stay (LOS) in the pediatric ICU and hospital LOS decreased from 2.6 d to 2.1 d and from 5.7 d to 4.7 d after protocol implementation, respectively. The use of noninvasive ventilation and the rate of intubation did not change significantly. RTs reported increased involvement in HFNC management decisions and appropriateness on how quickly the team weaned HFNC., Conclusions: An RT-driven HFNC management protocol was safely implemented in a pediatric ICU and decreased HFNC duration, pediatric ICU LOS, and hospital LOS. It allows the RT to work independently to the highest extent of their scope of practice, leading to improvement in RT job satisfaction., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2021 by Daedalus Enterprises.)

Background: Invasive mechanical ventilation is a lifesaving intervention that is associated with short- and long-term morbidities. Extubation readiness protocols aim to decrease extubation failure rates and simultaneously shorten the duration of invasive ventilation. This study sought to analyze extubation readiness practices at one institution and identify barriers to extubation in pediatric patients who have passed an extubation readiness test (ERT)., Methods: We performed a retrospective chart review of all pediatric subjects admitted between April 2017 and March 2018, and who were on mechanical ventilation. Exclusion criteria were cardiac ICU admission, tracheostomy, chronic ventilator support, limited resuscitation status, and death before extubation attempt. Data with regard to the method of ERT and reasons for delaying extubation were collected., Results: There were 427 subjects included in the analysis with 69% having had an ERT before extubation. Of those, 39% were extubated per our daily spontaneous breathing trial (SBT) protocol, and the daily SBT failed in 30% but they had passed a subsequent pressure support and CPAP trial on the same day. The most common reasons for failing the daily SBT were a lack of spontaneous breathing (30% [75/252]), being intubated < 24 h (24% [60/252]), breathing frequency outside the target range (22% [55/252]), and not meeting tidal volume goal (14% [34/252]). The most common documented reasons for delaying extubation despite passing daily SBT were planned procedure (29% [26/90]), neurologic status (23% [21/90]), and no leak around the endotracheal tube (18% [16/90]). The median time between passing ERT and extubation was 7 h (interquartile range, 5-10)., Conclusions: In our institution, there was variation in extubation readiness practices that could lead to a significant delay in liberation from invasive ventilation. Adjustment of our daily SBT to tolerate a higher work of breathing, such as higher breathing frequencies and lower tidal volumes, and incorporating sedation scoring into the protocol could be made without significantly affecting extubation failure rates., (Copyright © 2021 by Daedalus Enterprises.)

Children admitted to the pediatric intensive care unit (PICU) often require multiple medications to achieve comfort and sedation. Although starting doses are available, these medications are typically titrated to the desired effect. Both oversedation and undersedation are associated with adverse events. The aim of this retrospective study was to evaluate cumulative medication burden necessary to achieve comfort in patients in the PICU and determine relevant predictors of medication needs. In order to account for all of the sedative medications, z-scores were used to assess the population average dose of each medication and compare each patient day to this population average. Sedation regimens for 130 patients in the PICU were evaluated. Mean overall infusion rates of fentanyl, morphine, and hydromorphone were 1.67 ± 0.81 µg/kg/hour, 0.12 ± 0.08 mg/kg/hour, and 17.84 ± 13.4 µg/kg/hour, respectively. The mean infusion rate of dexmedetomidine was 0.59 ± 0.28 µg/kg/hour, and midazolam was 0.14 ± 0.1 mg/kg/hour. Summation z-sores were used to rank the amount of sedation medication needed to achieve comfort for each individual patient for his/her PICU stay in relation to the entire sample. Patient age, weight, and length of mechanical ventilation were all significant predictors of sedation requirement. This study will provide data necessary to develop a model of cumulative medication burden needed to achieve appropriate sedation in this population. This descriptive model in appropriately ranking patients based on sedative needs is the first step in exploring potential genetic factors that may provide an insight into homing in on the appropriate sedation regimen., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Mechanisms driving adaptive developmental responses to chronic high-altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and postnatal timeframe. We assessed lung growth and cardiopulmonary structure and function and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 ft elevation). Mating, pregnancy, and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNA-Seq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, and RV systolic pressure, as well as increased pulmonary artery remodeling. RNA-Seq analyses revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. Although there was considerable similarity between hypoxic lungs and RVs compared with RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune downregulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA.

Background: Depression is associated with an increased risk of cardiovascular disease in human immunodeficiency virus (HIV). We hypothesized that reducing depressive symptoms would improve HIV-related cardiovascular risk., Methods: We conducted a single-center, randomized (1:1), controlled, parallel-group, assessor-blinded, pilot trial comparing Beating the Blues US (BtB)-an evidence-based, 8-session, internet cognitive-behavioral therapy for depression-with usual care (UC) in HIV-positive participants receiving virologically suppressive antiretroviral therapy and with Patient Health Questionnaire (PHQ)-9 scores ≥10. The primary endpoint was change in brachial artery flow-mediated dilation (FMD) at 12 weeks. Secondary endpoints were FMD change at 24 weeks and inflammation, coagulation, and metabolic biomarker changes at 12 and 24 weeks., Results: Fifty-four participants were randomized (27 in each arm). Mean reductions in PHQ-9 scores were significantly greater with BtB versus UC at 12 weeks (-5.60 vs -1.52; P  = .007) and 24 weeks (-6.00 vs -1.38; P  = .008); reductions in the Hopkins Symptom Checklist Depression Scale-20 scores were also significantly greater with BtB versus UC at 24 weeks (-0.72 vs -0.35; P  = .029). Changes in FMD between arms were not significantly different at 12 or 24 weeks. Significantly larger reductions in soluble (s)CD14 and sCD163 with BtB versus UC were found at 12 and 24 weeks, respectively., Conclusions: Compared with UC, internet cognitive-behavioral therapy using BtB resulted in greater improvements in depressive symptoms and monocyte activation markers but did not improve FMD in this pilot trial. These data support performing larger studies to determine the potential salutatory effects of behavioral therapies for depression on HIV-related inflammation., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Many children with inflammatory bowel disease (IBD) are taking immunosuppressant medications that place them at risk for vaccine preventable diseases. Despite national guidelines, children with IBD have low vaccination rates. Adult data suggest that there is concern about the safety of vaccines. There are no current studies addressing perceived safety about vaccinations among families of children with IBD., Methods: A total of 108 caregivers of children (ages 10-25 years) were surveyed during their outpatient visit, with approximately half having a diagnosis of IBD. The survey consisted of validated questions regarding vaccine safety and opinions. After enrollment, state-wide vaccine registry data was collected. Demographics between the two groups were compared using Ch-square and the Wilcoxon rank-sum tests to analyze Likert scale questions., Results: The majority of children followed for IBD were Caucasian males, had Crohn's disease (68%) and were immunosuppressed. Results from the survey revealed a concern about vaccine safety (40% vs. 16%, p=0.03) and overall effectiveness (34% vs. 12%, p<0.01) in the IBD group compared to the non-IBD. Furthermore, more IBD families were worried that vaccines would worsen their child's symptoms (36% vs. 10%, p=<0.01). The majority of children were missing the flu and/or HPV vaccine. Finally, 96% of the children on a biologic for their IBD were missing the PPSV23 booster., Conclusions: Caregivers of children with IBD are more concerned about vaccine safety and effectiveness than those with non-IBD diagnosis. Despite being on immunosuppressant medications, many patients were missing recommended vaccines.

Objective: Understanding lung cancer screening behaviour is crucial to identifying potentially modifiable factors for future intervention. Qualititative work has explored attitudes and beliefs about lung cancer screening from the perspective of the participant, but the theoretically grounded factors that influence screening-eligible individuals to screen are unknown. We tested an explanatory framework for lung cancer screening participation from the individual's perspective., Methods: Data were collected as part of a sequential explanatory mixed methods study, the quantitative component of which is reported here. A national purposive sample of 515 screening-eligible participants in the United States was recruited using Facebook-targeted advertisement. Participants completed surveys assessing constructs of the Conceptual Model for Lung Cancer Screening Participation. Path analysis was used to assess the relationships between variables., Results: Path analyses revealed that a clinician recommendation to screen, higher self-efficacy scores, and lower mistrust scores were directly associated with screening participation (p < 0.05). However, the link between screening behaviour and self-efficacy appeared to be fully mediated by fatalism, lung cancer fear, lung cancer family history, knowledge of lung cancer risk and screening, income, clinician recommendation, and social influence (p < 0.05)., Conclusions: This study found that medical mistrust, self-efficacy, and clinician recommendation were significant in the decision of whether to screen for lung cancer. These findings offer insight into potentially modifiable targets most appropriate on which to intervene. This understanding is critical to design meaningful clinician- and patient-focused interventions.

Importance: An important aspect of high-quality care is ensuring that treatments are in alignment with patient or surrogate decision-maker goals. Treatment discordant with patient goals has been shown to increase medical costs and prolong end-of-life difficulties., Objectives: To evaluate discordance between surrogate decision-maker goals of care and medical orders and treatments provided to hospitalized, incapacitated older patients., Design, Setting, and Participants: This prospective cohort study included 363 patient-surrogate dyads. Patients were 65 years or older and faced at least 1 major medical decision in the medical and medical intensive care unit services in 3 tertiary care hospitals in an urban Midwestern area. Data were collected from April 27, 2012, through July 10, 2015, and analyzed from October 5, 2018, to December 5, 2019., Main Outcomes and Measures: Each surrogate's preferred goal of care was determined via interview during initial hospitalization and 6 to 8 weeks after discharge. Surrogates were asked to select the goal of care for the patient from 3 options: comfort-focused care, life-sustaining treatment, or an intermediate option. To assess discordance, the preferred goal of care as determined by the surrogate was compared with data from medical record review outlining the medical treatment received during the target hospitalization., Results: A total of 363 dyads consisting of patients (223 women [61.4%]; mean [SD] age, 81.8 [8.3] years) and their surrogates (257 women [70.8%]; mean [SD] age, 58.3 [11.2] years) were included in the analysis. One hundred sixty-nine patients (46.6%) received at least 1 medical treatment discordant from their surrogate's identified goals of care. The most common type of discordance involved full-code orders for patients with a goal of comfort (n = 41) or an intermediate option (n = 93). More frequent in-person contact between surrogate and patient (adjusted odds ratio [AOR], 0.43; 95% CI, 0.23-0.82), patient residence in an institution (AOR, 0.44; 95% CI, 0.23-0.82), and surrogate-rated quality of communication (AOR, 0.98; 95% CI, 0.96-0.99) were associated with lower discordance. Surrogate marital status (AOR for single vs married, 1.92; 95% CI, 1.01-3.66), number of family members involved in decisions (AOR for ≥2 vs 0-1, 1.84; 95% CI, 1.05-3.21), and religious affiliation (AOR for none vs any, 4.87; 95% CI, 1.12-21.09) were associated with higher discordance., Conclusions and Relevance: This study found that discordance between surrogate goals of care and medical treatments for hospitalized, incapacitated patients was common. Communication quality is a modifiable factor associated with discordance that may be an avenue for future interventions.

Background: When working with surrogate decision-makers, physicians often encounter ethical challenges that may cause moral distress which can have negative consequences for physicians., Objective: To determine frequency of and factors associated with physicians' moral distress caring for patients requiring a surrogate., Design: Prospective survey., Participants: Physicians (n = 154) caring for patients aged 65 years and older and their surrogate decision-makers (n = 362 patient/surrogate dyads). Patients were admitted to medicine or medical intensive care services, lacked decisional capacity and had an identified surrogate., Main Measures: Moral distress thermometer., Key Results: Physicians experienced moral distress in the care of 152 of 362 patients (42.0%). In analyses adjusted for physician, patient, and surrogate characteristics, physician/surrogate discordance in preferences for the plan of care was not significantly associated with moral distress. Physicians were more likely to experience moral distress when caring for older patients (1.06, 1.02-1.10), and facing a decision about life-sustaining treatment (3.58, 1.54-8.32). Physicians were less likely to experience moral distress when caring for patients residing in a nursing home (0.40, 0.23-0.69), patients who previously discussed care preferences (0.56, 0.35-0.90), and higher surrogate ratings of emotional support from clinicians (0.94, 0.89-0.99). Physicians' internal discordance when they prefer a more comfort-focused plan than the patient is receiving was associated with significantly higher moral distress (2.22, 1.33-3.70) after adjusting for patient, surrogate, and physician characteristics., Conclusions: Physician moral distress occurs more frequently when the physician is male, the patient is older or requires decisions about life-sustaining treatments. These findings may help target interventions to support physicians. Prior discussions about patient wishes is associated with lower distress and may be a target for patient-centered interventions.

Background: Patients with Alzheimer's disease and related dementias (ADRD) and traumatic brain injury (TBI) and their caregivers require cognitive and behavioral symptom management, interdisciplinary care, support for caregivers, and seamless care coordination between providers. Caring for someone with ADRD or TBI is associated with higher rates of psychological morbidity and burden, social isolation, financial hardship, and deterioration of physical health. Tremendous need exists for primary care-based interventions that concurrently address the care needs of dyads and aim to improve care and outcomes for both individuals with ADRD and TBI and their family caregivers., Methods: The Aging Brain Care Acquiring New Skills While Enhancing Remaining Strengths (ABC ANSWERS) study is a randomized controlled trial that tests the effectiveness of an intervention based on two evidence-based programs that have been developed for and previously tested in populations with ADRD, TBI, stroke, and late-life depression and/or who have survived an intensive care unit stay. This study includes 200 dyads comprised of a veteran with a diagnosis of ADRD or TBI and the veteran's primary informal caregiver. Dyads are randomized to receive the ABC ANSWERS intervention or routine Veterans Health Administration (VHA) primary care with a standardized educational and resource information packet. Data collection occurs at baseline and three follow-up time points (3 months, 6 months, and 12 months). The primary outcome is caregiver quality of life (QoL). A secondary measure for the caregiver is caregiver burden. Secondary measures for both the veteran and caregiver include symptoms of depression and anxiety., Discussion: The ABC ANSWERS intervention integrates common features of an evidence-based collaborative care model for brain health while concurrently attending to the implementation barriers of delivering care and skills to dyads. We hypothesize that caregivers in dyads randomized to the ABC ANSWERS program will experience higher levels of QoL and lower levels of depression, anxiety, dyadic strain, and caregiver burden at 12 months than those receiving usual VHA primary care., Trial Registration: ClinicalTrials.gov, NCT03397667. Registered on 12 January 2018.

Objective: To correlate the clinical severity of laryngomalacia (LM) with endoscopic findings, swallowing evaluations and polysomnography in a cohort of patients. Method: We conducted a retrospective analysis between 2017-2018 on a cohort of patients diagnosed with upper airway obstruction (UAO), stridor, noisy breathing or laryngomalacia. This study took place at the Pediatric Pulmonology Department, Riley Children's Hospital, Indianapolis, United States of America., Results:   There were 157 patients with laryngomalacia included in the study. Patients with severe LM were significantly younger than those with mild LM (p=0.0214) and moderate LM (p=0.0220). Subjects with type I of LM were significantly older than type III (p=0.0051). When associations were tested between polysomnogram (PSG) variables and clinical severity, there were significant associations with age at PSG. The overall apnea-hypopnea index (AHI) in mild (p=0.0103) and moderate (p=0.0242) were significantly lower than the severe group. The rapid eye movement (REM) AHI was significantly lower in moderate cases than severe (p=0.0134). The end-tidal carbon dioxide (EtCO2) peak was significantly lower in mild cases than severe (p=0.0141). The total sleep time (TST) peripheral capillary oxygen saturation (SpO2) 90% occurs in both mild (p=0.0197) and moderate (p=0.0498) were significantly lower than the severe group., Conclusions: The severity of the clinical manifestations of LM did not correlate with the different endoscopic types in our study. The presence of cyanosis was associated with type III LM. Rapid eye movement AHI and EtCO2 in polysomnogram were remained significantly associated with clinical severity.

Exposure to high-dose total body irradiation (TBI) can result in hematopoietic acute radiation syndrome (H-ARS), characterized by leukopenia, anemia, and coagulopathy. Death from H-ARS occurs from hematopoietic insufficiency and opportunistic infections. Following radiation exposure, red blood cells (RBCs) undergo hemolysis from radiation-induced hemoglobin denaturation, causing the release of iron. Free iron can have multiple detrimental biological effects, including suppression of hematopoiesis. We investigated the impact of radiation-induced iron release on the bone marrow following TBI and the potential impact of the ACE inhibitor captopril, which improves survival from H-ARS. C57BL/6J mice were exposed to 7.9 Gy, 60 Co irradiation, 0.6 Gy/min (LD 70-90/30 ). RBCs and reticulocytes were significantly reduced within 7 days of TBI, with the RBC nadir at 14-21 days. Iron accumulation in the bone marrow correlated with the time course of RBC hemolysis, with an ∼10-fold increase in bone marrow iron at 14-21 days post-irradiation, primarily within the cytoplasm of macrophages. Iron accumulation in the bone marrow was associated with increased expression of genes for iron binding and transport proteins, including transferrin, transferrin receptor 1, ferroportin, and integrin αMβ2. Expression of the gene encoding Nrf2, a transcription factor activated by oxidative stress, also increased at 21 days post-irradiation. Captopril did not alter iron accumulation in the bone marrow or expression of iron storage genes, but did suppress Nrf2 expression. Our study suggests that following TBI, iron is deposited in tissues not normally associated with iron storage, which may be a secondary mechanism of radiation-induced tissue injury., Competing Interests: Conflict of interest disclosure All authors confirm that there are no financial or nonfinancial conflicts of interest., (Published by Elsevier Inc.)

Background: Kidney transplant (KT) recipients have higher incidence of malignancies, including Human Papillomavirus (HPV)-associated cancers. Thus, HPV vaccines may have an important role in preventing HPV-related disease in this population; however, immunogenicity and safety data are lacking. Objective: To examine the immunological response and tolerability to HPV vaccination in pediatric KT recipients compared to future KT candidates. Methods: The quadrivalent HPV vaccine was administered to girls and boys age 9-18 recruited from seven centers part of the Pediatric Nephrology Research Consortium. Subjects were recruited for three groups: (1) CKD: chronic kidney disease stages 3, 4, and 5 not on dialysis; (2) Dialysis; (3) KT recipients. The outcome consisted of antibody concentrations against HPV 6, 11, 16, and 18. Geometric mean titers (GMTs) and seroconversion rates were compared. Vaccine tolerability was assessed. Results: Sixty-five participants were recruited: 18 in the CKD, 18 in the dialysis, and 29 into the KT groups. KT patients had significantly lower GMTs after vaccination for all serotypes. The percentages of subjects who reached seroconversion were overall lower for the KT group, reaching statistical significance for HPV 6, 11, and 18. Comparing immunosuppressed subjects (anyone taking immunosuppression medications, whether KT recipient or not) with the non-immunosuppressed participants, the former had significantly lower GMTs for all the HPV serotypes and lower seroconversion rates for HPV 6, 11, and 18. KT females had higher GMTs and seroconversion rates for certain serotypes. There were no adverse events in either group. Conclusions: HPV vaccine was well-tolerated in this population. Pediatric KT recipients had in general lower GMTs and seroconversion rates compared to their peers with CKD or on dialysis. Immunosuppression played a role in the lack of seroconversion. Our results emphasize the importance of advocating for HPV vaccination prior to KT and acknowledge its safety post transplantation. Future studies are needed to investigate the effect of a supplemental dose of HPV vaccine in KT recipients who do not seroconvert and to evaluate the long-term persistence of antibodies post-KT., (Copyright © 2020 Nailescu, Nelson, Verghese, Twombley, Chishti, Mills, Mahan, Slaven and Shew.)