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Abstract Background and aims Several non-invasive tests for detecting bladder cancer (BC) are commercially available and are based on detecting small panels of BC-associated mutations and/or methylation changes in urine DNA. However, it is not clear which type of biomarker is best, or if a combination of the two is needed. In this study we address this question by taking a 23-gene mutation panel (GALEAS™ Bladder, GB) and testing if adding a panel of methylation markers improves the sensitivity of BC detection. Methods Twenty-three methylation markers were assessed in urine DNA by bisulphite conversion, multiplex PCR, and next generation sequencing in 118 randomly selected haematuria patients with pre-existing GB data (56 BCs and 62 non-BCs), split into training and test sets. We also analysed an additional 16 GB false-negative urine DNAs. Results The methylation panel detected bladder cancer in haematuria patients with 69% sensitivity at 96% specificity (test set results, 95% CIs 52-87% and 80-99%, respectively). Corresponding sensitivity and specificity for GB were 92% and 89%. Methylation and mutation markers were highly concordant in urine, with all GB false-negative samples also negative for methylation markers. Conclusions and limitations Our data show that, with a comprehensive mutation panel, any gains from adding methylation markers are, at best, marginal. It is likely that low tumour content is the commonest cause of false-negative urine test results. Our study does have a limited sample size and other methylation markers might behave differently to the those studied here.

Research investigating social media use typically focus on late adolescents and young adults, despite a growing number of early adolescents, 93% to 97%--having at least one social media platform. Also, early adolescents are more likely to engage with newer sites, such as Snapchat and Instagram, than older platforms such as Facebook and Twitter. Given the evolving landscape of social media, the present study examines the impact of the use of various social media platforms, along with its moderating effects, on adolescents' academic achievement, using a sample of N = 1,459 early adolescents. Results were such that, as frequency of use on each platform: Facebook, Twitter, Instagram, and Snapchat increased, academic achievement decreased. Specific to interaction effects, frequent use of Facebook and Instagram and early adolescents' academic achievement were moderated by mother-adolescent communication; while gender moderated the association between frequent use of Twitter and Snapchat and early adolescents' academic achievement. Implications are discussed.

Should theoretical discourse supporting state crimes be protected as free speech or prosecuted as atrocity speech? The relationship between Neo-Hobbesian Nazi collaborator Carl Schmitt and progressive Futurology founder Ossip Flechtheim provides a fascinating framework for exploring that question. In 1933, Schmitt rejected Flechtheim as a PhD student, on antisemitic grounds. Meanwhile, becoming Nazism’s “Crown Jurist,” he helped force Jewish lawyers, including Flechtheim, into exile. Post-war, Flechtheim, now on the US Nuremberg prosecution staff, arrested Schmitt. Through Flechtheim’s experience, this article explores how Schmitt’s prosecution, within a contemplated “Propaganda and Education Case” (PEC), might have determined how to treat atrocity-complicit academic propagandists. It chronicles how the PEC/Schmitt case collapsed when Flechtheim’s investigation was curtailed due to resource constraints, equivocal precedent, and prosecutor Robert Kempner’s botched interrogations. Nonetheless, Flechtheim contributed to the Ministries Trial conviction of propagandist Otto Dietrich. The article concludes by juxtaposing that case with Schmitt’s near-prosecution to contemplate norms for charging theorists laying needed groundwork for atrocity, via sufficiently proximate speech, even absent direct incitement. Such an international justice future would mirror immediate post-Cold War intellectual developments, which vindicated Flechtheim’s vision, not Schmitt’s. Exploring this topic is timely, as Russian academic discourse has enabled/fueled Ukraine’s invasion and related atrocities.

Background: Buprenorphine maintenance treatment remains unavailable in most jails in the US. We provide data on a four-day rapid sublingual buprenorphine (SL-B) induction strategy followed by a weekly dose of extended-release injectable buprenorphine (XR-B) with incarcerated individuals with opioid use disorder (OUD) who were not opioid tolerant. Methods: Between October 2020 to April 2024, N = 65 individuals with an opioid use disorder in jails participating in a larger randomized, controlled trial received SL-B and XR-B prior to release. Primary outcomes included completing the proposed dose induction and any reported adverse events (AEs). Results: Sixty-five individuals received SL-B dose induction from our team’s medical staff, 53 (81.5 %) completed the four-day SL-B dose induction and received their first weekly XR‑B injection on day 5. Of the 65 individuals, 10 (15.38 %) participants reported AEs during the dosing period and/or in the week following the dosing period. All but one of the AEs were rated as mild. One participant experienced a serious adverse event in the week following dose induction. The study medical team determined that this was unlikely to be related to the intervention. Discussion: Overall, our study findings demonstrate the feasibility of implementing a four-day sublingual dose induction followed by a weekly XR-B injection with incarcerated individuals who are not opioid tolerant. This study provides important data to illustrate a dose induction strategy that might assist in reducing illicit diversion in jails, which is a main barrier to buprenorphine delivery cited by correctional administrators.

Fifty-five sugarcane genotypes from around the world were collected and evaluated for potential use as parental material in the USDA ARS Canal Point (CP) sugarcane breeding program in Florida, USA. The genotypes were planted in a trial with four check cultivars on organic soils with four replications, and data were collected for two years [i.e., plant cane (PC) and first ratoon (FR) crops] to assess sucrose-yield-related traits and the cane-yield-related traits in PC. Using a multivariate analysis, variation was observed in all cane—[i.e., stalk weight, stalk population and cane yield] and sugar-yield-related traits [i.e., Brix, Pol, sucrose content and commercial recoverable sucrose (CRS)]. The mean CRS content was greater in the FR crop than the PC crop. Significant variations were attributed to genotype (G), crop cycles (C) and G × C effects. Variations between crop cycles were highly significant for all sucrose yield components, which could complicate the downstream selection of genotypes for sucrose yield. Based on CRS content, genotypes could be grouped into six distinct clusters. Based on plant cane data, cane yield traits (stalk weight, stalk population and cane yield) were used to estimate the breeding values of parents. Of the 55 genotypes, 8 had significantly greater t-BLUP values for cane yield, along with CP 00-1101. Combined sucrose yield traits, (Brix, Pol and sucrose content) from the two crops were used to estimate the breeding values of parents. Of the 55 genotypes, 10 genotypes had significantly greater t-BLUP values for CRS, along with CP 00-1101, CP 96-1252 and CP 01-2390, and can be considered as elite parents in future breeding efforts. These results provide a foundation for the efficient integration of genetic diversity in developing commercial cultivars, with improved sucrose yields, into the CP sugarcane breeding program.

Abstract Background A previous phase IB/II study of nab‐paclitaxel + cisplatin + gemcitabine (NABPLAGEM) in 25 patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC) demonstrated favorable results. This phase II study was conducted to further evaluate the safety, efficacy, and impact on quality of life (QOL) of NABPLAGEM in a multi‐center setting. Methods Participants were ≥18 years; had measurable PDAC; Karnofsky performance status of ≥70%; life expectancy ≥12 weeks;

Abstract CAR-T therapy is a promising, novel treatment modality for B-cell malignancies and yet many patients relapse through a variety of means, including loss of CAR-T cells and antigen escape. To investigate leukemia-intrinsic CAR-T resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screens in an immunocompetent murine model of B-cell acute lymphoblastic leukemia (B-ALL) utilizing a modular guide RNA library. We identified IFNγR/JAK/STAT signaling and components of antigen processing and presentation pathway as key mediators of resistance to CAR-T therapy in vivo; intriguingly, loss of this pathway yielded the opposite effect in vitro (sensitized leukemia to CAR-T cells). Transcriptional characterization of this model demonstrated upregulation of these pathways in tumors relapsed after CAR-T treatment, and functional studies showed a surprising role for natural killer (NK) cells in engaging this resistance program. Finally, examination of data from B-ALL patients treated with CAR-T revealed an association between poor outcomes and increased expression of JAK/STAT and MHC-I in leukemia cells. Overall, our data identify an unexpected mechanism of resistance to CAR-T therapy in which tumor cell interaction with the in vivo tumor microenvironment, including NK cells, induces expression of an adaptive, therapy-induced, T-cell resistance program in tumor cells.

Red meat has been a critical part of human diets for millennia, providing a source of high-quality protein, micronutrients and essential fatty acids. However, as societies evolved and industrialisation reshaped our food systems, there has been a noticeable shift in meat-eating trends driven by concerns about the environmental impact of meat production and its potential risk to health. Yet, despite falling out of favour with some dietary experts and influencers, meat has an important role in a healthy diet and most adults still consume it. This article explores the nutritional value of red meat, authorised nutrition and health claims, how red meat fits into diet, providing the example of the United Kingdom (UK), and the health benefits and risks associated with both eating and avoiding red meat. Benefits of red meat include nutrient density and bioavailability while risks include colorectal cancer at high intakes of processed meats, based on observational studies. Benefits of meat-free diets include a lower risk of chronic diseases, based on observational studies, while risks include nutrient inadequacy, higher bone fracture risk and low protein quality. Hence, a wholesale shift to plant-based diets may not benefit adults who are vulnerable to sub-optimal nutrient intakes, such as women of child-bearing age and the elderly. More evidence from randomised controlled trials is recommended to fully understand the benefits and risks of both meat-containing and meat-free diets.

Abstract The objective of this case report is to describe the use of extracorporeal therapy, specifically hemodialfiltration, for the treatment of caffeine intoxication. A 12 year old Border Terrier consumed up to 1440 mg/kg of caffeine and rapidly developed clinical signs of tachycardia and tremors. Hemodiafiltration was instituted, using an M60 PrismaFlex cartridge using blood to prime the system due to patient size. Treatment with 11.25 L of therapy fluid (83% dialysate, 17% replacement fluid), or 1.8 L/kg, was provided over 6 h. Pre‐treatment serum caffeine concentration of 233 µg/mL was decreased by 89% to 25 µg/nL by the end of treatment. Despite prompt institution of extracorporeal toxin removal therapy, ventricular ectopy developed necessitating sotolol treatment for the following week. Caffeine is efficiently removed via hemodialysis, as predicted by small size, small volume of distribution, and minimal protein binding. A CRRT platform can be used to provide adequate clearance.

Abstract Background Hypertensive disorders during pregnancy continue to increase in prevalence and are associated with several adverse outcomes and future cardiovascular risk for mothers. This study evaluated the association of hypertensive disorders compared to no hypertension during pregnancy with neonatal and maternal outcomes. We then evaluated risk factors associated with progression from a less to more severe hypertensive disorder during pregnancy. Methods We conducted a propensity-matched retrospective cohort study utilizing Medicaid claims data from a national insurer. The study population consisted of mothers with and without hypertensive disorders who delivered between 7/1/2016–12/31/2018 and their infants. Hypertensive disorders included gestational hypertension, chronic hypertension, preeclampsia, and superimposed preeclampsia. Propensity score matching was used to match mothers without to those with hypertensive disorders. Regression models were used to compare maternal and neonatal outcomes. Stepwise logistic regression was used to determine characteristics associated with the progression of gestational hypertension to preeclampsia or chronic hypertension to superimposed preeclampsia. Results We observed the highest risk of cesarean delivery (odds ratio [OR]:1.61 and 1.99) in mothers and preterm delivery (OR:2.22 and 5.37), respiratory distress syndrome (OR:2.39 and 4.19), and low birthweight (OR:3.64 and 9.61) in babies born to mothers with preeclampsia or superimposed preeclampsia compared to no hypertension, respectively (p

Abstract Objective Bariatric procedures have become safer in recent years, warranting new data on long‐term costs. This study examined the impact of bariatric procedures on a person's long‐term healthcare costs up to 10 years and if it differed by socio‐economic status (SES). Methods This retrospective observational study compared the downstream health care cost of patients with obesity who had undergone bariatric surgery (BS) between 2009 and 2018 to a 1:1 matched group of members with obesity but no surgery. Results 167,764 individuals from administrative claims data with an obesity diagnosis were included; 83,882 in the BS group and 83,882 in the non‐surgical group. In follow‐up years 2–10, the BS group was associated with lower total medical healthcare cost compared to the non‐surgical group (cost ratios ranged 0.85–0.93, p values 0.05). Conclusions BS was associated with lower long‐term follow‐up medical cost and cost savings appeared similar among the SES quartiles in the BS group. The study results may help policy makers and employers in designing benefits and extending coverage for bariatric surgical procedures.

BackgroundMany emerging adults (EAs) are prone to making unhealthy choices, which increase their risk of premature cancer morbidity and mortality. In the era of social media, rigorous research on interventions to promote health behaviors for cancer risk reduction among EAs delivered over social media is limited. Cancer prevention information and recommendations may reach EAs more effectively over social media than in settings such as health care, schools, and workplaces, particularly for EAs residing in rural areas. ObjectiveThis pragmatic randomized trial aims to evaluate a multirisk factor intervention using a social media campaign designed with community advisers aimed at decreasing cancer risk factors among EAs. The trial will target EAs from diverse backgrounds living in rural counties in the Four Corners states of Arizona, Colorado, New Mexico, and Utah. MethodsWe will recruit a sample of EAs (n=1000) aged 18 to 26 years residing in rural counties (Rural-Urban Continuum Codes 4 to 9) in the Four Corners states from the Qualtrics’ research panel and enroll them in a randomized stepped-wedge, quasi-experimental design. The inclusion criteria include English proficiency and regular social media engagement. A social media intervention will promote guideline-related goals for increased physical activity, healthy eating, and human papillomavirus vaccination and reduced nicotine product use, alcohol intake, and solar UV radiation exposure. Campaign posts will cover digital and media literacy skills, responses to misinformation, communication with family and friends, and referral to community resources. The intervention will be delivered over 12 months in Facebook private groups and will be guided by advisory groups of community stakeholders and EAs and focus groups with EAs. The EAs will complete assessments at baseline and at 12, 26, 39, 52, and 104 weeks after randomization. Assessments will measure 6 cancer risk behaviors, theoretical mediators, and participants’ engagement with the social media campaign. ResultsThe trial is in its start-up phase. It is being led by a steering committee. Team members are working in 3 subcommittees to optimize community engagement, the social media intervention, and the measures to be used. The Stakeholder Organization Advisory Board and Emerging Adult Advisory Board were formed and provided initial input on the priority of cancer risk factors to target, social media use by EAs, and community resources available. A framework for the social media campaign with topics, format, and theoretical mediators has been created, along with protocols for campaign management. ConclusionsSocial media can be used as a platform to counter misinformation and improve reliable health information to promote health behaviors that reduce cancer risks among EAs. Because of the popularity of web-based information sources among EAs, an innovative, multirisk factor intervention using a social media campaign has the potential to reduce their cancer risk behaviors. Trial RegistrationClinicalTrials.gov NCT05618158; https://classic.clinicaltrials.gov/ct2/show/NCT05618158 International Registered Report Identifier (IRRID)PRR1-10.2196/50392

In this study, we examined the impact of the number and type of arterial grafts, and surgical dressing type, on deep and organ/space surgical site infection following coronary artery bypass graft procedures. Bilateral internal mammary artery grafts and negative pressure wound therapy were associated with higher odds of infection.

Summary: Background: Hypoglycaemia from diabetes treatment causes morbidity and lower quality of life, and prevention should be routinely addressed in clinical visits. Methods: This mixed methods study evaluated how primary care providers (PCPs) assess for and prevent hypoglycaemia by analyzing audio-recorded visits from five Veterans Affairs medical centres in the US. Two investigators independently coded visit dialogue to classify discussions of hypoglycaemia history, anticipatory guidance, and adjustments to hypoglycaemia-causing medications according to diabetes guidelines. Findings: There were 242 patients (one PCP visit per patient) and 49 PCPs. Two thirds of patients were treated with insulin and 40% with sulfonylureas. Hypoglycaemia history was discussed in 78/242 visits (32%). PCPs provided hypoglycaemia anticipatory guidance in 50 visits (21%) that focused on holding diabetes medications while fasting and carrying glucose tabs; avoiding driving and glucagon were not discussed. Hypoglycaemia-causing medications were de-intensified or adjusted more often (p

Abstract Background Morning report is a core educational activity in internal medicine resident education. Attending physicians regularly participate in morning report and influence the learning environment, though no previous study has described the contribution of attending physicians to this conference. This study aims to describe attending comments at internal medicine morning reports. Methods We conducted a prospective, observational study of morning reports conducted at 13 internal medicine residency programs between September 1, 2020, and March 30, 2021. Each attending comment was described including its duration, whether the comment was teaching or non-teaching, teaching topic, and field of practice of the commenter. We also recorded morning report-related variables including number of learners, report format, program director participation, and whether report was scripted (facilitator has advance knowledge of the case). A regression model was developed to describe variables associated with the number of attending comments per report. Results There were 2,344 attending comments during 250 conferences. The median number of attendings present was 3 (IQR, 2–5). The number of comments per report ranged across different sites from 3.9 to 16.8 with a mean of 9.4 comments/report (SD, 7.4). 66% of comments were shorter than one minute in duration and 73% were categorized as teaching by observers. The most common subjects of teaching comments were differential diagnosis, management, and testing. Report duration, number of general internists, unscripted reports, and in-person format were associated with significantly increased number of attending comments. Conclusions Attending comments in morning report were generally brief, focused on clinical teaching, and covered a wide range of topics. There were substantial differences between programs in terms of the number of comments and their duration which likely affects the local learning environment. Morning report stakeholders that are interested in increasing attending involvement in morning report should consider employing in-person and unscripted reports. Additional studies are needed to explore best practice models of attending participation in morning report.

Abstract Mutations at specific hotspots in non-coding regions of ADGRG6, PLEKHS1, WDR74, TBC1D12 and LEPROTL1 frequently occur in bladder cancer (BC). These mutations could function as biomarkers for the non-invasive detection of BC but this remains largely unexplored. Massively-parallel sequencing of non-coding hotspots was applied to 884 urine cell pellet DNAs: 591 from haematuria clinic patients (165 BCs, 426 non-BCs) and 293 from non-muscle invasive BC surveillance patients (29 with recurrence). Urine samples from 142 non-BC haematuria clinic patients were used to optimise variant calling. Non-coding mutations are readily detectable in the urine of BC patients and undetectable, or present at much lower frequencies, in the absence of BC. The mutations can be used to detect incident BC with 66% sensitivity (95% CI 58–75) at 92% specificity (95% CI 88–95) and recurrent disease with 55% sensitivity (95% CI 36–74) at 85% specificity (95% CI 80–89%) using a 2% variant allele frequency threshold. In the NMIBC surveillance setting, the detection of non-coding mutations in urine in the absence of clinically detectable disease was associated with an increased relative risk of future recurrence (RR = 4.62 (95% CI 3.75–5.48)). As urinary biomarkers, non-coding hotspot mutations behave similarly to driver mutations in BC-associated genes and could be included in biomarker panels for BC detection.

BackgroundTobacco use continues to be a leading preventable cause of death and disease in the United States, accounting for >480,000 deaths each year. Although treatments for tobacco use are effective for many, there is substantial variability in outcomes, and these approaches are not effective for all individuals seeking to quit smoking cigarettes. New, effective therapeutic approaches are needed to meet the preferences of people who want to stop smoking. Guided imagery (GI) is a mind-body technique that involves the guided visualization of specific mental images, which is enhanced with other sensory modalities and emotions. Preliminary evidence provides initial support for the use of GI as a treatment for cigarette smoking. Meta-analyses have shown that standard treatment for cigarette smoking delivered over the telephone via quitlines is effective. A telephone-based intervention that uses GI might provide another effective treatment option and increase the reach and effectiveness of quitlines. ObjectiveThis study aims to test the efficacy of Be Smoke Free, a telephone-delivered GI treatment for smoking cessation. MethodsThis multisite randomized clinical trial (RCT) will compare a novel telephone-delivered GI tobacco cessation treatment with a standard evidence-based behavioral treatment. The study will be conducted over 5 years. In phase 1, we refined protocols and procedures for the New York State and West Virginia sites for use in the RCT. During phase 2, we will conduct an RCT with 1200 participants: 600 (50%) recruited via quitlines and 600 (50%) recruited via population-based methods. Participants will be randomly assigned to either the GI condition or the behavioral condition; both treatments will be delivered by trained study coaches located at the University of Arizona. Assessments will be conducted at baseline and 3 and 6 months after enrollment by University of Arizona research staff. The primary outcome will be self-reported 30-day point prevalence abstinence 6 months after enrollment. Secondary outcomes include biochemically verified 7-day point prevalence abstinence 6 months after enrollment. ResultsRecruitment in West Virginia and New York began in October 2022. As of March 31, 2023, a total of 242 participants had been enrolled. Follow-up assessments began in November 2022. As of March 31, 2023, of the 118 eligible participants, 97 (82.2%) had completed the 3-month assessment, and 93% (26/28) of eligible participants had completed the 6-month assessment. Biochemical verification and qualitative interviews began in April 2023. Recruitment will continue through 2025 and follow-up assessments through 2026. Primary results are expected to be published in 2027. ConclusionsThe Be Smoke Free study is a first-of-its-kind RCT that incorporates GI into telephone-based tobacco cessation treatment. If successful, Be Smoke Free will have substantial benefits for the long-term health of people who use tobacco across the United States. Trial RegistrationClinicalTrials.gov NCT05277831; https://clinicaltrials.gov/ct2/show/NCT05277831 International Registered Report Identifier (IRRID)PRR1-10.2196/48898

Background: Almost eight million Americans suffer from Posttraumatic Stress Disorder (PTSD). Current PTSD drug therapies rely on repurposed antidepressants and anxiolytics, which produce undesirable side effects and have recognized compliance issues. Vasopressin represents a promising and novel target for pharmacological intervention. Logistical issues implementing a clinical trial for a novel PTSD pharmaceutical are relatively uncharted territory as trials concerning a new agent have not been published in the past several decades. All published trials have repurposed FDA-approved psychoactive medications with known risk profiles. Our recruitment challenges are discussed in this context. Methods: An 18-week proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist (SRX246) for PTSD was conducted. All participants received SRX246 for 8 weeks, the placebo for 8 weeks, and the drug vs. placebo arms were compared. Participants were assessed every 2 weeks for PTSD symptoms as well as other medication effects. Results were expected to provide an initial demonstration of safety and tolerability in this clinical population and potentially clinical efficacy in SRX246-treated patients measured by Clinician Administered PTSD Scale (CAPS) score changes, clinical impression, and other indices compared to placebo. The primary hypothesis was that SRX246 would result in a clinically meaningful 10-point reduction in mean CAPS score compared to placebo. Discussion: This study is the first to investigate an oral vasopressin 1a receptor antagonist for PTSD. As a wave of PTSD clinical trials with new pharmaceutical compounds are beginning now, lessons learned from our recruitment challenges may be invaluable to these endeavors.

We present SCUBA-2/POL-2 850 μ m polarimetric observations of the circumstellar envelope (CSE) of the carbon-rich asymptotic giant branch (AGB) star IRC+10216. Both far-IR (FIR) and optical polarization data indicate grains aligned with their long axis in the radial direction relative to the central star. The 850 μ m polarization does not show this simple structure. The 850 μ m data are indicative, albeit not conclusive, of a magnetic dipole geometry. Assuming such a simple dipole geometry, the resulting 850 μ m polarization geometry is consistent with both Zeeman observations and small-scale structure in the CSE. While there is significant spectral-line polarization contained within the SCUBA-2 850 μ m passband for the source, it is unlikely that our broadband polarization results are dominated by line polarization. To explain the required grain alignment, grain mineralogy effects, due to either fossil silicate grains from the earlier oxygen-rich AGB phase of the star or due to the incorporation of ferromagnetic inclusions in the largest grains, may play a role. We argue that the most likely explanation is due to a new alignment mechanism wherein a charged grain, moving relative to the magnetic field, precesses around the induced electric field and therefore aligns with the magnetic field. This mechanism is particularly attractive as the optical, FIR, and submillimeter-wave polarization of the carbon dust can then be explained in a consistent way, differing simply due to the charge state of the grains.

Abstract Blinding in non-invasive brain stimulation research is a topic of intense debate, especially regarding the efficacy of sham-controlled methods for transcranial direct current stimulation (tDCS). A common approach to assess blinding success is the inclusion of correct guess rate. However, this method cannot provide insight into the effect of unblinding on observed stimulation outcomes. Thus, the implementation of measures to systematically evaluate subjective expectation regarding stimulation is needed. Previous work evaluated subjective effects in an earlier study which reported a mind-wandering and tDCS data set and concluded that subjective belief drove the pattern of results observed. Here we consider the subjective and objective intervention effects in a key contrast from that data set—2 mA vs. sham—which was not examined in the reanalysis. In addition, we examine another key contrast from a different tDCS mind-wandering study that employed similar methodology. Our findings support objective intervention as the strongest predictor of the observed effects of mind-wandering in both re-analyses, over and above that of subjective intervention. However, it is important to control for and understand the possible inadequacies of sham-controlled methods.

Abstract Background Three-quarters of bladder cancer patients present with early-stage disease (non-muscle-invasive bladder cancer, NMIBC, UICC TNM stages Ta, T1 and Tis); however, most next-generation sequencing studies to date have concentrated on later-stage disease (muscle-invasive BC, stages T2+). We used exome and transcriptome sequencing to comprehensively characterise NMIBCs of all grades and stages to identify prognostic genes and pathways that could facilitate treatment decisions. Tumour grading is based upon microscopy and cellular appearances (grade 1 BCs are less aggressive, and grade 3 BCs are most aggressive), and we chose to also focus on the most clinically complex NMIBC subgroup, those patients with grade 3 pathological stage T1 (G3 pT1) disease. Methods Whole-exome and RNA sequencing were performed in total on 96 primary NMIBCs including 22 G1 pTa, 14 G3 pTa and 53 G3 pT1s, with both exome and RNA sequencing data generated from 75 of these individual samples. Associations between genomic alterations, expression profiles and progression-free survival (PFS) were investigated. Results NMIBCs clustered into 3 expression subtypes with different somatic alteration characteristics. Amplifications of ARNT and ERBB2 were significant indicators of worse PFS across all NMIBCs. High APOBEC mutagenesis and high tumour mutation burden were both potential indicators of better PFS in G3pT1 NMIBCs. The expression of individual genes was not prognostic in BCG-treated G3pT1 NMIBCs; however, downregulated interferon-alpha and gamma response pathways were significantly associated with worse PFS (adjusted p-value < 0.005). Conclusions Multi-omic data may facilitate better prognostication and selection of therapeutic interventions in patients with G3pT1 NMIBC. These findings demonstrate the potential for improving the management of high-risk NMIBC patients and warrant further prospective validation.

Background: Mutations in STAG2 cause complete loss of STAG2 protein in approximately one-third of non–muscle-invasive bladder cancers (NMIBCs). STAG2 protein expression is easily determined via immunohistochemistry (IHC) and published data suggest that loss of STAG2 expression is a good prognostic indicator in NMIBC. Objective: To confirm the relationship between STAG2 protein expression and clinical outcomes and tumour characteristics in NMIBC. Design, setting, and participants: IHC was used to determine STAG2 expression in 748 incident urothelial bladder cancers (UBCs) and recurrence-free, progression-free, and disease-specific survival were compared for patients with and without STAG2 loss. Exome and RNA sequencing were used to explore links between STAG2 loss and tumour molecular characteristics. Results and limitations: STAG2 loss was observed in 19% of UBC patients and was 1.6-fold more common among female patients. Loss was frequent among grade 1 pTa tumours (40%), decreasing with stage and grade to only 5% among grade 3 pT2+ tumours. Loss was associated with fewer copy-number changes and less aggressive expression subtypes. In UBC, STAG2 loss was a highly significant prognostic indicator of better disease-free survival but was not independent of stage and grade. STAG2 loss was not a statistically significant predictor of NMIBC recurrence. STAG2 loss was significantly associated with better progression-free survival in NMIBC and appeared to be more prognostic for males than for females. Conclusions: A simple IHC-based STAG2 test shows promise for identifying NMIBC patients at lower risk of progression to MIBC for whom more conservative treatments may be suitable. Patient summary: A protein called STAG2 is frequently lost in early bladder cancers, most often in less aggressive tumours. STAG2 loss is easily measured and could be used as a biomarker to help guide treatment decisions.

Abstract Background While several safe and effective COVID-19 vaccines have been available since December 2020, many eligible individuals choose to remain unvaccinated. This vaccine hesitancy is an important factor affecting our ability to combat the COVID-19 pandemic. Methods The objective of the study was to examine the attitudes and willingness among US Veterans toward receiving COVID-19 vaccination. The study used a quantitative qualitative mixed methods design with a telephone survey and then in-depth interviews in a subset of those surveyed. Participants were unvaccinated Veterans (N = 184) selected randomly from a registry of patients who had received VA healthcare during the pandemic and had a diagnostic test for COVID-19. The primary outcome was willingness to accept COVID-19 vaccination. Survey data collection and in-depth interviews were conducted by telephone. Analyses of the survey data compared the primary outcome with demographics, clinical data, and survey responses using bivariate and multiple regression analyses. A subset (N = 10) of those surveyed, participated in an in-depth interview. Interview transcripts were analyzed to derive themes using qualitative content analysis. Results Almost 40% of participants disagreed they would receive a COVID-19 vaccine. Participants who were younger, female, and had fewer comorbid conditions were more likely (P

Abstract Background Pediatric emergency department (PED) and urgent care (UC) professionals can play a key role in delivering evidence-based guidelines to address parental tobacco use and child tobacco smoke exposure (TSE). Understanding PED/UC professionals’ perceptions regarding these guidelines is the first step in developing and implementing a TSE screening and counseling intervention in these settings. This study aimed to use the theoretical domains framework (TDF) to identify current screening and counseling behaviors of PED/UC professionals related to parental tobacco use and child TSE, and determine barriers and enablers that influence these behaviors. Methods Semi-structured, focused interviews were conducted with 29 actively practicing PED/UC clinical staff who worked at one large, Midwestern children’s hospital. The interview guide was informed by the TDF and included open-ended questions. Content analysis of interview transcripts was guided by the TDF. Nurses, physicians, and healthcare administrators were assessed overall and by group membership to ensure each group was represented based on their varying PED/UC roles. Results Fifty-one percent were nurses, 38% were physicians, and 11% were healthcare administrators. Most PED/UC professionals did not currently follow the guidelines, but perceived addressing parental tobacco use as part of their role. All 14 TDF domains were identified by nurses, physicians, and administrators in relation to counseling for parental tobacco use and child TSE. Domains with the most sub-themes were (1) knowledge: lack of knowledge about tobacco counseling, including implementing counseling, cessation resources/referrals, and thirdhand smoke; (2) beliefs about capabilities: not comfortable counseling parents, easier to discuss with parents who are receptive and to ask and advise when patients have a TSE-related complaint, and more likely to discuss if there were resources/referrals; and (3) environmental context and resources: barriers include lack of time, training, and resources and referral information to give to parents, and an enabler is using TSE-related complaints as a context to offer counseling. Conclusions Study findings provide a strong foundation for developing and implementing clinical practice guidelines regarding parental tobacco use and child TSE in the PED/UC setting. Future intervention development will address all TDF domains and test the implementation of the intervention in the PED/UC setting.

Introduction/Objectives: In 2018, a Medicaid managed care plan launched a new community health worker (CHW) initiative in several counties within a state, designed to improve the health and quality of life of members who could benefit from additional services. The CHW program involved telephonic and face-to-face visits from CHWs who provided support, empowerment, and education to members, while identifying and addressing health and social issues. The primary objective of this study was to evaluate the impact of a generalized (not disease-specific), health plan-led CHW program on overall healthcare use and spending. Methods: This retrospective cohort study used data from adult members who received the CHW intervention (N = 538 participants) compared to those who were identified for participation but were unable to be reached (N = 435 nonparticipants). Outcomes measures included healthcare utilization, including scheduled and emergency inpatient admissions, emergency department (ED) visits, and outpatient visits; and healthcare spending. The follow-up period for all outcome measures was 6 months. Using generalized linear models, 6-month change scores were regressed on baseline characteristics to adjust for between-group differences (eg, age, sex, comorbidities) and an indicator for group. Results: Program participants experienced a greater increase in outpatient evaluation and management visits (0.09 per member per month [PMPM]) than the comparison group during the first 6 months of the program. This greater increase was observed across in-person (0.07 PMPM), telehealth (0.03 PMPM), and primary care (0.06 PMPM) visits. There was no observed difference in inpatient admissions, ED utilization or allowed medical spending and pharmacy spending. Conclusions: A health plan-led CHW program successfully increased multiple forms of outpatient utilization in a historically disadvantaged population of patients. Health plans may be particularly well positioned to finance, sustain, and scale programs that address social drivers of health.

This project surveyed Veterans’ COVID-19 vaccination beliefs and status. 1,080 (30.8%) Veterans responded. Factors associated with being unvaccinated, identified using binomial logistic regression, included negative feelings about vaccines (OR = 3.88, 95%CI = 1.52, 9.90) and logistical difficulties such as finding transportation (OR = 1.95, 95%CI = 1.01, 3.45). This highlights the need for education about and access to vaccination.

Introduction: Little is known about the effectiveness of immunotherapy alone or with chemotherapy for patients with non-small cell lung cancer (NSCLC) and programmed death ligand 1 (PD-L1) expression

The iron-regulatory hormone hepcidin is transcriptionally up-regulated by gluconeogenic signals. Recent evidence suggeststhat increases in circulating hepcidin may decrease dietary iron absorption following prolonged exercise, however evidence is limited on whether gluconeogenic signals contribute to post-exercise increases in hepcidin. Mice with genetic knockout of regulated in development and DNA response-1 (REDD1) display greater glycogen depletion following exercise, possibly indicating greater gluconeogenesis. The objective of the present study was to determine liver hepcidin, markers of gluconeogenesis and iron metabolism in REDD1 knockout and wild-type mice following prolonged exercise. Twelve-week-old male REDD1 knockout and wild-type mice were randomised to rest or 60 min treadmill running with 1, 3 or 6 h recovery (n = 5–8/genotype/group). Liver gene expression of hepcidin (Hamp) and gluconeogenic enzymes (Ppargc1a, Creb3l3, Pck1, Pygl) were determined by qRT-PCR. Effects of genotype, exercise and their interaction were assessed by two-way ANOVAs with Tukey's post-hoc tests, and Pearson correlations were used to assess the relationships between Hamp and study outcomes. Liver Hamp increased 1- and 4-fold at 3 and 6 h post-exercise, compared to rest (P-adjusted < 0⋅009 for all), and was 50% greater in REDD1 knockout compared to wild-type mice (P = 0⋅0015). Liver Ppargc1a, Creb3l3 and Pck1 increased with treadmill running (P < 0⋅0001 for all), and liver Ppargc1a, Pck1 and Pygl were greater with REDD1 deletion (P < 0⋅02 for all). Liver Hamp was positively correlated with liver Creb3l3 (R = 0⋅62, P < 0⋅0001) and Pck1 (R = 0⋅44, P = 0⋅0014). In conclusion, REDD1 deletion and prolonged treadmill running increased liver Hamp and gluconeogenic regulators of Hamp, suggesting gluconeogenic signalling of hepcidin with prolonged exercise.

Translational research should examine racism and bias and improve health equity. We designed and implemented a course for the Master of Science in Clinical Investigation program of the Northwestern University Clinical and Translational Sciences Institute. We describe curriculum development, content, outcomes, and revisions involving 36 students in 2 years of “Anti-Racist Strategies for Clinical and Translational Science.” Ninety-six percent of students reported they would recommend the course. Many reported changes in research approaches based on course content. A course designed to teach anti-racist research design is feasible and has a positive short-term impact on learners.

Objective: To test an intervention designed to improve patient engagement in telehealth visits by encouraging patients to use active communication behaviors. Methods: US Veterans with type 2 diabetes mellitus receiving primary care using telehealth were randomized 1:1 to receive both a pre-visit educational video and pamphlet (intervention) or pamphlet alone (control) prior to their scheduled telehealth visit. Data were collected before and after the intervention from the medical record and at telephone interviews (questionnaires). Analyses compared the intervention and control groups using bivariate statistics and multiple regression. Results: There were no statistically significant differences in baseline Hemoglobin A1c (HbA1c) between intervention and control groups (P > 0.05). Patient's ratings of physicians' communication and post-visit empathy were higher (P ≤ 0.05) in the intervention group than control group and after adjusting for baseline values the intervention group reported higher scores on post-visit therapeutic alliance with the provider and higher patient engagement, compared with the control group, P = 0.01 and P = 0.04, respectively, but post-visit HbA1c was not statistically different. Conclusions: The educational video was useful as pre-visit preparation for patients prior to a primary care telehealth visit. Innovation: This study showed the efficacy of a pre-visit video to improve patient engagement and therapeutic alliance after telehealth visits.ClinicalTrials.gov Identifier: NCT02522494

Abstract Background Mind-Body Skills Groups (MBSGs) have shown promise in reducing adolescent depression symptoms; however, little is known about adolescents’ perspectives on this treatment. The objective of this study was to understand the acceptability of a new treatment for depressed adolescents in primary care settings. Methods Adolescents participating in a 10-week MBSG treatment were interviewed to understand their perspectives on the acceptability and effectiveness of the treatment. Interviews were collected at post-intervention and at a 3-month follow-up visit. Results A total of 39 adolescents completed both the post-intervention and 3-month follow-up interview. At post-intervention and follow-up, 84% of adolescents stated the MBSGs helped them. When asked how the MBSGs helped them, 3 areas were identified: learning new MBSG activities and skills, social connection with others within the group, and outcomes related to the group. Many adolescents reported no concerns with the MBSGs (49% at post- intervention; 62% at follow-up). Those with concerns identified certain activities as not being useful, wanting the group to be longer, and the time of group (after school) being inconvenient. Most adolescents reported that their life had changed because of the group (72% at post-intervention; 61% at follow-up), and when asked how, common responses included feeling less isolated and more hopeful. Conclusions Adolescents found the MBSGs to be helpful and acceptable as a treatment option for depression in primary care. Given the strong emphasis on treatment preference autonomy and the social activities within the group, MBSGs appear well-suited for this age group. Trial registration NCT03363750 ; December 6th, 2017.