Engineering CREB-activated promoters for adenosine-induced gene expression.

Accumulation of the ribonucleoside, adenosine (ADO), triggers a cAMP response element binding protein (CREB)-mediated signaling pathway to suppress the function of immune cells in tumors. Here, we describe a collection of CREB-activated promoters that allow for strong and tunable ADO-induced gene expression in human cells. By optimizing number of CREB transcription factor binding sites and altering the core promoter region of CREB-based hybrid promoters, we created synthetic constructs that drive gene expression to higher levels than strong, endogenous mammalian promoters in the presence of ADO. These synthetic promoters are induced up to 47-fold by ADO, with minimal expression in their "off" state. We further determine that our CREB-based promoters are activated by other compounds that act as signaling analogs, and that combinatorial addition of ADO and these compounds has a synergistic impact on gene expression. Surprisingly, we also detail how background ADO degradation caused by the common cell culture media additive, fetal bovine serum (FBS), confounds experiments designed to determine ADO dose-responsiveness. We show that only after long-term heat deactivation of FBS can our synthetic promoters enable gene expression induction at physiologically relevant levels of ADO. Finally, we demonstrate that the strength of a CREB-based promoter is enhanced by incorporating other transcription factor binding sites.

Congenital Vertebral Malformation in a Neonatal Elk (Cervus canadensis) in Kentucky, USA.

We captured a <1-d-old male elk calf (Cervus canadensis) with a shortened neck. Postmortem examination revealed trauma, meconium aspiration syndrome, and cervical vertebral malformation (partial fusion and narrowed disc spaces). This observation is novel in a wild elk calf, although the gross lesions resembled complex vertebral malformation in neonatal cattle.

How Safe Is Cancer Care?

Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.

Sphinganine is associated with 24-h MAP in the non-sleepy with OSA.

INTRODUCTION: Excessive daytime sleepiness is a debilitating symptom of obstructive sleep apnea (OSA) linked to cardiovascular disease, and metabolomic mechanisms underlying this relationship remain unknown. We examine whether metabolites from inflammatory and oxidative stress-related pathways that were identified in our prior work could be involved in connecting the two phenomena. METHODS: This study included 57 sleepy (Epworth Sleepiness Scale (ESS) ≥ 10) and 37 non-sleepy (ESS < 10) participants newly diagnosed and untreated for OSA that completed an overnight in-lab or at home sleep study who were recruited from the Emory Mechanisms of Sleepiness Symptoms Study (EMOSS). Differences in fasting blood samples of metabolites were explored in participants with sleepiness versus those without and multiple linear regression models were utilized to examine the association between metabolites and mean arterial pressure (MAP). RESULTS: The 24-h MAP was higher in sleepy 92.8 mmHg (8.4) as compared to non-sleepy 88.8 mmHg (8.1) individuals (P = 0.03). Although targeted metabolites were not significantly associated with MAP, when we stratified by sleepiness group, we found that sphinganine is significantly associated with MAP (Estimate = 8.7, SE = 3.7, P = 0.045) in non-sleepy patients when controlling for age, BMI, smoking status, and apnea-hypopnea index (AHI). CONCLUSION: This is the first study to evaluate the relationship of inflammation and oxidative stress related metabolites in sleepy versus non-sleepy participants with newly diagnosed OSA and their association with 24-h MAP. Our study suggests that Sphinganine is associated with 24 hour MAP in the non-sleepy participants with OSA.

Protein engineering: a driving force toward synthetic immunology.

The full application of the diverse toolkit of protein engineering has made it easier to control the immune system. In particular, synthetic cytokine variants and engineered immune receptor platforms have shown promise for the treatment of various indications with dysregulated immune function, particularly cancer. Here, we review recent advances in the control of immune cell signaling and therapeutic potency that have employed protein engineering strategies. We further discuss how safety concerns are driving the design of immunotherapeutics toward 'user-defined' control or requiring multiple distinct inputs before a functional response, highlighting emergent control strategies employed for chimeric antigen receptor (CAR) engineering.

Oncology Medical Home: ASCO and COA Standards.

PURPOSE: To provide Standards on the basis of evidence and expert consensus for a pilot of the Oncology Medical Home (OMH) certification program. The OMH model is a system of care delivery that features coordinated, efficient, accessible, and evidence-based care and includes a process for measurement of outcomes to facilitate continuous quality improvement. The OMH pilot is intended to inform further refinement of Standards for OMH model implementation. METHODS: An Expert Panel was formed, and a systematic review of the literature on the topics of OMH, clinical pathways, and survivorship care plans was performed using PubMed and Google Scholar. Using this evidence base and an informal consensus process, the Expert Panel developed a set of OMH Standards. Public comments were solicited and considered in preparation of the final manuscript. RESULTS: Three comparative peer-reviewed studies of OMH met the inclusion criteria. In addition, the results from 16 studies of clinical pathways and one systematic review of survivorship care plans informed the evidence review. Limitations of the evidence base included the small number of studies of OMH and lack of longer-term outcomes data. More data were available to inform the specific Standards for pathways and survivorship care; however, outcomes were mixed for the latter intervention. The Expert Panel concluded that in the future, practices should be encouraged to publish the results of OMH interventions in peer-reviewed journals to improve the evidence base. STANDARDS: Standards are provided for OMH in the areas of patient engagement, availability and access to care, evidence-based medicine, equitable and comprehensive team-based care, quality improvement, goals of care, palliative and end-of-life care discussions, and chemotherapy safety. Additional information, including a Standards implementation manual, is available at www.asco.org/standards.

Prior Frequent Emergency Department Use as a Predictor of Emergency Department Visits After a New Cancer Diagnosis.

PURPOSE: To determine whether emergency department (ED) visit history prior to cancer diagnosis is associated with ED visit volume after cancer diagnosis. METHODS: This was a retrospective cohort study of adults (≥ 18 years) with an incident cancer diagnosis (excluding nonmelanoma skin cancers or leukemia) at an academic medical center between 2008 and 2018 and a safety-net hospital between 2012 and 2016. Our primary outcome was the number of ED visits in the first 6 months after cancer diagnosis, modeled using a multivariable negative binomial regression accounting for ED visit history in the 6-12 months preceding cancer diagnosis, electronic health record proxy social determinants of health, and clinical cancer-related characteristics. RESULTS: Among 35,090 patients with cancer (49% female and 50% non-White), 57% had ≥ 1 ED visit in the 6 months immediately following cancer diagnosis and 20% had ≥ 1 ED visit in the 6-12 months prior to cancer diagnosis. The strongest predictor of postdiagnosis ED visits was frequent (≥ 4) prediagnosis ED visits (adjusted incidence rate ratio [aIRR]: 3.68; 95% CI, 3.36 to 4.02). Other covariates associated with greater postdiagnosis ED use included having 1-3 prediagnosis ED visits (aIRR: 1.32; 95% CI, 1.28 to 1.36), Hispanic (aIRR: 1.12; 95% CI, 1.07 to 1.17) and Black (aIRR: 1.21; 95% CI, 1.17 to 1.25) race, homelessness (aIRR: 1.95; 95% CI, 1.73 to 2.20), advanced-stage cancer (aIRR: 1.30; 95% CI, 1.26 to 1.35), and treatment regimens including chemotherapy (aIRR: 1.44; 95% CI, 1.40 to 1.48). CONCLUSION: The strongest independent predictor for ED use after a new cancer diagnosis was frequent ED visits before cancer diagnosis. Efforts to reduce potentially avoidable ED visits among patients with cancer should consider educational initiatives that target heavy prior ED users and offer them alternative ways to seek urgent medical care.

Reimbursement Matters: Overcoming Barriers to Clinical Trial Accrual.

BACKGROUND: Accrual to cancer clinical trials is suboptimal. Few data exist regarding whether financial reimbursement might increase accruals. OBJECTIVE: The objective of this study was to assess perceptions about reimbursement to overcome barriers to trial accrual. RESEARCH DESIGN: This was a cross-sectional survey. SUBJECTS: Oncologists identified from the American Medical Association Physician Masterfile. MEASURES: We report descriptive statistics, associations of physician characteristics with perceptions of reimbursement, domains, and subthemes of free-text comments. RESULTS: Respondents (n=1030) were mostly medical oncologists (59.4%), ages 35-54 (67%), and male (75%). Overall, 30% reported discussing trials with >25% of patients. Barriers perceived were administrative/regulatory, physician/staff time, and eligibility criteria. National Cancer Institute cooperative group participants and practice owners were more likely to endorse higher reimbursement. Respondents indicated targeted reimbursement would help improve infrastructure, but also noted potential ethical problems with reimbursement for discussion (40.7%) and accrual (85.9%). Free-text comments addressed reimbursement sources, recipients, and concerns about the real and apparent conflict of interest. CONCLUSIONS: Though concerns about a potential conflict of interest remain paramount and must be addressed in any new system of reimbursement, oncologists believe reimbursement to enhance infrastructure could help overcome barriers to trial accrual.

Disparities in Characteristics, Access to Care, and Oncologic Outcomes in Young-Onset Colorectal Cancer at a Safety-Net Hospital.

PURPOSE: Young-onset colorectal cancer is an emerging cause of significant morbidity and mortality globally. Despite this, limited data exist regarding clinical characteristics and outcomes, particularly in safety-net populations where access to care is limited. We aimed to study disparities in clinical characteristics and outcomes in patients with young-onset colorectal cancer in the safety-net setting. METHODS: We performed a retrospective review of patients < 50 years old diagnosed and/or treated for colorectal cancer between 2001 and 2017 at a safety-net hospital. Kaplan-Meier and Cox regression models were constructed to compare overall survival (OS), progression-free survival (PFS), and relapse-free survival (RFS) by race and ethnicity, stratifying for relevant clinical and pathologic factors. RESULTS: A total of 395 young-onset patients diagnosed at a safety-net hospital were identified and 270 were included in the analysis (49.6% Hispanic, 25.9% non-Hispanic Black, 20.0% non-Hispanic White, and 4.4% other). Non-Hispanic White race was independently associated with worse OS (hazzard ratio [HR], 0.53; 95% CI, 0.29 to 0.97), as were lack of insurance, higher clinical stage, and mismatch repair proficiency. There was no significant difference seen in PFS or RFS between racial and ethnic groups. CONCLUSION: Non-Hispanic White race or ethnicity was found to be independently associated with worse OS in a safety-net population of patients with young-onset colorectal cancer. Other independent predictors of worse OS include higher stage, lack of insurance, and mismatch repair proficiency.

Daytime sleepiness predicts inflammation and ambulatory blood pressure in sleep apnoea.

INTRODUCTION: Sleepiness in obstructive sleep apnoea is associated with cardiovascular risk; however, the biological mechanisms are not known. This study explored whether those with subjective sleepiness have increased plasma tumour necrosis factor-related protein 1 (C1qTNF1), a novel adipose-derived hormone (adipokine), and 24-h ambulatory blood pressure (ABP) compared to those without sleepiness in newly diagnosed, treatment-naïve participants with obstructive sleep apnoea. METHODS: Overall, 94 participants were included in the analysis. Participants completed the Epworth Sleepiness Scale (ESS), 24-h ABP was monitored, and plasma C1qTNF1 was measured. Sleepy participants were defined as ESS≥10 and nonsleepy as ESS<10. Multiple linear regression was used to explore differences in C1qTNF1, and 24-h mean arterial pressure (MAP) between sleepy and nonsleepy participants, adjusting for age, sex, body mass index, apnoea-hypopnoea index, and smoking status. RESULTS: C1qTNF1 was significantly higher in sleepy participants (n=57) compared to nonsleepy participants (n=37) (ß=0.41 NPX, 95% CI 0.02, 0.80; p=0.04). The 24-h MAP was significantly higher in sleepy participants compared to nonsleepy participants (ß=4.06 mmHg, 95% CI 0.36, 7.77; p=0.03). CONCLUSIONS: Our findings show that sleepiness is associated with inflammation and higher 24-h MAP in sleep apnoea.

A randomized trial of mail and email recruitment strategies for a physician survey on clinical trial accrual.

BACKGROUND: Patient participation in cancer clinical trials is suboptimal. A challenge to capturing physicians' insights about trials has been low response to surveys. We conducted a study using varying combinations of mail and email to recruit a nationally representative sample of medical, surgical, and radiation oncologists to complete a survey on trial accrual. METHODS: We randomly assigned eligible physicians identified from the American Medical Association MasterFile (n = 13,251) to mail- or email-based recruitment strategies. Mail-based recruitment included a survey packet with: (1) cover letter describing the survey and inviting participation; (2) paper copy of the survey and postage-paid return envelope; and (3) a web link for completing the survey online. Email-based recruitment included an e-mail describing the survey and inviting participation, along with the web link to the survey, and a reminder postcard 2 weeks later. RESULTS: Response was higher for mail-based (11.8, 95% CI 11.0-12.6%) vs. email-based (4.5, 95% CI 4.0-5.0%) recruitment. In email-based recruitment, only one-quarter of recipients opened the email, and even fewer clicked on the link to complete the survey. Most physicians in mail-based recruitment responded after the first invitation (362 of 770 responders, 47.0%). A higher proportion of responders vs. non-responders were young (ages 25-44 years), men, and radiation or surgical (vs. medical) oncologists. CONCLUSIONS: Most physicians assigned to mail-based recruitment actually completed the survey online via the link provided in the cover letter, and those in email-based recruitment did not respond until they received a reminder postcard by mail. Providing the option to return a paper survey or complete it online may have further increased participation in the mail-based group, and future studies should examine how combinations of delivery mode and return options affect physicians' response to surveys.

Characteristics of women with different perinatal depression trajectories.

Maternal perinatal depression (PND), a common mental disorder with a prevalence of over 10%, is associated with long-term health risks for both mothers and offspring. This study aimed at describing characteristics related to background and lifestyle, pregnancy, delivery, and postpartum of different PND trajectories defined according to the onset of depressive symptoms. Participants were drawn from a large population-based cohort study in Uppsala, Sweden (n = 2,466). Five trajectory groups of depressive symptom onset were created using the Edinburgh Postnatal Depression Scale ≥13 (pregnancy) or ≥12 points (postpartum): (a) healthy (60.6%), (b) pregnancy depression (8.5%), (c) early postpartum onset (10.9%), (d) late postpartum onset (5.4%), and (e) chronic depression (14.6%). In multinomial logistic regressions, the associations between trajectories and the included characteristics were tested using the healthy trajectory as reference. Background characteristics (younger age, lower education, unemployment) were primarily associated with pregnancy depression and chronic depression. Characteristics associated with all PND trajectories were smoking prior to pregnancy, migraine, premenstrual mood symptoms, intimate partner violence, interpersonal trauma, negative delivery expectations, pregnancy nausea, and symphysiolysis. Nulliparity, instrumental delivery, or a negative delivery experience was associated with early postpartum onset. Postpartum factors (e.g., infantile colic, lack of sleep, low partner support, and bonding difficulties) were associated with early and late postpartum onset together with chronic depression. The findings suggest that different PND trajectories have divergent characteristics, which could be used to create individualized treatment options. To find the most predictive characteristics for different PND trajectories, studies with even larger and more diverse samples are warranted.

Patient and provider perspectives on delivery of oral cancer therapies.

OBJECTIVE: The introduction of oral cancer therapies presents new challenges to delivery of quality cancer care. Little is known about how patients and providers address and overcome these challenges. We conducted a qualitative study exploring the range of patient and provider perspectives on oral cancer therapies. METHODS: We conducted semi-structured interviews with patients and providers at a tertiary referral center and county safety-net hospital in Dallas, TX. Interviews probed perspectives on differences between parenteral chemotherapy and oral therapies, adherence, communication, and cost/insurance. Interview transcripts were analyzed thematically using a deductively-driven coding scheme corresponding to the interview guide. RESULTS: We conducted 22 patient (13 at tertiary referral center, 9 at safety-net hospital) and 10 provider (7 oncologists, 2 nurses, 1 pharmacist) interviews. Key themes from interviews included: (1) differences in parenteral chemotherapy vs. oral therapy; (2) adherence and dosing; and (3) experiences related to cost and communication. CONCLUSIONS: Nearly all providers described challenges engaging with and educating patients about oral cancer therapies. Despite our initial hypothesis, safety-net patients encountered few barriers accessing oral therapies compared to patients receiving care in the tertiary referral center. PRACTICE IMPLICATIONS: Our findings will guide future interventions to monitor and support cancer patients receiving oral therapies.

The Centers for Medicare & Medicaid Services Oncology Care Model Halfway Through: Perspectives from Diverse Participants.

The Oncology Care Model (OCM) is a 5-year model developed and tested by the Centers for Medicare & Medicaid Services that uses an episode-based payment model triggered by the receipt of chemotherapy to test if changing payment mechanisms, in conjunction with a requirement for enhanced patient services, can generate clinical transformation that will orient practices toward more patient-centered, high-value care to reduce expenditures and preserve or enhance quality of care for beneficiaries. The model is geographically diverse with practices in 34 states and encompasses practices ranging in size from 1 to more than 400 practitioners, with a multitude of business structures. Given these varied clinical and business environments, we believe that OCM-participating practices will have different opportunities and challenges as they work toward practice transformation, but they will likely share similarities with other practices in similar clinical and business settings. This commentary shares the experiences of four diverse groups participating in OCM-three practices and one network of practices-halfway through the model's projected 5-year life cycle in the expectation that these experiences will be of value to other practices embarking toward patient-centered, high-value practice transformation.

Thirty years with the Edinburgh Postnatal Depression Scale: voices from the past and recommendations for the future.

The Edinburgh Postnatal Depression Scale (EPDS) was published over 30 years ago as a ten-item self-report questionnaire to facilitate the detection of perinatal depression - and for use in research. It is widely used at the present time in many regions of the world and has been translated into over 60 languages. It is occasionally misused. In this editorial, updated recommendations for optimal use in primary and secondary care as well as research are provided. Future studies to evaluate its use and validity in naturalistic community populations are now required, and to determine the psychometric properties and practical usefulness of the EPDS when completed online.Declaration of interestJ.C. has no financial interest in the use of, or reproduction of, the EPDS.