Quantification of Long-Term Consequences Associated with Components of the CHOP Chemotherapy Regimen

Introduction: A common chemotherapy regimen for Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV + PTLD) following solid organ transplants is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Long-term adverse consequences of CHOP, particularly the incidence, timing, and risk factors associated with these events, in any cancer survivor remain poorly understood. In this study, we review the evidence to determine how often long-term consequences associated with the components of CHOP occur. Methods: Potential long-term consequences of CHOP components were identified from the Children's Oncology Group Long-Term Follow-Up (COG LTFU) Guidelines. Abstracts were screened and eligibility was based on reporting data for the identified COG LTFU long-term consequences along with pre-specified criteria (English, systematic review, randomized controlled trial n>100, observation study n>100, case series n>20). Studies that met the inclusion criteria were extracted and synthesized. Quantification of late effects evaluated in >3 studies were reported. Results: Long-term consequences in the 45 studies that met the pre-specified criteria included cardiac toxicity, hormone deficiencies/infertility, secondary leukemia, osteonecrosis (ON), and urotoxicity/bladder cancer. Although none of the studies focused specifically on the CHOP regimen, 30%, 23%, and 15% evaluated alkylating agents (eg, cyclophosphamide), anthracyclines (eg, doxorubicin), and corticosteroids (eg, prednisone), respectively. Time to onset from treatment was as early as 1 year for cardiac toxicity, <5 for infertility, 2 for ON, 3 for secondary leukemia, and 5 for bladder cancer. Longer follow-up times were associated with higher percentages of long-term consequences. For example, cardiac toxicity and hormone deficiencies/infertility affected >20% of patients, and secondary leukemia, ON, urotoxicity/bladder malignancy affected 10-20% of patients (Table 1). A wide range in the incidence and timing of these late effects was observed, likely due to variation in the treatment regimens, follow-up time, and event definition. The synthesized evidence supports that CHOP components increased the risk of long-term consequences in a dose-dependent manner. Cardiac toxicity risk was elevated even at anthracycline doses of <150 mg/m 2 (traditionally considered a 'safe' dose range). Hazard ratios (HRs) for heart failure at doses of ≤300 to <400 mg/m 2 were 4.33 and 13.19 for daunorubicin and doxorubicin, respectively. Studies also reported significantly elevated risk of cardiac toxicity in patients with lymphoma treated with anthracyclines (eg, HR of up to 12.2) compared with the sibling cohort. Patients <5 years of age vs ≥5 years of age at exposure had a significantly higher risk of cardiac toxicity (HR of 1.89). Patients exposed to cumulative doses of cyclophosphamide ≥6 g/m 2 had significant reproductive risks. The risk of early menopause was shown to be dose dependent and as much as 27-fold higher in patients treated with both radiation below the diaphragm and alkylating agent chemotherapy. Patients exposed to high-dose cyclophosphamide (>7.5 g/m 2) were at statistically significantly higher risk (odds ratio of 12.0) for diminished ovarian reserve as measured by their Anti-Müllerian hormone level. One study reported 3.8- and 3.2-fold increases in risk of ovarian failure in patients who had been diagnosed with Hodgkin's lymphoma and Non-Hodgkin's lymphoma, respectively. High-doses of anthracyclines and alkylating agents were associated with up to 16-fold increases in risk of secondary leukemia. The risk of bladder cancer significantly increased with increasing dose of cyclophosphamide, with a 6- and 14.5-fold increased risk at cumulative doses of 20‒49 g and ≥50 g, respectively. Intensive corticosteroid therapy was associated with significant risk of ON, with one study showing cancer survivors had a 6.2 times higher likelihood of ON as compared to their sibling comparison group. Conclusions: Patients exposed to components of CHOP have a dose-dependent risk of cardiac toxicity, infertility, secondary leukemia, ON, and bladder cancer that are often significant, impacted a high percentage of patients, and occurred as early as 1 year after treatment. Safe and effective PTLD treatments that potentially avoid these long-term consequences are urgently needed. Figure 1 Figure 1. Disclosures Watson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Gadikota: Maple Health Group: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Beckerman: Maple Health Group: Current Employment.

How to Address Consumers’ Concerns and Information Needs about Emerging Chemical and Microbial Contaminants in Drinking Water; The Case of GenX in The Netherlands

The perceived safety of tap water is an important condition for consumers to drink it. Therefore, addressing consumers’ concerns should be included in the roadmap towards the UN SDG 6 on safe drinking water for all. This paper studies consumers’ information needs regarding emerging contaminants in drinking water using a mental model approach for the development of targeted risk communication. As most consumers expect safe drinking water, free of contamination, communication on emerging contaminants may increase concerns. Here, we showed that communication strategies better tailored to consumers’ information needs result in smaller increases in risk perception compared with existing strategies.

Assessing the safety of home oximetry for COVID-19: a multisite retrospective observational study

ObjectivesTo determine the safety and effectiveness of home oximetry monitoring pathways for patients with COVID-19 in the English National Health Service.DesignRetrospective, multisite, observational study of home oximetry monitoring for patients with suspected or proven COVID-19.SettingThis study analysed patient data from four COVID-19 home oximetry pilot sites in England across primary and secondary care settings.ParticipantsA total of 1338 participants were enrolled in a home oximetry programme across four pilot sites. Participants were excluded if primary care data and oxygen saturations at rest at enrolment were not available. Data from 908 participants were included in the analysis.InterventionsHome oximetry monitoring was provided to participants with a known or suspected diagnosis of COVID-19. Participants were enrolled following attendance to emergency departments, hospital admission or referral through primary care services.ResultsOf 908 patients enrolled into four different COVID-19 home oximetry programmes in England, 771 (84.9%) had oxygen saturations at rest of 95% or more, and 320 (35.2%) were under 65 years of age and without comorbidities. 52 (5.7%) presented to hospital and 28 (3.1%) died following enrolment, of which 14 (50%) had COVID-19 as a named cause of death. All-cause mortality was significantly higher in patients enrolled after admission to hospital (OR 8.70 (2.53–29.89)), compared with those enrolled in primary care. Patients enrolled after hospital discharge (OR 0.31 (0.15–0.68)) or emergency department presentation (OR 0.42 (0.20–0.89)) were significantly less likely to present to hospital than those enrolled in primary care.ConclusionsThis study finds that home oximetry monitoring can be a safe pathway for patients with COVID-19; and indicates increases in risk to vulnerable groups and patients with oxygen saturations <95% at enrolment, and in those enrolled on discharge from hospital. Findings from this evaluation have contributed to the national implementation of home oximetry across England.

Effects of COVID-19 Uncertainty Visualizations on Novice Risk Estimates

Policy-makers and the general public have made decisions using COVID-19 data visualizations that have affected the health of the global population. However, the impact that such wide use of data visualizations has had on people's beliefs about their personal risk for COVID-19 is unclear. We conducted two experiments (N = 2,549) during the height of the COVID-19 epidemic in the United States to examine if real-time COVID-19 visualizations influenced participants' beliefs about the risk of the pandemic to themselves and others. This work also examined the impact of two elements of COVID-19 data visualizations, data properties (cumulative- vs. incident-death metrics) and uncertainty visualization techniques (historical data only, and forecasts with no uncertainty, vs. nine uncertainty visualization techniques). The results revealed that viewing COVID-19 visualizations with rising trends resulted in participants believing themselves and others at greater risk than before viewing the COVID-19 visualizations. Further, uncertainty visualization techniques that showed six or more models evoked the largest increases in risk estimates compared to the visualizations tested. These results could inform the design of public pandemic risk communication.

Application of a 27-protein candidate cardiovascular surrogate endpoint to track risk ascendancy and resolution in COVID-19

ABSTRACTBackgroundThere is an urgent need for tools allowing the early prognosis and subsequent monitoring of individuals with heterogeneous COVID-19 disease trajectories. Pre-existing cardiovascular (CV) disease is a leading risk factor for COVID-19 susceptibility and poor outcomes, and cardiac involvement is prevalent in COVID-19 patients both during the acute phase as well as in convalescence. The utility of traditional CV risk biomarkers in mild COVID-19 disease or across disease course is poorly understood. We sought to determine if a previously validated 27-protein predictor of CV outcomes served a purpose in COVID-19.MethodsThe 27-protein test of residual CV (RCV) risk was applied without modification to n=860 plasma samples from hospitalized and non-hospitalized SARS-CoV-2 infected individuals at disease presentation from three independent cohorts to predict COVID-19 severity and mortality. The same test was applied to an additional n=991 longitudinal samples to assess sensitivity to change in CV risk throughout the course of infection into convalescence.ResultsIn each independent cohort, RCV predictions were significantly related to maximal subsequent COVID-19 severity and to mortality. At the baseline blood draw, the mean protein-predicted likelihood of an event in subjects who died during the study period ranged from 88-99% while it ranged from 8-36% in subjects who were not admitted to hospital. Additionally, the test outperformed existing risk predictors based on commonly used laboratory chemistry values or presence of comorbidities. Application of the RCV test to sequential samples showed dramatic increases in risk during the first few days of infection followed by risk reduction in the survivors; a period of catastrophically high cardiovascular risk (above 50%) typically lasted 8-12 days and had not resolved to normal levels in most people within that timescale.ConclusionsThe finding that a 27-protein candidate CV surrogate endpoint developed in multi-morbid patients prior to the pandemic is both prognostic and acutely sensitive to the adverse effects of COVID-19 suggests that this disease activates the same biologic risk-related mechanisms. The test may be useful for monitoring recovery and drug response.

Social determinants of health affect unplanned readmissions following acute myocardial infarction

Background: Low socioeconomic status predicts inferior clinical outcomes in many patient populations. The effects of patient insurance status and hospital safety-net status on readmission rates following acute myocardial infarction are unclear. Materials & methods: A retrospective review of State Inpatient Databases for New York, California, Florida and Maryland, 2007–2014. Results: A total of 1,055,162 patients were included. Medicaid status was associated with 37.7 and 44.0% increases in risk-adjusted readmission odds at 30 and 90 days (p < 0.0001). Uninsured status was associated with reduced odds of readmission at both time points. High-burden safety-net status was associated with 9.6 and 9.5% increased odds of readmission at 30 and 90 days (p < 0.0003). Conclusion: Insurance status and hospital safety-net burden affect readmission odds following acute myocardial infarction.

Places & Spaces: A Critical Analysis of Cancer Disparities and Access to Cancer Care Among First Nations Peoples in Canada

Despite advancements in research and medicine, health inequities and disparities among First Nations peoples (FN) in Canada are well documented and continue to grow. Once virtually unheard of, cancer now is a leading cause of death among FN. Many factors contribute to cancer disparities, but FN face unique challenges in accessing healthcare. In this critical review and analysis, we explore potential links between cancer disparities and poor access to cancer care among FN. Research suggests FN experience difficulty accessing cancer services in several ‘places’ of care, including screening, diagnosis, treatment, survivorship and palliative care. Furthermore, there are notable ‘spaces’ or gaps both within and between these ‘places’ of care likely contributing to cancer disparities among First Nations. Gaps in care result from jurisdictional ambiguities, geographical location, unsafe social spaces, and marginalization of FN ways of knowing, and can be linked to colonial and neocolonial policies and ideologies. By drawing attention to these broader structural influences on health, we aim to challenge discourses that attribute growing cancer disparities among FN in Canada solely to increases in ‘risk factors’.

Dynamic adaptations of the Mesolithic pioneers of Gotland in the Baltic Sea

Mesolithic pioneers reached Gotland around 9200 cal BP and adopted seal-hunting. The subsistence economy was flexible, and the importance of freshwater fish is reflected in the location of settlements and available stable isotope data. Overgrowing lakes provided an important subsistence base, and marine resources were mainly related to raw material needs. The narrower breadth of resources is reflected in the osseous production, where implements were made from seal bones. The lithic technology exhibits local adaptations over time – in the form of a simplification of the technology – that we relate to sedentism and increases in risk management and external networks.

Funding Constraints and Informational Efficiency

We analyze a tractable rational expectations equilibrium model with margin constraints. We argue that constraints affect and are affected by informational efficiency, leading to a novel amplification mechanism. A decline in wealth tightens constraints and reduces investors’ incentive to acquire information, lowering price informativeness. Lower informativeness, in turn, increases the risk borne by financiers who fund trades, leading them to further tighten constraints faced by investors. This information spiral leads to (a) significant increases in risk premium and return volatility in crises, when investors wealth declines, (b) complementarities in information acquisition in crises, and (c) complementarities in margin requirements.

Willingness to Accept Tradeoffs among Covid-19 Cases, Social-Distancing Restrictions, and Economic Impact: A Nationwide US Study

We designed a discrete-choice experiment to quantify the extent to which US adults would accept greater risk of infection with SARS-CoV-2 in return for lifting social-distancing restrictions and diminishing the economic impact of the COVID-19 pandemic. 5953 adults representing all 50 states had 4 distinctly different preference patterns. About 37% were risk minimizers reluctant to accept any increases in risk of contracting the virus. Another group (26%) was primarily concerned about time required for economic recovery, accepting increases in COVID-19 risk levels up to 16% to shorten recovery from 3 to 2 years. The remaining two groups diverged on the relative importance of reopening nonessential businesses. The larger group (26%) strongly preferred delaying reopening while the smaller group (13%) would accept COVID-19 risks well beyond 20% to avoid a delay in reopening. Political affiliation, race, household income and employment status were predictive of group membership.