The tumor microenvironment (TME) is an evolutionally low-level and embryonically featured tissue comprising heterogenic populations of malignant and stromal cells as well as noncellular components. Under radiotherapy (RT), the major modality for the treatment of malignant diseases [1], TME shows an adaptive response in multiple aspects that affect the efficacy of RT. With the potential clinical benefits, interests in RT combined with immunotherapy (IT) are intensified with a large scale of clinical trials underway for an array of cancer types. A better understanding of the multiple molecular aspects, especially the cross talks of RT-mediated energy reprogramming and immunoregulation in the irradiated TME (ITME), will be necessary for further enhancing the benefit of RT-IT modality. Coming studies should further reveal more mechanistic insights of radiation-induced instant or permanent consequence in tumor and stromal cells. Results from these studies will help to identify critical molecular pathways including cancer stem cell repopulation, metabolic rewiring, and specific communication between radioresistant cancer cells and the infiltrated immune active lymphocytes. In this chapter, we will focus on the following aspects: radiation-repopulated cancer stem cells (CSCs), hypoxia and re-oxygenation, reprogramming metabolism, and radiation-induced immune regulation, in which we summarize the current literature to illustrate an integrated image of the ITME. We hope that the contents in this chapter will be informative for physicians and translational researchers in cancer radiotherapy or immunotherapy.

OBJECTIVE: Most outpatients with pulmonary embolism (PE) are diagnosed in the emergency department (ED). The relationship between means of arrival, site of diagnosis, and disposition in ED patients with PE is unknown. We compared discharge home between patients arriving by emergency medical services (EMS) and those arriving by other means. Within the EMS cohort, we compared those with a recent PE diagnosis in the outpatient clinic setting to those who were diagnosed with PE in the ED. METHODS: This study was a secondary analysis of a retrospective cohort that included all adult, non-pregnant ED patients treated for acute PE across 21 community EDs from January 2013 to April 2015. The primary outcome was discharge home within 24 h of ED registration; we also examined mortality. We described associations with patient arrival method and other patient characteristics. RESULTS: Among 2996 ED patient encounters with acute PE, 644 (21.5%) arrived by EMS. This group had a lower frequency of discharge (9.2% vs 26.4%) and higher 30-day all-cause mortality (8.7% vs 3.1%) than their counterparts (p < 0.001 for both). These associations remained after adjusting for confounding variables. Among the EMS cohort, 14 patients (2.2%) arrived with a PE diagnosis recently made in the outpatient setting. CONCLUSION: Patients with PE who arrived at the ED by EMS were less likely to be discharged home within 24 h and more likely to die within 30 days than those who arrived by other means. Less than 3% of the EMS group had been diagnosed with PE before ED arrival.

Background

Health information technology (HIT) may improve health care quality and outcomes, in part by making information available in a timelier manner. However, there are few studies documenting the changes in timely availability of data with the use of a sophisticated electronic medical record (EMR), nor a description of how the timely availability of data might differ with different types of EMRs. We hypothesized that timely availability of data would improve with use of increasingly sophisticated forms of HIT.

Methods

We used an historical observation design (2004-2006) using electronic data from office visits in an integrated delivery system with three types of HIT: Basic, Intermediate, and Advanced. We calculated the monthly percentage of visits using the various types of HIT for entry of visit diagnoses into the delivery system's electronic database, and the time between the visit and the availability of the visit diagnoses in the database.

Results

In January 2004, when only Basic HIT was available, 10% of office visits had diagnoses entered on the same day as the visit and 90% within a week; 85% of office visits used paper forms for recording visit diagnoses, 16% used Basic at that time. By December 2006, 95% of all office visits had diagnoses available on the same day as the visit, when 98% of office visits used some form of HIT for entry of visit diagnoses (Advanced HIT for 67% of visits).

Conclusion

Use of HIT systems is associated with dramatic increases in the timely availability of diagnostic information, though the effects may vary by sophistication of HIT system. Timely clinical data are critical for real-time population surveillance, and valuable for routine clinical care.

Cardiac neural crest cells are essential for outflow tract remodeling in animals with divided systemic and pulmonary circulatory systems, but their contributions to cardiac development in animals with a single-loop circulatory system are less clear. Here we genetically labeled neural crest cells and examined their contribution to the developing zebrafish heart. We identified two populations of neural crest cells that contribute to distinct compartments of zebrafish cardiovascular system at different developmental stages. A stream of neural crest cells migrating through pharyngeal arches 1 and 2 integrates into the myocardium of the primitive heart tube between 24 and 30 h post fertilization and gives rise to cardiomyocytes. A second wave of neural crest cells migrating along aortic arch 6 envelops the endothelium of the ventral aorta and invades the bulbus arteriosus after three days of development. Interestingly, while inhibition of FGF signaling has no effect on the integration of neural crest cells to the primitive heart tube, it prevents these cells from contributing to the outflow tract, demonstrating disparate responses of neural crest cells to FGF signaling. Furthermore, neural crest ablation in zebrafish leads to multiple cardiac defects, including reduced heart rate, defective myocardial maturation and a failure to recruit progenitor cells from the second heart field. These findings add to our understanding of the contribution of neural crest cells to the developing heart and provide insights into the requirement for these cells in cardiac maturation.

Importance

Approximately 8% of acute pulmonary emboli are confined to the subsegmental arteries. The 2016 and 2021 American College of Chest Physicians (CHEST) guidelines and expert panel reports suggest the use of structured surveillance without anticoagulation for select ambulatory patients with subsegmental pulmonary embolism who do not have active cancer, deep vein thrombosis, impaired cardiopulmonary reserve, marked symptoms, or increased risk of recurrent venous thromboembolism; however, guideline uptake in community practice is unknown, as is the proportion of outpatients eligible for surveillance.

Objective

To describe the prevalence of surveillance among outpatients with acute subsegmental pulmonary embolism and to estimate the proportion of patients eligible for structured surveillance using modified CHEST criteria.

Design, setting, and participants

This retrospective cohort study was conducted across 21 US community hospitals in the Kaiser Permanente Northern California integrated health system from January 1, 2017, to December 31, 2021. Adult outpatients with acute subsegmental pulmonary embolism were included. Patients with the following higher-risk characteristics were excluded: codiagnoses requiring hospitalization, non-low-risk vital signs (ie, systolic blood pressure <90 mm Hg, pulse ≥110 bpm, or peripheral cutaneous pulse oximetry ≤92%), prediagnosis anticoagulant use, or hospice care. Data analysis was performed from November 2022 to February 2023.

Main outcomes and measures

The main outcomes were the (1) prevalence of surveillance and (2) eligibility for surveillance using 2 sets of criteria: the CHEST criteria modified by excluding patients with higher-risk characteristics or right ventricular dysfunction and a stricter set of criteria requiring age younger than 65 years and no more than 1 embolus. The prevalence of structured surveillance was calculated and the proportion of patients eligible for surveillance was estimated.

Results

Of the 666 outpatients with acute subsegmental pulmonary embolism included in this study, 229 with lower-risk characteristics were examined. Their median age was 58 (IQR, 42-68) years; more than half were men (120 [52.4%]) and self-identified as non-Hispanic White (128 [55.9%]). Six patients (2.6%) were initially not treated with anticoagulants. Among the lower-risk cohort, only 1 patient (0.4% [95% CI, 0.01%-2.4%]) underwent structured surveillance, without 90-day sequelae. Thirty-five patients (15.3% of the lower-risk group and 5.3% of the full cohort) were surveillance eligible using modified CHEST criteria. Fifteen patients (6.6% of the lower-risk group and 2.3% of the full cohort) were surveillance eligible using stricter criteria.

Conclusions and relevance

In this cohort study of lower-risk outpatients with subsegmental pulmonary embolism, few were eligible for structured surveillance, and only a small proportion of eligible patients underwent surveillance despite the CHEST guideline. If forthcoming trials find surveillance safe and effective, substantial uptake into clinical practice may require more than passive diffusion.

Objective

To compare drug costs and adherence among Medicare beneficiaries with the standard Part D coverage gap versus supplemental gap coverage in 2006.

Data sources

Pharmacy data from Medicare Advantage Prescription Drug (MAPD) plans.

Study design

Parallel analyses comparing beneficiaries aged 65+ with diabetes in an integrated MAPD with a gap versus no gap (n=28,780); and in a network-model MAPD with a gap versus generic-only coverage during the gap (n=14,984).

Principal findings

Drug spending was 3 percent (95 percent confidence interval [CI]: 1-4 percent) and 4 percent (CI: 1-6 percent) lower among beneficiaries with a gap versus full or generic-only gap coverage, respectively. Out-of-pocket expenditures were 189 percent higher (CI: 185-193 percent) and adherence to three chronic drug classes was lower among those with a gap versus no gap (e.g., odds ratio=0.83, CI: 0.79-0.88, for oral diabetes drugs). Annual out-of-pocket spending was 14 percent higher (CI: 10-17 percent) for beneficiaries with a gap versus generic-only gap coverage, but levels of adherence were similar.

Conclusions

Among Medicare beneficiaries with diabetes, having the Part D coverage gap resulted in lower total drug costs, but higher out-of-pocket spending and worse adherence compared with having no gap. Having generic-only coverage during the gap appeared to confer limited benefits compared with having no gap coverage.

Study objective

To assess trends over time in red blood cell (RBC) transfusion practice among emergency department (ED) patients with gastrointestinal (GI) bleeding within an integrated healthcare system, inclusive of 21 EDs.

Methods

Retrospective cohort of ED patients diagnosed with GI bleeding between July 1st, 2012 and September 30th, 2016. The primary outcome was receipt of an RBC transfusion in the ED. Secondary outcomes included 90-day rates of RBC transfusion, repeat ED visits, rehospitalization, and all-cause mortality. Logistic regression was used to obtain confounder-adjusted outcome rates.

Results

A total of 24,868 unique patient encounters were used for the primary analysis. The median hemoglobin level in the ED prior to RBC transfusion decreased from 7.5 g/dl to 6.9 g/dl in the first versus last twelve months of the study period (p < 0.0001). A small trend was observed in the overall adjusted rate of ED RBC transfusion (absolute quarterly change of -0.1%, R2 = 0.18, p = 0.0001) largely attributable to the subgroup of patients with hemoglobin nadirs between 7.0 and 9.9 g/dl (absolute quarterly change of -0.4%, R2 = 0.38, p < 0.0001). Rates of RBC transfusions through 90 days likewise decreased (absolute quarterly change of -0.4%, R2 = 0.85, p < 0.0001) with stable to decreased corresponding rates of repeat ED visits, rehospitalizations and mortality.

Conclusion

Rates of ED RBC transfusion decreased over time among patients with GI bleeding, particularly in those with hemoglobin nadirs between 7.0 and 9.9 g/dl. These findings suggest that ED providers are willing to adopt evidence-based restrictive RBC transfusion recommendations for patients with GI bleeding.