Spatial patterning controls neuron numbers in the Drosophila visual system.

Neurons must be made in the correct proportions to communicate with the appropriate synaptic partners and form functional circuits. In the Drosophila visual system, multiple subtypes of distal medulla (Dm) inhibitory interneurons are made in distinct, reproducible numbers-from 5 to 800 per optic lobe. These neurons are born from a crescent-shaped neuroepithelium called the outer proliferation center (OPC), which can be subdivided into specific domains based on transcription factor and growth factor expression. We fate mapped Dm neurons and found that more abundant neural types are born from larger neuroepithelial subdomains, while less abundant subtypes are born from smaller ones. Additionally, morphogenetic Dpp/BMP signaling provides a second layer of patterning that subdivides the neuroepithelium into smaller domains to provide more granular control of cell proportions. Apoptosis appears to play a minor role in regulating Dm neuron abundance. This work describes an underappreciated mechanism for the regulation of neuronal stoichiometry.

High-throughput identification of the spatial origins of Drosophila optic lobe neurons using single-cell mRNA-sequencing.

The medulla is the largest neuropil of the Drosophila optic lobe. It contains about 100 neuronal types that have been comprehensively characterized morphologically and molecularly. These neuronal types are specified from a larval neuroepithelium called the Outer Proliferation Center (OPC) via the integration of temporal, spatial, and Notch-driven mechanisms. Although we recently characterized the temporal windows of origin of all medulla neurons, as well as their Notch status, their spatial origins remained unknown. Here, we isolated cells from different OPC spatial domains and performed single-cell mRNA-sequencing to identify the neuronal types produced in these domains. This allowed us to characterize in a high-throughput manner the spatial origins of all medulla neurons and to identify two new spatial subdivisions of the OPC. Moreover, our work shows that the most abundant neuronal types are produced from epithelial domains of different sizes despite being present in a similar number of copies. Combined with our previously published scRNA-seq developmental atlas of the optic lobe, our work opens the door for further studies on how specification factor expression in progenitors impacts gene expression in developing and adult neurons.

Assessing the impact of transplant case management on clinical outcomes.

OBJECTIVES: Case management is commonly used by health plans to attempt to improve the care received by their members who have complex needs, such as those who undergo transplantation. There are few observational studies evaluating the effects that transplant case management programs have on clinical outcomes following a solid organ transplant. This limits the understanding of the quantitative effectiveness of such programs. STUDY DESIGN: This retrospective cohort study of solid organ transplant recipients with access to a transplant case management program used a case-control study design. Propensity score 1:1 matching was used to balance the comparison groups on demographic and pretransplant clinical characteristics. METHODS: Health care claims data were used to determine whether program participation affected clinical outcomes following the transplant. A cohort of 1756 adults 18 years and older (878 cases and 878 controls) who had a solid organ transplant between 2018 and 2020 was followed beginning at the time of referral to transplant until 90 days following the transplant procedure. RESULTS: Transplant recipients who participated in the case management program had significantly lower 30-day and 90-day rejection rates, fewer 90-day readmissions, lower discharge mortality and 90-day mortality, and fewer bed days post transplant compared with those who did not participate in case management. CONCLUSIONS: Patients undergoing a solid organ transplant had improved clinical outcomes when they participated in a specialized case management program sponsored by their health plan.

Long-term follow-up of smokers following lung and colorectal cancer diagnosis.

BACKGROUND: Continued smoking after a cancer diagnosis limits the effectiveness of treatment, increases the risk of cancer recurrence or secondary malignancies, and is associated with poorer quality of life and survival. A cancer diagnosis may provide a meaningful timepoint for quitting, but the prevalence and characteristics of continued smoking through survivorship are poorly understood. METHODS: In the multi-regional Cancer Care Outcomes Research and Surveillance (CanCORS) cohort, we examined smoking rates and factors associated with continued smoking at long-term follow-up among lung and colorectal cancer patients. This paper builds upon previous CanCORS participant data addressing quit rates and associated characteristics at baseline and 5 months post-diagnosis. RESULTS: At long-term follow-up (median 7.3 years post-diagnosis [IQR = 5.9-8.7]), 16.7% of lung cancer and 11.6% of colorectal cancer survivors continued to smoke combustible cigarettes. Factors independently associated with continued smoking at long-term follow-up included being male, younger, not married or partnered, having Medicare, Medicaid/other public or no insurance, more depression symptoms, smoking more cigarettes per day, and having a history of lung disease (p < .05). Continued smoking did not vary by lung vs. colorectal cancer diagnosis. CONCLUSION: Of active smokers at the time of diagnosis, an important minority of lung and colorectal cancer survivors continued to smoke well into survivorship. Understanding characteristics associated with continued smoking after a cancer diagnosis may help inform the development of tobacco treatment programs for cancer patients and survivors. IMPLICATIONS FOR SURVIVORS: While addressing smoking cessation at the time of diagnosis is critical to ensure better long-term treatment outcomes and quality of life, it is essential to continue smoking cessation discussions and efforts throughout care and survivorship.

Neural specification, targeting, and circuit formation during visual system assembly.

Like other sensory systems, the visual system is topographically organized: Its sensory neurons, the photoreceptors, and their targets maintain point-to-point correspondence in physical space, forming a retinotopic map. The iterative wiring of circuits in the visual system conveniently facilitates the study of its development. Over the past few decades, experiments in Drosophila have shed light on the principles that guide the specification and connectivity of visual system neurons. In this review, we describe the main findings unearthed by the study of the Drosophila visual system and compare them with similar events in mammals. We focus on how temporal and spatial patterning generates diverse cell types, how guidance molecules distribute the axons and dendrites of neurons within the correct target regions, how vertebrates and invertebrates generate their retinotopic map, and the molecules and mechanisms required for neuronal migration. We suggest that basic principles used to wire the fly visual system are broadly applicable to other systems and highlight its importance as a model to study nervous system development.

Measure Scan and Synthesis of Palliative and End-of-Life Process Quality Measures for Advanced Cancer.

PURPOSE: Monitoring and improving the quality of palliative and end-of-life cancer care remain pressing needs in the United States. Among existing measures that assess the quality of palliative and end-of-life care, many operationalize similar concepts. We identified existing palliative care process measures and synthesized these measures to aid stakeholder prioritization that will facilitate health system implementation in patients with advanced cancer. METHODS: We reviewed MEDLINE/PubMed-indexed articles for process quality measures related to palliative and end-of-life care for patients with advanced cancer, supplemented by expert input. Measures were inductively grouped into "measure concepts" and higher-level groups. RESULTS: Literature review identified 226 unique measures from 23 measure sources, which we grouped into 64 measure concepts within 12 groups. Groups were advance care planning (11 measure concepts), pain (7), dyspnea (9), palliative care-specific issues (6), other specific symptoms (17), comprehensive assessment (2), symptom assessment (1), hospice/palliative care referral (1), spiritual care (2), mental health (5), information provision (2), and culturally appropriate care (1). CONCLUSION: Measure concepts covered the spectrum of care from acute symptom management to advance care planning and psychosocial needs, with variability in the number of measure concepts per group. This taxonomy of process quality measure concepts can be used by health systems seeking stakeholder input to prioritize targets for improving palliative and end-of-life care quality in patients with advanced cancer.

Neuronal diversity and convergence in a visual system developmental atlas.

Deciphering how neuronal diversity is established and maintained requires a detailed knowledge of neuronal gene expression throughout development. In contrast to mammalian brains1,2, the large neuronal diversity of the Drosophila optic lobe3 and its connectome4-6 are almost completely characterized. However, a molecular characterization of this neuronal diversity, particularly during development, has been lacking. Here we present insights into brain development through a nearly complete description of the transcriptomic diversity of the optic lobes of Drosophila. We acquired the transcriptome of 275,000 single cells at adult and at five pupal stages, and built a machine-learning framework to assign them to almost 200 cell types at all time points during development. We discovered two large neuronal populations that wrap neuropils during development but die just before adulthood, as well as neuronal subtypes that partition dorsal and ventral visual circuits by differential Wnt signalling throughout development. Moreover, we show that the transcriptomes of neurons that are of the same type but are produced days apart become synchronized shortly after their production. During synaptogenesis we also resolved neuronal subtypes that, although differing greatly in morphology and connectivity, converge to indistinguishable transcriptomic profiles in adults. Our datasets almost completely account for the known neuronal diversity of the Drosophila optic lobes, and serve as a paradigm to understand brain development across species.

Real-World Outcomes and Value of First-Line Therapy for Metastatic Non-Small Cell Lung Cancer†.

Although physicians rely on clinical trial data to guide cancer treatment decisions, patient characteristics and outcomes often differ between real-world and clinical trial populations. We analyzed retrospective clinical data collected from a prior authorization (PA) tool linked with payer claims data to describe outcomes of first-line treatment for metastatic non-small cell lung cancer among 2,108 patients. Duration of therapy was shorter than observed in clinical trials. Healthcare costs and hospitalizations varied substantially by regimen. PA clinical data linked with administrative claims enable head-to-head comparisons of contemporary cancer treatments used in routine clinical practice, which are not available from clinical trials.

Smoking Status and Survival Among a National Cohort of Lung and Colorectal Cancer Patients.

INTRODUCTION: The purpose of this study was to explore the association of smoking status and clinically relevant duration of smoking cessation with long-term survival after lung cancer (LC) or colorectal cancer (CRC) diagnosis. We compared survival of patients with LC and CRC who were never-smokers, long-term, medium-term, and short-term quitters, and current smokers around diagnosis. METHODS: We studied 5575 patients in Cancer Care Outcomes Research and Surveillance (CanCORS), a national, prospective observational cohort study, who provided smoking status information approximately 5 months after LC or CRC diagnosis. Smoking status was categorized as: never-smoker, quit >5 years prior to diagnosis, quit between 1-5 years prior to diagnosis, quit less than 1 year before diagnosis, and current smoker. We examined the relationship between smoking status around diagnosis with mortality using Cox regression models. RESULTS: Among participants with LC, never-smokers had lower mortality risk compared with current smokers (HR 0.71, 95% CI 0.57 to 0.89). Among participants with CRC, never-smokers had a lower mortality risk as compared to current smokers (HR 0.79, 95% CI 0.64 to 0.99). CONCLUSIONS: Among both LC and CRC patients, current smokers at diagnosis have higher mortality than never-smokers. This effect should be further studied in the context of tumor biology. However, smoking cessation around the time of diagnosis did not affect survival in this sample. IMPLICATIONS: The results from our analysis of patients in the CanCORS consortium, a large, geographically diverse cohort, show that both LC and CRC patients who were actively smoking at diagnosis have worse survival as compared to never-smokers. While current smoking is detrimental to survival, cessation upon diagnosis may not mitigate this risk.

Cherub versus brat.

A long non-coding RNA molecule called cherub is a driver of tumor development.

Real-World Impact of a Decision Support Tool on Colony-Stimulating Factor Use and Chemotherapy-Induced Febrile Neutropenia Among Patients With Breast Cancer.

Background: White blood cell colony-stimulating factors (CSFs) decrease the incidence of chemotherapy-induced febrile neutropenia (FN). Widespread use of CSFs that is not guideline-concordant has been reported. Among patients with breast cancer receiving chemotherapy, the ability of evidence-based decision support tools to promote risk-appropriate reductions in CSF use without increased incidence of FN has not been examined. Methods: A retrospective cohort design and US commercial claims data were used. The impact of CSF decision support was analyzed among women with breast cancer receiving first-cycle chemotherapy from April 1, 2013, to March 30, 2015. The tool was implemented as part of a prior authorization process in 9 states starting July 1, 2014. Patients were assigned to intervention (ie, states where the decision support tool had been implemented) or nonintervention states (ie, 39 states where the tool had not been implemented). CSF use and subsequent incidence of FN were compared using difference-in-difference (DID) regressions adjusting for baseline differences in FN risk factors such as comorbidities and various infections. Results: The study sample of 7,224 patients (intervention states: pre-implementation, 1,991 and post-implementation, 2,010; nonintervention states: pre-implementation, 1,569 and post-implementation, 1,654) showed no significant difference in risk factors. Before and after implementation, a significant decrease in the proportion of patients with CSF use was observed in the intervention states (75% to 69%) compared with no significant change in the nonintervention (72% to 71%) states (DID, -5.4%; 95% CI, -6.0% to -4.7%; P=.006). No significance increase in FN incidence occurred in intervention (5.0% to 5.5%) and nonintervention (5.4% to 4.8%) states (DID, 0.2%; 95% CI, -0.20 to 0.30; P=.78). Similar results were obtained in subgroups by comorbidities and in sensitivity analyses by claims-based FN definitions. Conclusions: CSF use decreased modestly after implementation of the decision support tool, with no observed changes in FN rates. Such tools can reduce practice variation to improve care standards.

Effect and Efficiency of an Embedded Palliative Care Nurse Practitioner in an Oncology Clinic.

PURPOSE: To test a simultaneous care model for palliative care for patients with advanced cancer by embedding a palliative care nurse practitioner (NP) in an oncology clinic. METHODS: We evaluated the effect of the intervention in two oncologists' clinics beginning March 2014 by using implementation strategies, including use of a structured referral mechanism, routine symptom screening, integration of a psychology-based cancer supportive care center, implementation team meetings, team training, and a metrics dashboard for continuous quality improvement. After 1 year of implementation, we evaluated key process and outcome measures for supportive oncology and efficiency of the model by documenting tasks completed by the NP during a subset of patient visits and time-motion studies. RESULTS: Of approximately 10,000 patients with active cancer treated in the health system, 2,829 patients had advanced cancer and were treated by 42 oncologists. Documentation of advance care planning increased for patients of the two intervention oncologists compared with patients of the other oncologists. Hospice referral before death was not different at baseline, but was significantly higher for patients of intervention oncologists compared with patients of control oncologists (53% v 23%; P = .02) over the intervention period. Efficiency evaluation revealed that approximately half the time spent by the embedded NP potentially could have been completed by other staff (eg, a nurse, a social worker, or administrative staff). CONCLUSION: An embedded palliative care NP model using scalable implementation strategies can improve advance care planning and hospice use among patients with advanced cancer.

Physician variation in lung cancer treatment at the end of life.

OBJECTIVES: To determine whether a treating oncologist's characteristics are associated with variation in use of chemotherapy for patients with advanced non-small cell lung cancer (aNSCLC) at the end of life. STUDY DESIGN: Retrospective cohort. METHODS: Using the 2009 Surveillance, Epidemiology, and End Results-Medicare database, we studied chemotherapy receipt within 30 days of death among Medicare enrollees who were diagnosed with aNSCLC between 1999 and 2006, received chemotherapy, and died within 3 years of diagnosis. A multilevel model was constructed to assess the contribution of patient and physician characteristics and geography to receiving chemotherapy within 30 days of death. RESULTS: Among 21,894 patients meeting eligibility criteria, 43.1% received chemotherapy within 30 days of death. In unadjusted bivariate analyses, female sex, Asian or black race, older age, and a greater number of comorbid diagnoses predicted lower likelihood of receiving chemotherapy at the end of life (P ≤.038 for all comparisons). Adjusting for patient and physician characteristics, physicians in small independent practices were substantially more likely than those employed in other practice models, particularly academic practices or nongovernment hospitals, to order chemotherapy for a patient in the last 30 days of life (P <.001 for all comparisons); female physicians were less likely than males to prescribe such treatment (P = .04). CONCLUSIONS: Patients receiving care for aNSCLC in small independent oncology practices are more likely to receive chemotherapy in the last 30 days of life.

Reducing Overuse of Colony-Stimulating Factors in Patients With Lung Cancer Receiving Chemotherapy: Evidence From a Decision Support-Enabled Program.

PURPOSE: Colony-stimulating factors (CSFs) are frequently overused for the primary prevention of febrile neutropenia (FN) in patients receiving chemotherapy. METHODS: A retrospective cohort study design was used to analyze commercial claims data in adults with lung cancer initiated on chemotherapy from April 1, 2013, to March 30, 2015. The tool was implemented at oncology practices in phases across 14 US states. Patients were assigned to intervention and nonintervention states according to whether they resided in service areas where the tool had been implemented. Patients were followed up to 6 months after initiating chemotherapy. Difference in pre- and postimplementation CSF use and FN incidence rates were compared with the use of difference-in-differences (DID) models that were adjusted for baseline FN risk factors. RESULTS: The study population of 3,467 patients (intervention states: pre, 707; post, 1,150; nonintervention states: pre, 636; post, 974) showed no significant differences in FN risk factors at baseline. In adjusted results before and after implementation, CSF use decreased from 48.4% to 35.6% in the intervention states versus 43.2% to 44.4% in the nonintervention states (DID, -8.7%; 95% CI, -14.65% to -2.67%; P ≤ .001). The rates of FN were consistent for both groups in both periods, with no statistical difference in trend for the intervention (2.8% to 4.3%) versus the nonintervention (3.1% to 5.1%) states (DID, -0.13; 95% CI, -0.35 to 0.10; P = .927). CONCLUSION: These findings demonstrate that a decision support-enabled utilization management tool can improve risk-appropriate, guideline-adherent CSF use in patients with lung cancer.

Differences in Health Care Use and Costs Among Patients With Cancer Receiving Intravenous Chemotherapy in Physician Offices Versus in Hospital Outpatient Settings.

PURPOSE: The current shift in site of care from community oncology practices to the hospital outpatient department to deliver oncology services may have significant implications for the economic and clinical outcomes of cancer care. Therefore, this study compares health care use and costs among patients with cancer receiving intravenous (IV) chemotherapy in physician offices (PO) versus in hospital outpatient settings (HOP). METHODS: This retrospective study, which was based on medical and pharmacy claims data, included patients (age, 18 to 64 years) initiating IV chemotherapy/biologic treatment between January 1, 2006, and August 31, 2012, who were diagnosed with early or metastatic breast cancer, metastatic lung cancer, metastatic colorectal cancer, or non-Hodgkin lymphoma or chronic lymphocytic leukemia. Patients were assigned to PO or HOP groups on the basis of where they received > 95% of their IV cancer therapy. RESULTS: The study sample included 18,740 patients (12,899 PO; 5,841 HOP) who had a mean age of 51.6 years and a Deyo-Charlson Comorbidity Index score of 5.37. Overall office visits (21.8 ± 13.8 PO v 21.2 ± 12.9, P < .005) and outpatient services (50.8 ± 35.5 PO v 48.5 ± 33.6, P < .001) were higher in the PO group than in the HOP group. Cancer-related inpatient hospitalizations (0.6 ± 1.2 PO v 0.7 ± 1.4 HOP, P = .002) were lower in the PO group than in the HOP group. Although quality-of-care metrics were similar between the HOP and PO groups, follow-up all-cause costs ($82,773 PO v $122,473 HOP) and cancer-related health care costs ($69,037 PO v $108,177 HOP) were higher in the HOP group than in the PO group. CONCLUSION: Despite similar resource use, all-cause and cancer-related health care costs in HOP were significantly higher compared with those in PO settings.

The Symptom Experience in Rectal Cancer Survivors.

CONTEXT: As the number of rectal cancer survivors grows, it is important to understand the symptom experience after treatment. Although data show that rectal cancer survivors experience a variety of symptoms after diagnosis, little has been done to study the way these symptoms are grouped and associated. OBJECTIVES: To determine symptom prevalence and intensity in rectal cancer survivors and if clusters of survivors exist, who share similar symptom-defined survivor subgroups that may vary based on antecedent variables. METHODS: A secondary analysis of the Cancer Care and Outcomes Research and Surveillance database was undertaken. Cluster analysis was performed on 15-month postdiagnosis data to form post-treatment survivor subgroups, and these were examined for differences in demographic and clinical characteristics. Data were analyzed using cluster analysis, chi-square, and analysis of variance. RESULTS: A total of 275 rectal cancer survivors were included who had undergone chemotherapy, radiation therapy, and surgery. Most frequently reported symptoms included feeling "worn out" (87%), feeling "tired" (85%), and "trouble sleeping" (66%). Four symptom-defined survivor subgroups (minimally symptomatic n = 40, tired and trouble sleeping n = 138, moderate symptoms n = 42, and highly symptomatic n = 55) were identified with symptom differences existing among each subgroup. Age and being married/partnered were the only two antecedents found to differ across subgroups. CONCLUSION: This study documents differences in the symptom experience after treatment. The identification of survivor subgroups allows researchers to further investigate tailored, supportive care strategies to minimize ongoing symptoms in those with the greatest symptom burden.