The Perceived Usability of Virtual Visits Among Black Adults' Receiving Oncology Care: A Qualitative Analysis.

BACKGROUND: With the COVID-19 pandemic came rapid uptake in virtual oncology care. During this, sociodemographic inequities in access to virtual visits (VVs) have become apparent. To better understand these issues, we conducted a qualitative study to describe the perceived usability and acceptability of VVs among Black adults diagnosed with cancer. METHODS: Adults who self-identified as Black and had a diagnosis of prostate, multiple myeloma, or head and neck cancer were recruited from 2 academic medical centers, and their community affiliates to participate in a semi-structured interview, regardless of prior VV experience. A patient and family advisory board was formed to inform all components of the study. Interviews were conducted between September 2, 2021 and February 23, 2022. Transcripts were organized topically, and themes and subthemes were determined through iterative and interpretive immersion/crystallization cycles. RESULTS: Of the 49 adults interviewed, 29 (59%) had participated in at least one VV. Three overarching themes were derived: (1) VVs felt comfortable and convenient in the right contexts; (2) the technology required for VVs with video presented new challenges, which were often resolved by an audio-only telephone call; and (3) participants reported preferring in-person visits, citing concerns regarding gaps in nonverbal communication, trusting providers, and distractions during VV. CONCLUSION: While VVs were reported to be acceptable in specific circumstances, Black adults reported preferring in-person care, in part due to a perceived lack of interpersonal connectedness. Nonetheless, retaining reimbursement for audio-only options for VVs is essential to ensure equitable access for those with less technology savvy and/or limited device/internet capabilities.

A UK-wide study to describe resource consumption and waste management practices in skin surgery including Mohs micrographic surgery.

BACKGROUND: There is a lack of national guidance specifying how skin surgery, including Mohs micrographic surgery (MMS), should be conducted, leading to a degree of heterogeneity in the set-up of skin surgery services and how skin surgeries are performed. OBJECTIVES: To provide the first UK-wide cross-sectional study reporting real-world data on the set-up and waste management practices of skin surgery, including MMS. METHODS: A UK-wide service evaluation study was conducted between 1 March 2022 and 30 June 2022 using a standardized data collection pro forma. Twelve participating sites from England, Northern Ireland, Scotland and Wales provided data from 115 skin surgery lists involving 495 patients and 547 skin surgery procedures between 1 March 2022 and 30 June 2022. RESULTS: Mean total weight of nonsharps skin surgery waste was 0.52 kg per procedure (0.39 kg clinical waste, 0.05 kg general waste and 0.08 kg recycling waste). Data from a single site using disposable surgical instruments reported a mean of only 0.25 kg of sharps waste per procedure. The recycling rate ranged between 0% and 44% across the cohort with a mean recycling rate of 16%. CONCLUSIONS: We advocate that staff transition to the British Society of Dermatological Surgery 2022 sustainability guidance, which made wide-ranging recommendations to facilitate staff to transition to sustainable practices in skin surgery.

Increased Ephrin-B2 expression in pericytes contributes to retinal vascular death in rodents.

AIMS: Diabetes-induced retinal vascular cell death aggravates diabetic retinopathy (DR) to the proliferative stage and blindness. Pericytes play a crucial role in retinal capillaries survival, stability, and angiogenesis. Ephrin-B2 is a tyrosine kinase that regulates pericytes/endothelial cells communication during angiogenesis; yet, its role in DR is still unclear. We hypothesize that diabetes increases Ephrin-B2 signaling in pericytes, which contributes to inflammation and retinal vascular cell death. METHODS: Selective inhibition of the Ephrin-B2 expression in the retinal pericytes was achieved using an intraocular injection of adeno-associated virus (AAV) with a specific pericyte promotor. Vascular death was determined by retinal trypsin digest. Pathological angiogenesis was assessed using the oxygen-induced retinopathy model in pericyte-Ephrin-B2 knockout mice, wild type, and wild type injected with AAV. Angiogenic properties, inflammatory, and apoptotic markers were measured in human retinal pericytes (HRP) grown under diabetic conditions. KEY FINDING: Diabetes significantly increased the expression of Ephrin-B2, inflammatory, and apoptotic markers in the diabetic retinas and HRP. These effects were prevented by silencing Ephrin-B2 in HRP. Moreover, Ephrin-B2 silencing in retinal pericytes decreased pathological angiogenesis and acellular capillaries formation in diabetic retinas. SIGNIFICANCE: Increased Ephrin-B2 expression in the pericytes contributed to diabetes-induced retinal inflammation and vascular death. These results identify pericytes-Ephrin-B2 as a therapeutic target for DR.

A Review of Patient-Reported Outcomes Labeling for Oncology Drugs Approved by the FDA and the EMA (2012-2016).

OBJECTIVES: To compare US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labeling for evidence based on patient-reported outcomes (PROs) of new oncology treatments approved by both agencies. METHODS: Oncology drugs and indications approved between 2012 and 2016 by both the FDA and the EMA were identified. PRO-related language and analysis reported in US product labels and drug approval packages and EMA summaries of product characteristics were compared for each indication. RESULTS: In total, 49 oncology drugs were approved for a total of 64 indications. Of the 64 indications, 45 (70.3%) included PRO data in either regulatory submission. No FDA PRO labeling was identified. PRO language was included in the summary of product characteristics for 21 (46.7%) of 45 indications. European Organisation for Research and Treatment of Cancer and Functional Assessment of Cancer Therapy measures were used frequently in submissions. FDA's comments suggest that aspects of study design (eg, open labels) or the validity of PRO measures was the primary reason for the lack of labeling based on PRO endpoints. Both agencies identified missing PRO data as problematic for interpretation. CONCLUSIONS: During this time period, the FDA and the EMA used different evidentiary standards to assess PRO data from oncology studies, with the EMA more likely to accept data from open-label studies and broad concepts such as health-related quality of life. An understanding of the key differences between the agencies may guide sponsor PRO strategy when pursuing labeling. Patient-focused proximal concepts are more likely than distal concepts to receive positive reviews.

Inhibition of Ephrin-B2 in brain pericytes decreases cerebral pathological neovascularization in diabetic rats.

We have previously shown that diabetes causes dysfunctional cerebral neovascularization that increases the risk for cerebrovascular disorders such as stroke and cognitive impairment. Pericytes (PCs) play a pivotal role in the angiogenic process through their interaction with the endothelial cells (EC). Yet, the role of PCs in dysfunctional cerebral neovascularization in diabetes is unclear. In the present study, we tested the hypothesis that the increased proangiogenic Ephrin-B2 signaling in PCs contributes to the dysfunctional cerebral neovascularization in diabetes. Type-II diabetes was induced by a combination of high fat diet and low dose streptozotocin injection in male Wistar rats. Selective in vivo Ephrin-B2 silencing in brain PCs was achieved using the stereotactic injection of adeno-associated virus (AAV) with NG2-promoter that expresses Ephrin-B2 shRNA. Neovascularization was assessed using vascular fluorescent dye stain. Novel object recognition (NOR) test was used to determine cognitive functions. Human brain microvascular pericytes HBMVPCs were grown in high glucose 25 mM and palmitate 200 uM (HG/Pal) to mimic diabetic conditions. Scratch migration and tube formation assays were conducted to evaluate PC/EC interaction and angiogenic functions in PC/EC co-culture. Diabetes increased the expression of Ephrin-B2 in the cerebrovasculature and pericytes. Concomitant increases in cerebral neovascularization parameters including vascular density, tortuosity and branching density in diabetic rats were accompanied by deterioration of cognitive function. Inhibition of Ephrin-B2 expression in PCs significantly restored cerebral vascularization and improved cognitive functions. HG/Pal increased PC/EC angiogenic properties in co-culture. Silencing Ephrin-B2 in PCs significantly reduced PC migration and PC/EC co-culture angiogenic properties. This study emphasizes the significant contribution of PCs to the pathological neovascularization in diabetes. Our findings introduce Ephrin-B2 signaling as a promising therapeutic target to improve cerebrovascular integrity in diabetes.

Payer Perspectives on Patient-Reported Outcomes in Health Care Decision Making: Oncology Examples.

BACKGROUND: Health authorities and payers increasingly recognize the importance of patient perspectives and patient-reported outcomes (PROs) in health care decision making. However, given the broad variety of PRO endpoints included in clinical programs and variations in the timing of PRO data collection and country-specific needs, the role of PRO data in reimbursement decisions requires characterization. OBJECTIVES: To (a) determine the effect of PRO data on market access and reimbursement decisions for oncology products in multiple markets and (b) assess the effect of PRO data collected after clinical progression on payer decision making. METHODS: A 3-part assessment (targeted literature review, qualitative one-on-one interviews, and online survey) was undertaken. Published literature was identified through searches in PubMed/MEDLINE and Embase. In addition, a targeted search was conducted of health technology assessment (HTA) agency websites in the United States, the United Kingdom, France, and Germany. Qualitative one-on-one interviews were conducted with 16 payers from the RTI Health Solutions global advisory panel in 14 markets (Australia, Brazil, France, Germany, Italy, South Korea, Netherlands, Poland, Spain, Sweden, Taiwan, Turkey, the United Kingdom, and the United States [n = 3]). Of the 200 payers and payer advisors from the global advisory panel invited to participate in the online survey, 20 respondents (China, France, Germany, Spain [n = 2], Taiwan, the United Kingdom, and the United States [n = 13]) completed the survey, and 6 respondents (Australia, South Korea, and the United States [n = 4]) partially completed the survey. RESULTS: Reviews of the literature and publicly available HTAs and reimbursement decisions suggested that HTA bodies and payers have varying experience with and confidence in PRO data. Payers participating in the survey indicated that PRO data may be especially influential in oncology compared with other therapeutic areas. Payers surveyed offered little differentiation by cancer type in the importance of PRO data but felt that it was most important to collect PRO data in phase 3 and postmarketing studies. Payers surveyed also anticipated an increasing significance for PRO data over the next 5-10 years. Characteristics of PRO data that maximize influence on payer decision making were reported to be (a) quality, well-controlled, and transparent PRO evidence; (b) psychometric validation of the PRO measure in targeted populations; and (c) publication in peer-reviewed journals. In markets with decentralized health care decision making, PRO data currently have more influence at the local level. Inclusion of PRO data in cancer treatment guidelines is key for centralized markets. Payers surveyed generally considered collecting PRO data postprogression to be useful. Of the 16 interviewees, 11 indicated that it is worthwhile to collect PRO data postprogression and that positive PRO data may support continued therapy at the physician's discretion upon regulatory approval, even in progressive disease. CONCLUSIONS: PRO data may help to differentiate treatments, particularly after clinical progression in oncology. Payers worldwide recognize high-quality PRO data as a key component of their decision-making process and anticipate the growing importance of PRO data in the future. DISCLOSURES: This study and preparation of this article were funded by Novartis Pharmaceuticals. This research was performed under a research contract between RTI Health Solutions and Novartis Pharmaceuticals. Brogan, Hogue, Demuro, and Barrett are employees of RTI Health Solutions. D'Alessio and Bal are employees of Novartis Pharmaceuticals. Study concept and design were contributed by DeMuro, Barrett, Bal, and Hogue. Brogan and Hogue took the lead in data collection, assisted by DeMuro and Bal. Data interpretation was performed by Brogan and Hogue, assisted by the other authors. The manuscript was written by D'Alessio and Brogan, along with the other authors, and revised primarily by Brogan, along with Hogue and assisted by the other authors. The abstract for this article was presented as a research poster at the following meetings: Hogue SL, Brogan A P, De Muro C, D'Alessio D, Bal V. Patient-reported outcomes (PRO) in post-progression oncology: implications in health technology assessments and payer decision making. Poster presented at the ISPOR 18th Annual European Meeting; November 7-11, 2015. Milan, Italy. Hogue SL, Brogan AP, De Muro C, D'Alessio D, Bal V. Influence of patient-reported outcomes (PRO) on market access decisions in markets with centralized healthcare systems. Poster presented at the ISPOR 18th Annual European Meeting; November 7-11, 2015. Milan, Italy. Hogue SL, Brogan AP, De Muro C, Barrett A, D'Alessio D, Bal V. Influence of patient-reported outcomes on market access decisions in decentralized markets (Brazil, Italy, Spain and the United States). Poster presented at the ISPOR 20th Annual Meeting; May 16-20, 2015. Philadelphia PA. Hogue SL, Brogan A P, De Muro C, Barrett A, McLeod L, D'Alessio D, et al. Payer Perspectives of Patient-Reported Outcomes Data: An Online Assessment. Poster presented at the ISOQOL 22nd Annual Meeting; October 21-24, 2015. Vancouver, British Columbia, Canada.

Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants.

Most genetic association signals for type 2 diabetes risk are located in noncoding regions of the genome, hindering translation into molecular mechanisms. Physiological studies have shown a majority of disease-associated variants to exert their effects through pancreatic islet dysfunction. Systematically characterizing the role of regional transcripts in ß-cell function could identify the underlying disease-causing genes, but large-scale studies in human cellular models have previously been impractical. We developed a robust and scalable strategy based on arrayed gene silencing in the human ß-cell line EndoC-ßH1. In a screen of 300 positional candidates selected from 75 type 2 diabetes regions, each gene was assayed for effects on multiple disease-relevant phenotypes, including insulin secretion and cellular proliferation. We identified a total of 45 genes involved in ß-cell function, pointing to possible causal mechanisms at 37 disease-associated loci. The results showed a strong enrichment for genes implicated in monogenic diabetes. Selected effects were validated in a follow-up study, including several genes (ARL15, ZMIZ1, and THADA) with previously unknown or poorly described roles in ß-cell biology. We have demonstrated the feasibility of systematic functional screening in a human ß-cell model and successfully prioritized plausible disease-causing genes at more than half of the regions investigated.

Loss-of-Function Mutations in the Cell-Cycle Control Gene CDKN2A Impact on Glucose Homeostasis in Humans.

At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a noncoding region near CDKN2A. The disease-associated alleles have been implicated in reduced ß-cell function, but the underlying mechanism remains elusive. In mice, ß-cell-specific loss of Cdkn2a causes hyperplasia, while overexpression leads to diabetes, highlighting CDKN2A as a candidate effector transcript. Rare CDKN2A loss-of-function mutations are a cause of familial melanoma and offer the opportunity to determine the impact of CDKN2A haploinsufficiency on glucose homeostasis in humans. To test the hypothesis that such individuals have improved ß-cell function, we performed oral and intravenous glucose tolerance tests on mutation carriers and matched control subjects. Compared with control subjects, carriers displayed increased insulin secretion, impaired insulin sensitivity, and reduced hepatic insulin clearance. These results are consistent with a model whereby CDKN2A loss affects a range of different tissues, including pancreatic ß-cells and liver. To test for direct effects of CDKN2A-loss on ß-cell function, we performed knockdown in a human ß-cell line, EndoC-bH1. This revealed increased insulin secretion independent of proliferation. Overall, we demonstrated that CDKN2A is an important regulator of glucose homeostasis in humans, thus supporting its candidacy as an effector transcript for type 2 diabetes-associated alleles in the region.

Population whole-genome bisulfite sequencing across two tissues highlights the environment as the principal source of human methylome variation.

BACKGROUND: CpG methylation variation is involved in human trait formation and disease susceptibility. Analyses within populations have been biased towards CpG-dense regions through the application of targeted arrays. We generate whole-genome bisulfite sequencing data for approximately 30 adipose and blood samples from monozygotic and dizygotic twins for the characterization of non-genetic and genetic effects at single-site resolution. RESULTS: Purely invariable CpGs display a bimodal distribution with enrichment of unmethylated CpGs and depletion of fully methylated CpGs in promoter and enhancer regions. Population-variable CpGs account for approximately 15-20 % of total CpGs per tissue, are enriched in enhancer-associated regions and depleted in promoters, and single nucleotide polymorphisms at CpGs are a frequent confounder of extreme methylation variation. Differential methylation is primarily non-genetic in origin, with non-shared environment accounting for most of the variance. These non-genetic effects are mainly tissue-specific. Tobacco smoking is associated with differential methylation in blood with no evidence of this exposure impacting cell counts. Opposite to non-genetic effects, genetic effects of CpG methylation are shared across tissues and thus limit inter-tissue epigenetic drift. CpH methylation is rare, and shows similar characteristics of variation patterns as CpGs. CONCLUSIONS: Our study highlights the utility of low pass whole-genome bisulfite sequencing in identifying methylome variation beyond promoter regions, and suggests that targeting the population dynamic methylome of tissues requires assessment of understudied intergenic CpGs distal to gene promoters to reveal the full extent of inter-individual variation.

A comprehensive review of nongenetic prognostic and predictive factors influencing the heterogeneity of outcomes in advanced non-small-cell lung cancer.

While there have been advances in treatment options for those with advanced non-small-cell lung cancer, unmet medical needs remain, partly due to the heterogeneity of treatment effect observed among patients. The goals of this literature review were to provide updated information to complement past reviews and to identify a comprehensive set of nongenetic prognostic and predictive baseline factors that may account for heterogeneity of outcomes in advanced non-small-cell lung cancer. A review of the literature between 2000 and 2010 was performed using PubMed, Embase, and Cochrane Library. All relevant studies that met the inclusion criteria were selected and data elements were abstracted. A classification system was developed to evaluate the level of evidence for each study. A total of 54 studies were selected for inclusion. Patient-related factors (eg, performance status, sex, and age) were the most extensively researched nongenetic prognostic factors, followed by disease stage and histology. Moderately researched prognostic factors were weight-related variables and number or site of metastases, and the least studied were comorbidities, previous therapy, smoking status, hemoglobin level, and health-related quality of life/symptom severity. The prognostic factors with the most consistently demonstrated associations with outcomes were performance status, number or site of metastases, previous therapy, smoking status, and health-related quality of life. Of the small number of studies that assessed predictive factors, those that were found to be significantly predictive of outcomes were performance status, age, disease stage, previous therapy, race, smoking status, sex, and histology. These results provide a comprehensive overview of nongenetic prognostic and predictive factors assessed in advanced non-small-cell lung cancer over the last decade. This information can be used to inform the design of future clinical trials by suggesting additional subgroups based on nongenetic factors that may be analyzed to further investigate potential prognostic and predictive factors.

Systematic literature review assessing tobacco smoke exposure as a risk factor for serious respiratory syncytial virus disease among infants and young children.

BACKGROUND: The role of environmental tobacco smoke (ETS) exposure as a risk factor for serious respiratory syncytial virus (RSV) disease among infants and young children has not been clearly established. This systematic review was conducted to explore the association between ETS exposure and serious RSV disease in children younger than 5 years, including infants and young children with elevated risk for serious RSV disease. METHODS: A systematic review of English-language studies using the PubMed and EMBASE databases (1990-2009) was performed to retrieve studies that evaluated ETS as a potential risk factor for serious RSV illness. Studies assessing risk factors associated with hospitalization, emergency department visit, or physician visit due to RSV (based on laboratory confirmation of RSV or clinical diagnosis of RSV) in children under the age of 5 years were included. RESULTS: The literature search identified 30 relevant articles, categorized by laboratory confirmation of RSV infection (n = 14), clinical diagnosis of RSV disease (n = 8), and assessment of RSV disease severity (n = 8). Across these three categories of studies, at least 1 type of ETS exposure was associated with statistically significant increases in risk in multivariate or bivariate analysis, as follows: 12 of 14 studies on risk of hospitalization or ED visit for laboratory-confirmed RSV infection; 6 of 8 studies of RSV disease based on clinical diagnosis; and 5 of the 8 studies assessing severity of RSV as shown by hospitalization rates or degree of hypoxia. Also, 7 of the 30 studies focused on populations of premature infants, and the majority (5 studies) found a significant association between ETS exposure and RSV risk in the multivariate or bivariate analyses. CONCLUSION: We found ample evidence that ETS exposure places infants and young children at increased risk of hospitalization for RSV-attributable lower respiratory tract infection and increases the severity of illness among hospitalized children. Additional evidence is needed regarding the association of ETS exposure and outpatient RSV lower respiratory tract illness. Challenges and potential pitfalls of assessing ETS exposure in children are discussed.

Variability of gene expression profiles in human blood and lymphoblastoid cell lines.

BACKGROUND: Readily accessible samples such as peripheral blood or cell lines are increasingly being used in large cohorts to characterise gene expression differences between a patient group and healthy controls. However, cell and RNA isolation procedures and the variety of cell types that make up whole blood can affect gene expression measurements. We therefore systematically investigated global gene expression profiles in peripheral blood from six individuals collected during two visits by comparing five of the following cell and RNA isolation methods: whole blood (PAXgene), peripheral blood mononuclear cells (PBMCs), lymphoblastoid cell lines (LCLs), CD19 and CD20 specific B-cell subsets. RESULTS: Gene expression measurements were clearly discriminated by isolation method although the reproducibility was high for all methods (range rho = 0.90-1.00). The PAXgene samples showed a decrease in the number of expressed genes (P < 1*10(-16)) with higher variability (P < 1*10(-16)) compared to the other methods. Differentially expressed probes between PAXgene and PBMCs were correlated with the number of monocytes, lymphocytes, neutrophils or erythrocytes. The correlations (rho = 0.83; rho = 0.79) of the expression levels of detected probes between LCLs and B-cell subsets were much lower compared to the two B-cell isolation methods (rho = 0.98). Gene ontology analysis of detected genes showed that genes involved in inflammatory responses are enriched in B-cells CD19 and CD20 whereas genes involved in alcohol metabolic process and the cell cycle were enriched in LCLs. CONCLUSION: Gene expression profiles in blood-based samples are strongly dependent on the predominant constituent cell type(s) and RNA isolation method. It is crucial to understand the differences and variability of gene expression measurements between cell and RNA isolation procedures, and their relevance to disease processes, before application in large clinical studies.