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Chronic beryllium disease (CBD) is an exposure-related granulomatous disease mimicking sarcoidosis. Beryllium exposure-associated disease occurs mainly via inhalation, but skin may also be a source of sensitization. A 65-year-old male with a history of war-related shrapnel wounds was initially diagnosed with pulmonary sarcoidosis. Twenty years later, the possibility of a metal-related etiology for the lung disease was raised. A beryllium lymphocyte proliferation test, elemental analysis of removed shrapnel, and genetic studies were consistent with a diagnosis of CBD. This case demonstrates that retained beryllium-containing foreign bodies can be linked to a pathophysiologic response in the lung consistent with CBD.

In populations with separate sexes, genetic load due to deleterious mutations may be expressed differently in males and females. Evidence from insect models suggests that selection against mutations is stronger in males. This pattern will reduce deleterious allele frequencies at the expense of males, such that female mean fitness is greater than expected, preserving population persistence in the face of high mutation rates. While previous studies focus on reproductive success, mutation load depends on total selection in each sex, including selection for viability. We might expect minimal sex differences in viability effects in fruit flies, since male and female larvae behave similarly, yet many genes show sex-biased expression in larvae. We measured the sex-specific viability effects of nine "marker" mutations and 123 mutagenized chromosomes. We find that both types of mutations generally reduce viability in both sexes. Among marker mutations we detect instances of sex-biased effects in each direction; mutagenized chromosomes show little sex-specific mutational variance, but recessive lethals show a female bias, including in FlyBase records. We conclude that mutations regularly affect viability in a sex-specific manner, but that the strong pattern of male-biased mutational effects observed previously for reproductive success is not apparent at the pre-reproductive stage., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE). All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The cloning of beef carcasses that grade United States Department of Agriculture (USDA) Prime-yield grade (YG) 1 (P1) has produced a sire that ranked well against high-performing bulls from multiple breeds. An F1 (P1 × P1 - first generation offspring) sire would ideally outperform its high-performing parents. A terminal sire study was conducted comparing progeny of an F1 (P1 × P1) sire (AxG1) against progeny (heifers and steers) of four high-performing sires of varying breeds {P1 (ALPHA); Angus; Simmental; Angus × Simmental}. Production traits included morbidity and mortality frequencies, weaning weight, feedlot arrival weight, and days on feed; carcass traits included frequency of abscessed liver and lung health, quality grade and YG parameters, total carcass value (US$), and carcass value per hundredweight (CWT [45.4 kg]; US$). A completely randomized experimental design was used; data were analyzed using a mixed model with a fixed effect of sire and random effects of harvest date, sex, and pen. AxG1 sired heifers had the highest ( P  < 0.01) marbling score, the highest ( P  < 0.01) carcass value per CWT, and numerically had the lowest calculated YG and highest frequency of YG one carcass. Steers sired by AxG1 had the least ( P  = 0.05) backfat, lowest ( P  < 0.01) calculated YG, highest ( P  < 0.01) marbling score, highest ( P  < 0.01) frequency of USDA Prime carcasses, the greatest ( P  < 0.03) total carcass value, and greatest ( P  < 0.01) carcass value per CWT. Collectively, AxG1 steer and heifer carcasses exhibited the least 12th rib fat thickness and lowest USDA YG in addition to the largest longissimus muscle area, highest marbling score, and greatest frequency of USDA Prime. These data suggest that AxG1 performed comparably to other high-performing industry terminal sires in carcass quality and YG outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Objective: To understand US hospitals' initial strategic responses to the federal price transparency rule that took effect January 2021., Data Sources and Study Setting: Primary interview data collected from 12 not-for-profit hospital organizations in six US metropolitan markets. All but one organization were multihospital systems; the 12 organizations represent a total of 81 hospitals., Study Design: Exploratory, cross-sectional, qualitative interview study of a convenience sample of hospital organizations across six geographically and compliance diverse markets., Data Collection/extraction Methods: In-depth, semi-structured, qualitative interviews with 16 key informants across sampled organizations between November 2021 and March 2022. Interviews solicited data about internal organizational factors and external market factors affecting strategic responses. Transcribed interviews were de-identified, coded, and analyzed using the constant comparative method., Principal Findings: Hospitals' strategic responses were influenced internally by the degree of the regulation's alignment with organizational values and goals, and task complexity vis-a-vis available resources. We found extensive variation in organizational capabilities to comply, and all but one organization relied on consultants and vendors to some degree. Key external factors driving strategic responses were hospitals' variable perceptions about how available price information would affect their competitive position, bottom line, and reputation. Organizations with more confidence in their interpretation of the environment, including how peers or purchasers would behave, and greater clarity in their own organization's position and goals, had more definitive initial strategic responses. In the first year, organizations' strategic responses skewed toward compliance, especially for the rule's consumer shopping requirements., Conclusions: A deeper understanding of the realities of operationalizing price transparency policy for hospitals is needed to improve its impact., (© 2023 The Authors. Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Background: A large number of illnesses that lack physical visibility are characterised by troubled clinical encounters. Endometriosis is one such condition with very real and often debilitating symptoms that remain invisible to the clinician's eye, but are experienced and lived by the patient., Method: This paper probes into two first person accounts of endometriosis to find out how endometriosis patients experience health care. The Tiger and the Cage: A Memoir of a Body in Crisis (2022) by Emma Bolden and Vagina Problems: Endometriosis, Painful Sex, and Other Taboo Topics (2020) by Lara Parker are both memoirs that details on the trivialisation and delegitimization of the women's accounts of their own lived reality by a health care system that often privileges medical evidence over lived experiences of the patients. After giving a brief introduction on the condition, the paper goes on to detail on the method and conceptual frameworks chosen for analysis. This is followed by an in-depth analysis into the two texts using thematic analysis proposed by Virginia Braun and Victoria Clarke to identify shared patterns of meanings in the texts., Discussion: The identified themes take the form of emotions repeatedly narrated by the women. The findings indicate instances of disrespect, epistemic invalidation and compromised autonomy, due to which six shared categories of negative emotions are experienced by the patients: self-doubt, shame, fear, powerlessness, self-blame and anger., Conclusion: The paper concludes by indicating the urgency of improved medical training, that better educates and facilitates health care professionals in dealing with conditions with complicated aetiology, difficult diagnosis and no cure., (© 2024 John Wiley & Sons Ltd.)

Hypoxia-Inducible Factor-1α (HIF-1α) has presented a new direction for ischemic preconditioning of surgical flaps to promote their survival. In a previous study, we demonstrated the effectiveness of HIF-1a DNA plasmids in this application. In this study, to avoid complications associated with plasmid use, we sought to express HIF-1α through mRNA transfection and determine its biological activity by measuring the upregulation of downstream angiogenic genes. We transfected six different HIF-1a mRNAs-one predominant, three variant, and two novel mutant isoforms-into primary human dermal fibroblasts using Lipofectamine, and assessed mRNA levels using RT-qPCR. At all time points examined after transfection (3, 6, and 10 h), the levels of HIF-1α transcript were significantly higher in all HIF-1α transfected cells relative to the control (all p < 0.05, unpaired Student's T-test). Importantly, the expression of HIF-1α transcription response genes (VEGF, ANG-1, PGF, FLT1, and EDN1) was significantly higher in the cells transfected with all isoforms than with the control at six and/or ten hours post-transfection. All isoforms were transfected successfully into human fibroblast cells, resulting in the rapid upregulation of all five downstream angiogenic targets tested. These findings support the potential use of HIF-1α mRNA for protecting ischemic dermal flaps., (© 2024. The Author(s).)

Goal: As of January 1, 2021, the Centers for Medicare & Medicaid Services requires most U.S. hospitals to publish pricing information on their website to help consumers make decisions regarding services and to transform negotiations with health insurers. For this study, we evaluated changes in hospitals' compliance with the federal price transparency rule after the first year of enactment, during which the Centers for Medicare & Medicaid Services increased the penalty for noncompliance., Methods: Using a nationally representative random sample of 470 hospitals, we assessed compliance with both parts of the hospital transparency rule (publishing a machine-readable price database and a consumer shopping tool) in the first quarter of 2022 and compared its baseline level in the first quarter of 2021. Using data from the American Hospital Association and Clarivate, we next assessed how compliance varied by hospital factors (ownership, number of beds, system membership, teaching status, type of electronic health record system), market factors (hospital and insurer market concentration), and the estimated change in penalty for noncompliance., Principal Findings: By early 2022, 46% of hospitals had posted both machine-readable and consumer-shoppable data, an increase of 24% from the prior year. Almost 9 in 10 hospitals had complied with the consumer-shoppable data requirement by early 2022. Larger hospitals and public hospitals had lower probabilities of baseline compliance with the machine-readable and consumer-shoppable requirements, respectively, although public hospitals were significantly more likely to become compliant with the consumer-shoppable requirement by 2022. Higher hospital market concentration was also associated with higher baseline compliance for both the machine-readable and consumer-shoppable requirements. Furthermore, our analyses found that hospitals with certain electronic health record systems were more likely to comply with the consumer-shoppable requirement in 2021 and became increasingly compliant with the machine-readable requirement in 2022. Finally, we found that hospitals with a larger estimated penalty were more likely to become compliant with the machine-readable requirement., Practical Applications: Longitudinal analyses of compliance with the federal price transparency rule are valuable for monitoring changes in hospitals' behavior and assessing whether compliance changes vary systematically for specific types of hospitals and/or market structures. Our results suggest a trend toward increased hospital compliance between 2021 and 2022. Although hospitals perceive the consumer-shopping tools as being the most impactful, the value of this information depends on whether it is comprehensible and comparable across hospitals. The new price transparency rule has facilitated the creation of new data that have the potential to significantly alter the competitive landscape for hospitals and may require hospital leaders to consider how their organizational strategies change concerning their engagement with payers and patients. Finally, greater price transparency is likely to bolster national policy discussions related to price variation, affordability, and the role of regulation in healthcare markets., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Foundation of the American College of Healthcare Executives.)

Employers may respond to minimum wage increases by adjusting their health benefits. We examine the impact of state minimum wage increases on employer health benefit offerings using the 2002-2020 Medical Expenditure Panel Survey - Insurance/Employer Component data. Our primary regression specifications are difference-in-differences models that estimate the relationship between within-state changes in employer-sponsored insurance and minimum wage laws over time. We find that a $1 increase in minimum wages is associated with a 0.92 percentage point (p.p.) decrease in the percentage of employers offering health insurance, largely driven by small employers and employers with a greater share of low-wage employees. A $1 increase is also associated with a 1.83 p.p. increase in the prevalence of plans with a deductible requirement, but we do not find consistent evidence that other benefit characteristics are affected. We find no consequent change in uninsurance, likely explained by an increase in Medicaid enrollment., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To compare direct-to-consumer (DTC) telemedicine and in-person visits in rates of testing, follow-up health care use, and quality for urinary tract infections (UTIs) and sinusitis., Data Source: The Minnesota All Payer Claims Data provided 2008-2015 administrative claims data., Study Design: Using a difference-in-differences approach, we compared episodes of care for UTIs and sinusitis among enrollees of health plans introducing coverage for DTC telemedicine relative to those without DTC telemedicine coverage. Primary outcomes included number of laboratory tests, antibiotics filled, office and outpatient visits, emergency department (ED) visits, and standardized spending, based on standardized prices of health services., Data Collection: The study sample included non-elderly enrollees of commercial health insurance plans. We constructed 30-day episodes of care initiated by a DTC telemedicine or in-person visit., Principal Findings: The UTI and sinusitis samples were comprised of 215,134 and 624,630 episodes of care, respectively. Following the introduction of coverage for DTC telemedicine, 15.7% of UTI episodes and 8.9% of sinusitis episodes were initiated with DTC telemedicine. Compared to episodes without coverage for DTC telemedicine, UTI episodes with coverage had 0.25 fewer lab tests (95% CI: -0.33, -0.18; p < 0.001), lower standardized spending for the first UTI visit (-$11.18 [95% CI: -$21.62, -$0.75]; p < 0.05), and no change in office and outpatient visits, ED visits, antibiotics filled, or standardized medical spending. Sinusitis episodes with coverage for DTC telemedicine had fewer antibiotics filled (-0.08 [95% CI: -0.14, -0.01]; p < 0.05) and a very small increase in ED visits (0.001 [95% CI: 0.001, 0.010]; p < 0.05), but no change in lab tests, office and outpatient visits, or standardized medical spending., Conclusions: Among commercially insured patients, coverage of DTC telemedicine was associated with reductions in antibiotics for sinusitis and laboratory tests for UTI without changes in downstream total office and outpatient visits or changes in ED visits., (© 2023 Health Research and Educational Trust.)

Extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have recently been explored in clinical trials for treatment of diseases with complex pathophysiologies. However, production of MSC EVs is currently hampered by donor-specific characteristics and limited ex vivo expansion capabilities before decreased potency, thus restricting their potential as a scalable and reproducible therapeutic. Induced pluripotent stem cells (iPSCs) represent a self-renewing source for obtaining differentiated iPSC-derived MSCs (iMSCs), circumventing both scalability and donor variability concerns for therapeutic EV production. Thus, it is initially sought to evaluate the therapeutic potential of iMSC EVs. Interestingly, while utilizing undifferentiated iPSC EVs as a control, it is found that their vascularization bioactivity is similar and their anti-inflammatory bioactivity is superior to donor-matched iMSC EVs in cell-based assays. To supplement this initial in vitro bioactivity screen, a diabetic wound healing mouse model where both the pro-vascularization and anti-inflammatory activity of these EVs would be beneficial is employed. In this in vivo model, iPSC EVs more effectively mediate inflammation resolution within the wound bed. Combined with the lack of additional differentiation steps required for iMSC generation, these results support the use of undifferentiated iPSCs as a source for therapeutic EV production with respect to both scalability and efficacy., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Biomedical and philosophical traditions postulate the experience of pain either as quantifiable or as sociocultural phenomena. This critical assessment offers a close reading of Lara Parker's Vagina Problems: Endometriosis, Painful Sex, and Other Taboo Topics (2020) and Abby Norman's Ask Me About My Uterus: A Quest to Make Doctors Believe in Women's Pain (2018), analyzing the authors' use of language as a tool to comprehend and communicate pain. Norman's and Parker's memoirs narrate the lived experience of endometriosis, a condition diagnosed almost exclusively in women and characterized by chronic pain. The essay looks at how metaphors are employed in living and narrating endometriosis in medical, social, and cultural settings that are highly skeptical of women's pain and trace a shift in the use of pain metaphors towards an acceptance of the pain experience, which is conceptualized as empowering by the climax of the narrative.

Maternal mortality is disproportionately higher in low- and middle-income countries compared to other parts of the world. International research efforts are reflective of the urgency to improve global maternal outcomes. The existing literature of maternal health interventions in low- and middle-income countries targets a variety of populations and intervention types. However, there is a notable lack of systemic reviews that examine the wider contextual and mechanistic factors that have contributed to the outcomes produced by interventions. This article aims to use realist synthesis design to identify and examine the relationships between the contexts, mechanisms and outcomes of maternal health interventions conducted in low- and middle-income countries. This will inform evidence-based practice for future maternal health interventions. In May 2022, we searched four electronic databases for systematic reviews of maternal health interventions in low- and middle-income countries published in the last 5 years. We used open and axial coding of contexts, mechanisms and outcomes to develop an explanatory framework for intervention effectiveness. After eligibility screening and full-text analysis, 44 papers were included. The majority of effective interventions reported good healthcare system contexts, especially the importance of infrastructural capacity to implement and sustain the intervention. Most intervention designs used increasing knowledge and awareness at an individual and healthcare-provider level to produce intended outcomes. The majority of outcomes reported related to uptake of healthcare services by women. All mechanism themes had a relationship with this outcome. Health system infrastructure must be considered in interventions to ensure effective implementation and sustainability. Healthcare-seeking behaviours are embedded within social and cultural norms, environmental conditions, family influences and provider attitudes. Therefore, effective engagement with communities and families is important to create new norms surrounding pregnancy and delivery. Future research should explore community mobilization and involvement to enable tailored interventions with optimal contextual fit.

Background: Over 15.3 million Americans relied on the individual health insurance market for health coverage in 2021. Yet, little is known about the relationships between the organizational characteristics of individual market health insurers and quality of coverage, particularly with respect to clinical outcomes., Objective: To examine variation in marketplace insurers' quality performance and investigate how performance varies by insurer organizational characteristics., Design: Retrospective cohort study., Participants: 381 insurer products, representing 184 unique insurers in 50 states in 2019 and 2020., Main Measures: Marketplace plan clinical quality measures reported in the 2019-2020 CMS Plan Quality Rating System dataset and insurer-product organizational attributes identified from several data sources, including non-profit ownership, Blue Cross Blue Shield Association membership, Medicaid focus and whether or not the insurer product is vertically integrated with a provider organization., Key Results: Among the 381 insurer products in this study, 35% are part of a provider-sponsored health plan (PSHP) and 70% of these entities received four stars or above for overall quality performance. Overall, PSHPs exhibited higher quality than non-PSHPs for both clinical quality management (0.36 increased on a 5-point scale; 95% CI = 0.11 to 0.62; P = 0.005) and enrollee experience (0.27; 95% CI = 0.03 to 0.50; P = 0.03) summary indicators. Medicaid focused insurers were associated with lower performance on enrollee experience, plan administration, and various outcomes related to clinical quality., Conclusions: Provider-sponsored health plans in the health insurance marketplaces are associated with higher-quality care, as measured by CMS clinical quality measures., (© 2022. The Author(s) under exclusive licence to Society of General Internal Medicine.)

As of January 1, 2021, most U.S. hospitals are required to publish pricing information on their website to promote more informed decision making by consumers regarding their care. In a nationally representative sample of 470 hospitals, we analyzed whether hospitals met price transparency information reporting requirements and the extent to which complete reporting was associated with ownership status, bed size category, system affiliation, and location in a metropolitan area. Fewer than one quarter of sampled hospitals met the price transparency information requirements of the new rule, which include five types of standard charges in machine-readable form and the consumer-shoppable display of 300 shoppable services. Our analyses of hospital reporting by organizational and market attributes revealed limited differences, with some exceptions for nonprofit and system-member hospitals demonstrating greater responsiveness with respect to the consumer-shoppable aspects of the rule.

Performance improvement on clinical quality outcomes typically requires significant effort by personnel in health care organizations. Understanding the cost of quality improvement is important given diffusion of value-based contracting. This study investigates the organizational costs and benefits associated with planning and implementing the Ask about Aspirin intervention to increase use of low-dose aspirin in clinically recommended patient populations. Data from 4 health systems in Minnesota were used to estimate personnel effort and labor resource costs as well as corresponding benefits, measured as the change in aspirin use among eligible candidates during the study period. Overall personnel effort across the 4 systems was approximately 3900 hours with corresponding resource costs estimated to be $214,385. Aspirin use increased 4.7% overall, corresponding to roughly 1530 new users in the aspirin candidate population. Significant variation was observed by system in total hours reported, distribution of effort by activity type, and in benefits realized from the intervention., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Ischemic necrosis of surgical flaps after reconstruction is a major clinical problem. Hypoxia-inducible factor-1α (HIF-1α) is considered the master regulator of the adaptive response to hypoxia. Among its many properties, it regulates the expression of genes encoding angiogenic growth factors, which have a short half-life in vivo. To achieve a continuous application of the therapeutic, we utilized DNA plasmid delivery. Transcription of the DNA plasmid confirmed by qRT-PCR showed significantly increased mRNA for HIF-1α in the transfected tissue compared to saline control tissue. Rats were preconditioned by injecting with either HIF-1α DNA plasmid or saline intradermally in the designated flap region on each flank. Seven days after preconditioning, each rat had two isolated pedicle flaps raised with a sterile silicone sheet implanted between the skin flap and muscle layer. The flaps preconditioned with HIF-1α DNA plasmid had significantly less necrotic area. Angiogenesis measured by CD31 staining showed a significant increase in the number of vessels per high powered field in the HIF-1α group (p < 0.05). Our findings offer a potential therapeutic strategy for significantly promoting the viability of surgical pedicle flaps by ischemic preconditioning with HIF-1α DNA plasmid.

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Recently, long noncoding RNAs (lncRNAs) have been identified as key regulators of biological pathways. However, involvement of lncRNAs in the development of BE and EAC has not been well-studied. The aims of the current study were: (1) to study involvement of the lncRNA, miR205HG , in the development of BE and EAC; (2) to clarify the role of miR205HG in in vitro and in vivo experiments; and (3) to investigate the mechanism of miR205HG involving the Hedgehog (Hh) signaling pathway. These experiments revealed that miR205HG was downregulated in EAC vs. normal esophageal epithelia (NE) as well as in EAC cell lines, and its forced overexpression inhibited EAC cell proliferation and cell cycle progression in vitro. Similarly, overexpression of miR205HG inhibited xenograft tumor growth in mice In vivo. Finally, we show that one mechanism of action of miR205HG involves the Hh signaling pathway: miR205HG and Hh expression levels were inversely correlated in both EAC (r = -0.73) and BE (r = -0.83) tissues, and in vitro studies revealed details of Hh signaling inhibition induced by miR205HG. In conclusion, these findings establish that lncRNA miR205HG functions as a tumor suppressor in the development of BE and EAC, at least in part through its effect on the Hh signaling pathway.

Purpose of Review: People with cystic fibrosis (CF) are living longer. General age-related and CF-specific gastrointestinal symptoms are increasingly recognized. In this article, we review the latest data on luminal gastrointestinal manifestations in CF., Recent Findings: People with CF have increased incidence of gastroesophageal reflux disease symptoms and often prescribed proton-pump inhibitors (PPI). PPI use may increase risk of pulmonary exacerbations. Evidence to support gastric fundoplication to improve pulmonary outcomes is limited. Features of intestinal dysmotility are common. There are distinct differences in the gut microbiome in the CF population which may have clinical implications. CF is a possible hereditary digestive cancer syndrome, particularly in regard to colorectal cancer (CRC) with earlier incidence of CRC and advanced colonic neoplasia. Early screening colonoscopy is warranted in the CF population. Gastrointestinal manifestations in CF are prevalent across all digestive organs. More study on the effect of interventions for symptomatic treatment and cancer screening is needed.

Objective: Using 2019 Centers for Medicare and Medicaid Services data, the authors analyzed performance on behavioral health care quality measures among 168 marketplace insurers offering 185 products and investigated whether performance differed by insurer attributes., Methods: The authors considered four quality measures: antidepressant medication management, follow-up care for children prescribed attention-deficit hyperactivity disorder medication, follow-up care within 7 days after hospitalization for mental illness, and initiation and engagement of alcohol and other drug dependence treatment. Multivariate regression was used to determine whether performance varied by insurers' nonprofit ownership, Blue Cross-Blue Shield affiliation, Medicaid-managed care participation, and preferred provider organization status., Results: Performance levels were highest for management with antidepressant medication and lowest for initiation and engagement of drug dependence treatment. Systematic differ-ences were observed by ownership status and Medicaid-managed care plan status., Conclusions: Increasing the transparency of health plan quality information is important for aiding enrollee decision making and encouraging quality improvement among providers and insurers.

Purpose: Small employers, while motivated to implement wellness programs, often lack knowledge and resources to do so. As a result, these firms rely on external decision-making support from insurance brokers. The objective of this study was to analyze brokers' familiarity with wellness programs and to characterize their role and interactions with small employers., Design: Using a newly developed common interview guide (20 questions), protocol and analysis plan, 20 interviews were conducted with health insurance brokers in Illinois, Minnesota, North Carolina and Washington in 2016 and 2017. In addition to exploring patterns of broker interactions and familiarity by segment, we propose a framework to conceptualize the broker-client relationship using social capital theory and the RE-AIM model., Methods: Interviews were transcribed, summarized and a common codebook was established using DeDoose. Themes were identified following multi-rater coding and structured within the framework., Results: Participating brokers reported having a high to moderate familiarity with wellness programs (65%) and a majority (80%) indicated that they have previously advised their small business clients on the availability and features of them. Further, we find that brokers may help eliminate barriers to resources and act as a connector to wellness opportunities within their professional network., Conclusion: New initiatives to promote small employer wellness programs can benefit from examining the influence of brokers on the decision-making process. When engaged and supported with resources, brokers may be effective champions for employer wellness programs.

Background: Thiopurine methyltransferase (TPMT) activity influences azathioprine conversion into active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity correlates with high 6-TGN and risk for myelosuppression. Conversely, normal-to-high TPMT activity may be associated with low 6-TGN and drug resistance, the so-called hypermetabolizers. Our aim was to identify the effect of normal-to-high TPMT activity on 6-TGN concentrations in an inflammatory bowel disease population., Methods: A retrospective chart review of patients aged ≥18 with inflammatory bowel disease, on azathioprine, with documented TPMT activity and 6-TGN concentration was performed. Correlations were evaluated via the Spearman rho correlation coefficient. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for confounders. Relationships between TPMT activity, drug dose, and 6-TGN levels were defined via average causal mediation effects., Results: One hundred patients were included. No correlation was observed between TPMT activity, azathioprine dosing, and metabolite concentrations. Overall, 39% of the cohort had a therapeutic 6-TGN level of >230 pmol/8 × 10 8 red blood cells (RBCs). No patient under 1 mg/kg achieved a therapeutic 6-TGN level, whereas 42% of patients taking 2.5 mg/kg did. The median 6-TGN concentration was higher for those in remission (254 pmol/8 × 10 8 RBCs, interquartile range: 174, 309) versus those not in remission (177 pmol/8 × 10 8 RBCs, interquartile range: 94.3, 287.8), though not significantly ( P = 0.08). Smoking was the only clinical factor associated with 6-TGN level. On multivariate linear regression, only age, azathioprine dose, and obese body mass index were predictive of metabolite concentration., Conclusions: Variations within the normal range of TPMT activity do not affect 6-TGN concentration., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

One of the Affordable Care Act's (ACA) signature reforms was creating centralized Health Insurance Marketplaces to offer comprehensive coverage in the form of comprehensive insurance complying with the ACA's coverage standards. Yet, even after the ACA's implementation, millions of people were covered through noncompliant plans, primarily in the form of continued enrollment in "grandmothered" and "grandfathered" plans that predated ACA's full implementation and were allowed under federal and state regulations. Newly proposed and enacted federal legislation may grow the noncompliant segment in future years, and the employment losses of 2020 may grow reliance on individual market coverage further. These factors make it important to understand how the noncompliant segment affects the compliant segment, including the Marketplaces. We show, first, that the noncompliant segment of the individual insurance market substantially outperformed the compliant segment, charging lower premiums but with vastly lower costs, suggesting that insurers have a strong incentive to enter the noncompliant segment. We show, next, that state's decisions to allow grandmothered plans is associated with stronger financial performance of the noncompliant market, but weaker performance of the compliant segment, as noncompliant plans attract lower-cost enrollees. This finding indicates important linkages between the noncompliant and compliant segments and highlights the role state policy can play in the individual insurance market. Taken together, our results point to substantial cream-skimming, with noncompliant plans enrolling the healthiest enrollees, resulting in higher average claims cost in the compliant segment.

This article investigates changes in the affordability of individual health plans (Marketplace plans) that were compliant with the Affordable Care Act following the termination of cost-sharing reduction subsidy payments in 2017. We examined how states' and insurers' responses to these cuts affected enrollees differently depending on whether they lived in rural or urban geographic areas and were or were not eligible for Advance Premium Tax Credits. Using data for 2014-19 from the Health Insurance Exchange Compare database and other sources, we found that subsidy-eligible enrollees in rural markets gained access to Marketplace plans that were more affordable than those available to their urban counterparts, after the cuts affected premiums in 2018. Average minimum net monthly premiums for subsidized enrollees in majority-rural geographic rating areas decreased from $288 in 2017 to $162 in 2019, while those of their urban counterparts decreased from $275 to $180. In contrast, rural enrollees without subsidies faced the least affordable premiums for Marketplace plans.

Using the 2010-2015 Medical Expenditure Panel Survey-Insurance Component, this study investigates the effect of the Affordable Care Act's Medicaid eligibility expansion on four employer-sponsored insurance (ESI) outcomes: offers of health insurance, eligibility, take-up, and the out-of-pocket premium paid by employees for single coverage. Using a difference-in-differences identification strategy, we cannot reject the hypothesis of a zero effect of the Medicaid eligibility expansion on an establishment's probability of offering ESI, the percentage of an establishment's workforce that takes up coverage, or the out-of-pocket premium for single coverage. We find some evidence suggestive of an inverse relationship between the expansion of Medicaid and the percentage of an establishment's workers eligible for ESI. In line with other employer- and individual-level studies of the effect of the ACA on employment-related outcomes, we find that employer provision of health insurance was largely unaffected by the Medicaid expansions.

MicroRNAs (miRs) are post-transcriptional regulators involved in the initiation and progression of many tumors. Recently, naturally occurring circular RNAs (circRNAs) have been described in eukaryotic cells:;they comprise a new class of gene regulators. Naturally occurring circular miR sponges, which induce miR loss-of-function, can prevent endogenous onco-miRs from binding to their cognate mRNA targets. These findings suggest that synthetic (artificial) circular RNAs could be constructed as therapeutic molecular sponges to suppress harmful onco-miRs. Using enzymatic ligation, we designed and constructed a circular RNA containing both miR-21 and miR-93 binding sites. The synthetic circular sponge was resistant to digestion with RNase R. Luciferase assays and functional experiments showed that the circular multi-miR sponge was more stable than its linear counterpart. Moreover, endogenous miR-21 and miR-93 were inhibited by the circular sponge. In addition, the synthetic sponge significantly suppressed cellular proliferation and migration while promoting apoptosis in esophageal carcinoma cells. Finally, in a murine xenograft model, the circular sponge significantly inhibited tumor growth in vivo. Taken together, these findings establish that the design and construction of efficient artificial miR sponges represent a novel strategy to achieve miR loss-of-function in molecular cancer therapeutics.

Background: Hepatocellular carcinoma (HCC) is now the second-highest cause of cancer death worldwide. Recent studies have discovered a wide range of somatic mutations in HCC. These mutations involve various vital signaling pathways such as: Wnt/ β -Catenin, p53, telome-rase reverse transcriptase (TERT), chromatin remodeling, RAS/MAPK signaling, and oxidative stress. However, fusion transcripts have not been broadly explored in HCC., Methods: To identify novel fusion transcripts in HCC, in the first phase of our study, we performed targeted RNA sequencing (in HCC and paired non-HCC tissues) on 6 patients with a diagnosis of HCC undergoing liver transplantation., Results: As a result of these studies, we discovered the novel fusion transcript, VTI1A-CFAP46. In the second phase of our study, we measured the expression of wild-type VTI1A in 21 HCC specimens, which showed that 10 of 21 exhibited upregulation of wild-type VTI1A in their tumors. VTI1A (Vesicle Transport via Interaction with t-SNARE homolog 1A) is a member of the Soluble N-ethylmaleimide-Sensitive Factor (NSF) attachment protein receptor (SNARE) gene family, which is essential for membrane trafficking and function in endocytosis, autophagy, and Golgi transport. Notably, it is known that autophagy is involved in HCC., Conclusions: The link between novel fusion transcript VTI1A-CFAP46 and autophagy as a potential therapeutic target in HCC patients deserves further investigation. Moreover, this study shows that fusion transcripts are worthy of additional exploration in HCC., Competing Interests: Robert Anders received research fund from the Fibrolamellar Cancer Foundation. All other authors have no conflicts of interest., (Copyright © 2019 by S. Karger AG, Basel.)

Objective: To investigate how changes in insurer participation and composition as well as state policies affect health plan affordability for individual market enrollees., Data Sources: 2014-2019 Qualified Health Plan Landscape Files augmented with supplementary insurer-level information., Study Design: We measured plan affordability for subsidized enrollees using premium spreads, the difference between the benchmark plan and the lowest cost plan, and premium levels for unsubsidized enrollees. We estimated how premium spreads and levels varied with insurer participation, insurer composition, and state policies using log-linear models for 15 222 county-years., Principal Findings: Increased insurer participation reduces premium levels, which is beneficial for unsubsidized enrollees. However, it also reduces premium spreads, leading to lower plan affordability for subsidized enrollees. States responding to cost-sharing reduction subsidy payment cuts by increasing only silver plans' premiums increase premium spreads, particularly when premium increases are restricted to on-Marketplace silver plans. The latter approach also protects unsubsidized, off-Marketplace enrollees from experiencing premium shocks., Conclusions: Insurer participation and insurer composition affect subsidized and unsubsidized enrollees' health plan affordability in different ways. Decisions by state regulators regarding health plan pricing can significantly affect health plan affordability for each enrollee segment., (© Health Research and Educational Trust.)

Background: The increasing life expectancy of individuals with Cystic Fibrosis (CF) is likely to be associated with new age-related challenges, colorectal cancer (CRC) most notably; recent consensus recommendations for CRC screening published in 2018 represent an important early step in addressing the emerging awareness of CF as a gastrointestinal cancer syndrome. These recommendations, however, need to be further refined based on more systematic data. We discuss an illustrative first-ever case of synchronous CRC arising in a post-lung transplant individual with CF within the recommended surveillance interval after a well-documented prior normal colonoscopy., Case Presentation: A 51-year-old female individual with homozygous F508del CF, presents to clinic with abdominal discomfort and intermittent blood in stools. She had previously undergone bilateral lung transplantation 18 years earlier, as well as two kidney transplants related to immunosuppression-related nephrotoxicity. A diagnostic colonoscopy was performed which revealed the presence of two separate synchronous colon cancers in the cecum and transverse colon; she had undergone a colonoscopy three years prior to this exam which was structurally normal. Endoscopic quality indicators, including a good quality bowel preparation, colonoscopic withdrawal time > 12 min, and quarterly Adenoma Detection Rate (ADR) ranging from 50 to 70% for both male and female patients for the endoscopist from both colonoscopic exams, as well as secondary retrospective comparative review of the pertinent case images, diminish the risk for a "missed" cancer or advanced lesion on the index exam. These cancers did not demonstrate any immunohistochemical features suggestive of Lynch Syndrome, though the rapid progression to cancer within the surveillance interval (possibly non-polypoid in nature) is similar. This cancer presentation within the newly-established recommended colon cancer screening interval warrants concern., Conclusions: This case prompts serious discussion regarding the length of surveillance intervals in the post-transplant CF population (a population at 20-30 times greater risk for CRC compared to the general non-CF population), as well as the importance of documenting endoscopic quality benchmarks, particularly if a narrative of interval CRC development continues to develop with further prospective monitoring and multi-center experience.

The individual and small-group health insurance markets have experienced considerable changes since the passage of the Affordable Care Act in 2010, affecting access, choice, and affordability for enrollees in these markets. We examined how health plan access, choice, and affordability varied between the individual on-Marketplace, individual off-Marketplace, and small-group markets in 2018. We found relatively similar outcomes across the three markets with respect to deductibles and out-of-pocket spending maximums. However, the small-group market maintained greater plan choice and lower premiums-outcomes that appear to be associated with higher insurer participation. States may consider a variety of policy proposals such as reinsurance or the introduction of a public option to increase insurer participation and improve the plan choices offered in the individual market.

Purpose: Barrett's esophagus is the only known precursor of esophageal adenocarcinoma (EAC). Although endoscopy and biopsy are standard methods for Barrett's esophagus diagnosis, their high cost and risk limit their use as a screening modality. Here, we sought to develop a Barrett's esophagus detection method based on methylation status in cytology samples captured by EsophaCap using a streamlined sensitive technique, methylation on beads (MOB)., Experimental Design: We conducted a prospective cohort study on 80 patients (52 in the training set; 28 in the test set). We used MOB to extract and bisulfite-convert DNA, followed by quantitative methylation-specific PCR to assess methylation levels of 8 previously selected candidate markers. Lasso regression was applied to establish a prediction model in the training set, which was then tested on the independent test set., Results: In the training set, five of eight candidate methylation biomarkers ( p1 6, HPP1, NELL1, TAC1 , and AKAP12 ) were significantly higher in Barrett's esophagus patients than in controls. We built a four-biomarker-plus-age lasso regression model for Barrett's esophagus diagnosis. The AUC was 0.894, with sensitivity 94.4% [95% confidence interval (CI), 71%-99%] and specificity 62.2% (95% CI, 44.6%-77.3%) in the training set. This model also performed with high accuracy for Barrett's esophagus diagnosis in an independent test set: AUC = 0.929 ( P < 0.001; 95% CI, 0.810%-1%), with sensitivity=78.6% (95% CI, 48.8%-94.3%) and specificity = 92.8% (95% CI, 64.1%-99.6%)., Conclusions: EsophaCap, in combination with an epigenetic biomarker panel and the MOB method, is a promising, well-tolerated, low-cost esophageal sampling strategy for Barrett's esophagus diagnosis. This approach merits further prospective studies in larger populations., (©2019 American Association for Cancer Research.)

MicroRNA (miR) sponges containing miR binding sequences constitute a potentially powerful molecular therapeutic strategy. Recently, naturally occurring circular RNAs (circRNAs) were shown to function as efficient miR sponges in cancer cells. We hypothesized that synthetic circRNA sponges could achieve therapeutic loss-of-function targeted against specific miRs. Linear RNA molecules containing miR-21 binding sites were transcribed in vitro; after dephosphorylation and phosphorylation, circularization was achieved using 5'-3' end-ligation by T4 RNA ligase 1. circRNA stability was assessed using RNase R and fetal bovine serum. Competitive inhibition of miR-21 activity by a synthetic circRNA sponge was assessed using luciferase reporter, cell proliferation, and cell apoptosis assays in three gastric cancer cell lines. circRNA effects on downstream proteins were also delineated by Tandem Mass Tag (TMT) labeling (data available via ProteomeXchange identifier PRIDE: PXD008584), followed by western blotting. We conclude that artificial circRNA sponges resistant to nuclease digestion can be synthesized using simple enzymatic ligation steps. These sponges inhibit cancer cell proliferation and suppress the activity of miR-21 on downstream protein targets, including the cancer protein DAXX. In summary, synthetic circRNA sponges represent a simple, effective, convenient strategy for achieving targeted loss of miR function in vitro, with potential future therapeutic application in human patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

In recent years state and federal policies have encouraged the use of telemedicine by formalizing payments for it. Telemedicine has the potential to expand access to timely care and reduce costs, relative to in-person care. Using information from the Minnesota All Payer Claims Database, we conducted a population-level analysis of telemedicine service provision in the period 2010-15, documenting variation in provision by coverage type, provider type, and rurality of patient residence. During this period the number of telemedicine visits increased from 11,113 to 86,238, and rates of use varied extensively by coverage type and rurality. In metropolitan areas telemedicine visits were primarily direct-to-consumer services provided by nurse practitioners or physician assistants and covered by commercial insurance. In nonmetropolitan areas telemedicine use was chiefly real-time provider-initiated services delivered by physicians to publicly insured populations. Recent federal and state legislation that expanded coverage and increased provider reimbursement for telemedicine services could lead to expanded use of telemedicine, including novel approaches in new patient populations.

Primary organoid cultures generated from patient biopsies comprise a novel improved platform for disease modeling, being genetically stable and closely recapitulating in vivo scenarios. Barrett esophagus (BE) is the major risk factor for esophageal adenocarcinoma. There has been a dearth of long-term in vitro expansion models of BE neoplastic transformation. We generated a long-term virus-free organoid expansion model of BE neoplasia from patient biopsies. Both wild-type and paired APC-knockout (APC KO ) BE organoids genome-edited by CRISPR-Cas9 showed characteristic goblet cell differentiation. Autonomous Wnt activation was confirmed in APC KO organoids by overexpression of Wnt target genes and nuclear-translocated β-catenin expression after withdrawal of Wnt-3A and R-spondin-1. Wnt-activated organoids demonstrated histologic atypia, higher proliferative and replicative activity, reduced apoptosis, and prolonged culturability. Wnt-activated organoids also showed sustained protrusive migration ability accompanied by disrupted basement membrane reorganization and integrity. This CRISPR-Cas9 editing human-derived organoid model recapitulates the critical role of aberrant Wnt/β-catenin signaling activation in BE neoplastic transformation. This system can be used to study other 'driver' pathway alterations in BE-associated neoplasia, avoiding signaling noise present in immortalized or cancer-derived cell lines., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Elderly seasonal migrators share time between homes in different states, presenting challenges for care coordination and patient attribution methods. Medicare has prioritized alternative payment models, putting health care providers at risk for quality and value of services delivered to their attributed patients, regardless of the location of care. Little research is available to guide providers and payers on the service use of seasonal migrators. The authors use claims data on fee-for-service (FFS) Medicare beneficiaries' locations throughout the year to (1) identify seasonal migrators and (2) describe the care they receive in each seasonal home, focusing on primary care and emergency department (ED) visits and the relationships between the two. In all, 5.5% of the Medicare aged FFS population were identified as seasonal migrators, with 4.1% following the traditional snowbird pattern of migration, spending warm months in the north and cold months in the south. Migrators had higher rates of ED visits and primary care treatable (PCT) ED visits than the nonmigratory groups, controlling for location, age, race, sex, Medicaid status, season, and comorbidities. They also had more visits with specialist physicians, more days with outpatient services, and more days seeing a physician in any setting. Having local primary care strongly reduced rates of both PCT ED visits and total ED visits for all migration categories, with the greatest reduction seen in PCT ED visits by migrators (local primary care was associated with a 58% reduction in PCT ED visits by snowbirds and a 65% reduction in PCT ED visits by other migrators).

Objectives The United States is one of only three countries worldwide with no national policy guaranteeing paid leave to employed women who give birth. While maternity leave has been linked to improved maternal and child outcomes in international contexts, up-to-date research evidence in the U.S. context is needed to inform current policy debates on paid family leave. Methods Using data from Listening to Mothers III, a national survey of women ages 18-45 who gave birth in 2011-2012, we conducted multivariate logistic regression to predict the likelihood of outcomes related to infant health, maternal physical and mental health, and maternal health behaviors by the use and duration of paid maternity leave. Results Use of paid and unpaid leave varied significantly by race/ethnicity and household income. Women who took paid maternity leave experienced a 47% decrease in the odds of re-hospitalizing their infants (95% CI 0.3, 1.0) and a 51% decrease in the odds of being re-hospitalized themselves (95% CI 0.3, 0.9) at 21 months postpartum, compared to women taking unpaid or no leave. They also had 1.8 times the odds of doing well with exercise (95% CI 1.1, 3.0) and stress management (95% CI 1.1, 2.8), compared to women taking only unpaid leave. Conclusions for Practice Paid maternity leave significantly predicts lower odds of maternal and infant re-hospitalization and higher odds of doing well with exercise and stress management. Policies aimed at expanding access to paid maternity and family leave may contribute toward reducing socio-demographic disparities in paid leave use and its associated health benefits.

Wellness programs are a popular strategy utilized by large U.S. employers. As mobile health applications and wearable tracking devices increase in prevalence, many employers now offer physical activity tracking applications. This longitudinal study evaluates the impact of engagement with a web-based, physical activity tracking program on changes in individuals' biometric outcomes in an employer population. The study population includes active employees and adult dependents continuously enrolled in an eligible health plan and who have completed at least two biometric screenings (n=36,882 person-years with 11,436 unique persons) between 2011 and 2014. Using difference-in-differences (DID) regression, we estimate the effect of participation in the physical activity tracking application on BMI, total cholesterol, and blood pressure. Participation was significantly associated with a reduction of 0.275 in BMI in the post-period, relative to the comparison group, representing a 1% change from baseline BMI. The program did not have a statistically significant impact on cholesterol or blood pressure. Sensitivity checks revealed slightly larger BMI reductions among participants with higher intensity of tracking activity and in the period following the employer's shift to an outcomes-based incentive design. Results are broadly consistent with the existing literature on changes in biometric outcomes from workplace initiatives promoting increased physical activity. Employers should have modest expectations about the potential health benefits of such programs, given current designs and implementation in real-world settings., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We investigate determinants of market entry and premiums within the context of the Affordable Care Act's Marketplaces for individual insurance. Using Bresnahan and Reiss (1991) as the conceptual framework, we study how competition and firm heterogeneity relate to premiums in 36 states using Federally Facilitated or Supported Marketplaces in 2016. Our primary data source is the Qualified Health Plan Landscape File, augmented with market characteristics from the American Community Survey and Area Health Resource File as well as insurer-level information from federal Medical Loss Ratio annual reports. We first estimate a model of insurer entry and then investigate the relationship between a market's predicted number of entrants and insurer-level premiums. Our entry model results suggest that competition is increasing with the number of insurers, most notably as the market size increases from 3 to 4 entrants. Results from the premium regression suggest that each additional entrant is associated with approximately 4% lower premiums, controlling for other factors. An alternative explanation for the relationship between entrants and premiums is that more efficient insurers (who can price lower) are the ones that enter markets with many entrants, and this is reflected in lower premiums. An exploratory analysis of insurers' non-claims costs (a proxy for insurer efficiency) reveals that average costs among entrants are rising slightly with the number of insurers in the market. This pattern does not support the hypothesis that premiums decrease with more entrants because those entrants are more efficient, suggesting instead that the results are being driven mostly by price competition.

Since 1966 when the Cystic Fibrosis Foundation Patient Registry (CFFPR) was founded, clinicians have witnessed significant advances in both the quality and quantity of life for patients living with Cystic Fibrosis (CF). As patients with CF live longer and fuller lives, increasing encumbrances from gastrointestinal manifestations of CF will be observed. This article serves to discuss "below the diaphragm" concerns involving the large intestine (Distal Intestinal Obstruction Syndrome, Constipation, and Colorectal Cancer). Avenues for development and implementation of clinical care protocols, particularly regarding proactive management of known associated conditions and cancer screening, will continue to be refined in the coming years. It falls to the multidisciplinary CF care team to be actively engaged in addressing these concerns effectively as priority shifts from relative acuity (typically related to early nutrition and lung function) to the travails of longevity as the CF population continues to age., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

There have been no reports describing the effects of cancer cell-derived extracellular vesicles (EVs) on three-dimensional organoids. In this study, we delineated the proneoplastic effects of esophageal adenocarcinoma (EAC)-derived EVs on gastric organoids (gastroids) and elucidated molecular mechanisms underlying these effects. EVs were identified using PKH-67 staining. Morphologic changes, Ki-67 immunochemistry, cell viability, growth rates, and expression levels of miR-25 and miR-210, as well as of their target mRNAs, were determined in gastroids co-cultured with EAC-derived extracellular vesicles (c-EVs). C-EVs were efficiently taken up by gastroids. Notably, c-EV-treated gastroids were more crowded, compact, and multilayered and contained smaller lumens than did those cultured in organoid medium alone or in EAC-conditioned medium that had been depleted of EVs. Moreover, c-EV-treated gastroids manifested increased proliferation and cellular viability relative to medium-only or EV-depleted controls. Expression levels of miR-25 and miR-210 were significantly higher, and those of PTEN and AIFM3 significantly lower, in c-EV-treated versus medium-only or EV-depleted control groups. Inhibitors of miR-25 and miR-210 reversed the increased cell proliferation induced by c-exosomes in co-cultured gastroids by lowering miR-25 and miR-210 levels. In conclusion, we have constructed a novel model system featuring the co-culture of c-EVs with three-dimensional gastroids. Using this model, we discovered that cancer-derived EVs induce a neoplastic phenotype in gastroids. These changes are due, at least in part, to EV transfer of miR-25 and miR-210., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Studies of chromosomal rearrangements and fusion transcripts have elucidated mechanisms of tumorigenesis and led to targeted cancer therapies. This study was aimed at identifying novel fusion transcripts in esophageal adenocarcinoma (EAC)., Methods: To identify new fusion transcripts associated with EAC, targeted RNA sequencing and polymerase chain reaction (PCR) verification were performed in 40 EACs and matched nonmalignant specimens from the same patients. Genomic PCR and Sanger sequencing were performed to find the breakpoint of fusion genes., Results: Five novel in-frame fusion transcripts were identified and verified in 40 EACs and in a validation cohort of 15 additional EACs (55 patients in all): fibroblast growth factor receptor 2 (FGFR2)-GRB2-associated binding protein 2 (GAB2) in 2 of 55 or 3.6%, Niemann-Pick C1 (NPC1)-maternal embryonic leucine zipper kinase (MELK) in 2 of 55 or 3.6%, ubiquitin-specific peptidase 54 (USP54)-calcium/calmodulin dependent protein kinase II γ (CAMK2G) in 2 of 55 or 3.6%, megakaryoblastic leukemia (translocation) 1 (MKL1)-fibulin 1 (FBLN1) in 1 of 55 or 1.8%, and CCR4-NOT transcription complex subunit 2 (CNOT2)-chromosome 12 open reading frame 49 (C12orf49) in 1 of 55 or 1.8%. A genomic analysis indicated that NPC1-MELK arose from a complex interchromosomal translocation event involving chromosomes 18, 3, and 9 with 3 rearrangement points, and this was consistent with chromoplexy., Conclusions: These data indicate that fusion transcripts occur at a stable frequency in EAC. Furthermore, our results indicate that chromoplexy is an underlying mechanism that generates fusion transcripts in EAC. These and other fusion transcripts merit further study as diagnostic markers and potential therapeutic targets in EAC. Cancer 2017;123:3916-24. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

For many years, only a small fraction of the human genome was believed to regulate cell function and development. This protein-coding portion composed only 1% to 2% of 3 billion human DNA base pairs-the remaining sequence was classified as junk DNA. Subsequent research has revealed that most of the genome is transcribed into a broad array of noncoding RNAs, ranging in size from microRNA (20-23 nucleotides) to long noncoding RNA (lncRNA, more than 200 nucleotides). These noncoding RNA classes have been shown to use diverse molecular mechanisms to control gene expression and organ system development. As anticipated, alterations in this large control system can contribute to disease pathogenesis and carcinogenesis. We review the involvement of noncoding RNAs, lncRNAs in particular, in development of Barrett's esophagus and esophageal carcinoma., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Novel fusion transcripts (FTs) caused by chromosomal rearrangement are common factors in the development of cancers. In the current study, the authors used massively parallel RNA sequencing to identify new FTs in colon cancers., Methods: RNA sequencing (RNA-Seq) and TopHat-Fusion were used to identify new FTs in colon cancers. The authors then investigated whether the novel FT nuclear receptor subfamily 5, group A, member 2 (NR5A2)-Kelch-like family member 29 FT (KLHL29FT) was transcribed from a genomic chromosomal rearrangement. Next, the expression of NR5A2-KLHL29FT was measured by quantitative real-time polymerase chain reaction in colon cancers and matched corresponding normal epithelia., Results: The authors identified the FT NR5A2-KLHL29FT in normal and cancerous epithelia. While investigating this transcript, it was unexpectedly found that it was due to an uncharacterized polymorphic germline insertion of the NR5A2 sequence from chromosome 1 into the KLHL29 locus at chromosome 2, rather than a chromosomal rearrangement. This germline insertion, which occurred at a population frequency of 0.40, appeared to bear no relationship to cancer development. Moreover, expression of NR5A2-KLHL29FT was validated in RNA specimens from samples with insertions of NR5A2 at the KLHL29 gene locus, but not from samples without this insertion. It is interesting to note that NR5A2-KLH29FT expression levels were significantly lower in colon cancers than in matched normal colonic epithelia (P =.029), suggesting the potential participation of NR5A2-KLHL29FT in the origin or progression of this tumor type., Conclusions: NR5A2-KLHL29FT was generated from a polymorphism insertion of the NR5A2 sequence into the KLHL29 locus. NR5A2-KLHL29FT may influence the origin or progression of colon cancer. Moreover, researchers should be aware that similar FTs may occur due to transchromosomal insertions that are not correctly annotated in genome databases, especially with current assembly algorithms. Cancer 2017;123:1507-1515. © 2017 American Cancer Society., (© 2016 American Cancer Society.)