Advance Care Planning (ACP) in Medicare Beneficiaries with Heart Failure.

BACKGROUND: Heart failure is a leading cause of death in the USA, contributing to high expenditures near the end of life. Evidence remains lacking on whether billed advance care planning changes patterns of end-of-life healthcare utilization among patients with heart failure. Large-scale claims evaluation assessing billed advance care planning and end-of-life hospitalizations among patients with heart failure can fill evidence gaps to inform health policy and clinical practice. OBJECTIVE: Assess the association between billed advance care planning delivered and Medicare beneficiaries with heart failure upon the type and quantity of healthcare utilization in the last 30 days of life. DESIGN: This retrospective cross-sectional cohort study used Medicare fee-for-service claims from 2016 to 2020. PARTICIPANTS: A total of 48,466 deceased patients diagnosed with heart failure on Medicare. MAIN MEASURES: Billed advance care planning services between the last 12 months and last 30 days of life will serve as the exposure. The outcomes are end-of-life healthcare utilization and total expenditure in inpatient, outpatient, hospice, skilled nursing facility, and home healthcare services. KEY RESULTS: In the final cohort of 48,466 patients (median [IQR] age, 83 [76-89] years; 24,838 [51.2%] women; median [IQR] Charlson Comorbidity Index score, 4 [2-5]), 4406 patients had an advance care planning encounter. Total end-of-life expenditure among patients with billed advance care planning encounters was 19% lower (95% CI, 0.77-0.84) compared to patients without. Patients with billed advance care planning encounters had 2.65 times higher odds (95% CI, 2.47-2.83) of end-of-life outpatient utilization with a 33% higher expected total outpatient expenditure (95% CI, 1.24-1.42) compared with patients without a billed advance care planning encounter. CONCLUSIONS: Billed advance care planning delivery to individuals with heart failure occurs infrequently. Prioritizing billed advance care planning delivery to these individuals may reduce total end-of-life expenditures and end-of-life inpatient expenditures through promoting use of outpatient end-of-life services, including home healthcare and hospice.

The impact of surprise billing laws on emergency services.

Numerous states implemented laws to protect emergency patients from surprise out-of-network medical bills. We investigated the effects of the state laws on emergency clinician reimbursements, charges, network participation, and potential surprise billing episodes. We did not find consistent evidence of effects on prices or charges. However, the state laws resulted in increased network participation and a reduction in potential surprise billing episodes. Our results suggest that the federal No Surprises Act, which is similar to many of the state laws, is unlikely to lead to price increases, but may benefit patients through increased provider network participation and alignment.

Breast cancer screening among Medicare Advantage enrollees with dementia.

BACKGROUND: The decision to screen for breast cancer among older adults with dementia is complex and must often be individualized, as these individuals have an elevated risk of harm from over-screening. Medicare beneficiaries with dementia are increasingly enrolling in Medicare Advantage plans, which typically promote receipt of preventive cancer screening among their enrollees. This study examined the utilization of breast cancer screening among Medicare enrollees with dementia, in Medicare Advantage and in fee-for-service Medicare. METHODS: We conducted a pooled cross-sectional study of women with Alzheimer's disease and related dementias or cognitive impairment who were eligible for mammogram screening. We used Medicare Current Beneficiary Survey data to identify utilization of biennial mammogram screening between 2012 and 2019. Poisson regression models were used to estimate prevalence ratios of mammogram utilization and to calculate adjusted mammogram rates for Medicare Advantage and fee-for-service Medicare enrollees with dementia, and further stratified by rurality and by dual eligibility for Medicare and Medicaid. RESULTS: Mammogram utilization was 16% higher (Prevalence Ratio [PR] 1.16; 95% CI: 1.05, 1.29) among Medicare Advantage enrollees with dementia, compared to their counterparts in fee-for-service Medicare. Rural enrollees experienced no significant difference (PR 0.99; 95% CI: 0.72, 1.37) in mammogram use between Medicare Advantage and fee-for-service Medicare enrollees. Among urban enrollees, Medicare Advantage enrollment was associated with a 21% higher mammogram rate (PR 1.21; 95% CI: 1.09, 1.35). Dual-eligible Medicare Advantage enrollees had a 34% higher mammogram rate (PR 1.34; 95% CI: 1.10, 1.63) than dual-eligible fee-for-service Medicare enrollees. Among non-dual-eligible enrollees, adjusted mammogram rates were not significantly different (PR 1.11; 95% CI: 0.99, 1.24) between Medicare Advantage and fee-for-service Medicare enrollees. CONCLUSIONS: Medicare beneficiaries age 65-74 with Alzheimer's disease and related dementias or cognitive impairment had a higher mammogram use rate when they were enrolled in Medicare Advantage plans compared to fee-for-service Medicare, especially when they were dual-eligible or lived in urban areas. However, some Medicare Advantage enrollees with Alzheimer's disease and related dementias or cognitive impairment may have experienced over-screening for breast cancer.

Rural-urban disparities in preventive breast and cervical cancer screening among women with early-onset dementia.

BACKGROUND: The early onset of Alzheimer's disease and related dementias (ADRD) before age 65 can introduce life and health care complications. Preserving an early-onset ADRD patient's daily functioning longer and delaying declines in health from non-ADRD conditions become important preventive goals. This study examined the differences in utilization of preventive cancer screenings between patients with and without early-onset ADRD, and compared utilization of the screenings in rural versus urban areas among women with early-onset ADRD in the United States. METHODS: We conducted a cross-sectional study of women aged 40 to 64 years eligible for mammogram and cervical cancer screenings using commercial insurance claims from 2012 to 2018. We measured the use of biennial mammogram among women 50 to 64 years old, and the use of triennial Pap smear test among women 40 to 64 years old. We used inverse probability weighted logistic regressions to estimate the odds of receiving preventive cancer screenings by the presence of early-onset ADRD or cognitive impairments (CI). We used multivariable logistic regressions to estimate the odds of receiving preventive cancer screenings by rural or urban residence among women with early-onset ADRD/CI. RESULTS: Among 6,349,308 women in the breast cancer screening sample (mean [SD] age, 56.52 [4.03] years), 36,131 had early-onset ADRD/CI (mean [SD] age, 57.99 [3.98] years). Among 6,583,088 women in the cervical cancer screening sample (mean [SD] age, 52.37 [6.81] years), 30,919 had early-onset ADRD/CI (mean [SD] age, 55.79 [6.22] years). Having early-onset ADRD/CI was associated with lower utilization of mammogram (OR: 0.92, 95% CI: 0.90-0.95). No significant difference was observed in Pap smear screening (OR: 0.99, 95% CI: 0.96-1.02) between patients with and without early-onset ADRD/CI. Among patients with early-onset ADRD/CI, those in rural areas were less likely than those in urban areas to have mammograms (OR: 0.91, 95% CI: 0.85-0.97) and Pap smears (OR: 0.65, 95% CI: 0.61-0.71). CONCLUSIONS: The observed pattern of rural-urban differences in cancer screening in our study emphasizes the need for efforts to promote evidence-based, individualized decision-making processes in the early-onset ADRD population.

State Efforts to Regulate Provider Networks and Directories: Lessons for the Future.

Managed care arrangements are the dominant form of insurance coverage in the United States today. These arrangements rely on a network of contracted providers to deliver services to their enrollees. After the managed care backlash, governments moved to ensure consumer access by issuing a number of requirements for carriers related to the composition and size of their networks and how this information is shared with consumers. The authors provide a comprehensive review of these state-based efforts to regulate provider network adequacy and provider directory accuracy for commercial insurance markets. In addition to common measures of adequacy, they also include requirements specifically targeted to underserved populations. Their assessment comes on the heels of recent empirical work that has raised significant questions about whether these efforts are effective, particularly considering the limited nature of enforcement. They also provide a brief overview and assessment of recent federal government efforts that replicate these state regulations with a focus on lessons learned from state regulations that may help improve their federal counterparts. Furthermore, they outline a future research agenda focused on a more comprehensive evaluation of efforts to ensure consumer access.

Unconventional p97/VCP-Mediated Endoplasmic Reticulum-to-Endosome Trafficking of a Retroviral Protein.

Mouse mammary tumor virus (MMTV) encodes a Rem precursor protein that specifies both regulatory and accessory functions. Rem is cleaved at the endoplasmic reticulum (ER) membrane into a functional N-terminal signal peptide (SP) and the C terminus (Rem-CT). Rem-CT lacks a membrane-spanning domain and a known ER retention signal, and yet it was not detectably secreted into cell supernatants. Inhibition of intracellular trafficking by the drug brefeldin A (BFA), which interferes with the ER-to-Golgi secretory pathway, resulted in dramatically reduced intracellular Rem-CT levels that were not rescued by proteasomal or lysosomal inhibitors. A Rem mutant lacking glycosylation was cleaved into SP and Rem-CT but was insensitive to BFA, suggesting that unglycosylated Rem-CT does not reach this BFA-dependent compartment. Treatment with endoglycosidase H indicated that Rem-CT does not traffic through the Golgi apparatus. Analysis of wild-type Rem-CT and its glycosylation mutant by confocal microscopy revealed that both were primarily localized to the ER lumen. A small fraction of wild-type Rem-CT, but not the unglycosylated mutant, was colocalized with Rab5-positive (Rab5+) early endosomes. The expression of a dominant-negative (DN) form of ADP ribosylation factor 1 (Arf1) (containing a mutation of threonine to asparagine at position 31 [T31N]) mimicked the effects of BFA by reducing Rem-CT levels and increased Rem-CT association with early and late endosomes. Inhibition of the AAA ATPase p97/VCP rescued Rem-CT in the presence of BFA or DN Arf1 and prevented localization to Rab5+ endosomes. Thus, Rem-CT uses an unconventional p97-mediated scheme for trafficking to early endosomes. IMPORTANCE Mouse mammary tumor virus is a complex retrovirus that encodes a regulatory/accessory protein, Rem. Rem is a precursor protein that is processed at the endoplasmic reticulum (ER) membrane by signal peptidase. The N-terminal SP uses the p97/VCP ATPase to elude ER-associated degradation to traffic to the nucleus and serve a human immunodeficiency virus Rev-like function. In contrast, the function of the C-terminal glycosylated cleavage product (Rem-CT) is unknown. Since localization is critical for protein function, we used mutants, inhibitors, and confocal microscopy to localize Rem-CT. Surprisingly, Rem-CT, which lacks a transmembrane domain or an ER retention signal, was detected primarily within the ER and required glycosylation and the p97 ATPase for early endosome trafficking without passage through the Golgi apparatus. Thus, Rem-CT uses a novel intracellular trafficking pathway, potentially impacting host antiviral immunity.

Out-of-Network Care in Commercially Insured Pediatric Patients According to Medical Complexity.

BACKGROUND: Commercial health plans establish networks and require much higher cost sharing for out-of-network (OON) care. Yet, the adequacy of health plan networks for access to pediatric specialists, especially for children with medical complexity, is largely unknown. OBJECTIVE: To examine differences in OON care and associated cost-sharing payments for commercially insured children with different levels of medical complexity. DESIGN: Cross-sectional study using a nationwide commercial claims database. SUBJECTS: Enrollees 0-18 years old in employer-sponsored insurance plans. The Pediatric Medical Complexity Algorithm was used to classify individuals into 3 levels of medical complexity: children with no chronic disease, children with non-complex chronic diseases, and children with complex chronic diseases. MAIN OUTCOMES: OON care rates, cost-sharing payments for OON care and in-network care, OON cost sharing as a proportion of total health care spending, and OON cost sharing as a proportion of total cost sharing. RESULTS: The study sample included 6,399,006 individuals with no chronic disease, 1,674,450 with noncomplex chronic diseases, and 603,237 with complex chronic diseases. Children with noncomplex chronic diseases were more likely to encounter OON care by 6.77 percentage points with higher cost-sharing by $288 for OON care, relative to those with no chronic disease. For those with complex chronic diseases, these differences rose to 16.08 percentage points and $599, respectively. Among children who saw behavioral health providers, rates of OON care were especially high. CONCLUSIONS: Commercially insured children with medical complexity experience higher rates of OON care with higher OON cost-sharing payments compared with those with no chronic disease.

Impact of the Affordable Care Act Medicaid expansion on oral surgery delivery at community health centers: an observational study.

BACKGROUND: Unmet oral health needs routinely affect low-income communities. Lower-income adults suffer a disproportionate share of dental disease and often cannot access necessary oral surgery services. The Affordable Care Act (ACA) Medicaid expansion created new financial opportunities for community health centers (CHCs) to provide mission-relevant services in low-income areas. However, little is understood in the literature about how the ACA Medicaid expansion impacted oral surgery delivery at CHCs. Using a large sample of CHCs, we examined whether the ACA Medicaid expansion increased the likelihood of oral surgery delivery at expansion-state CHCs compared to non-expansion-state CHCs. METHODS: Exploiting a natural experiment, we estimated Poisson regression models examining the effects of the Medicaid expansion on the likelihood of oral surgery delivery at expansion-state CHCs relative to non-expansion-state CHCs. We merged data from multiple sources spanning 2012-2017. The analytic sample included 2054 CHC-year observations. RESULTS: Compared to the year prior to expansion, expansion-state CHCs were 13.5% less likely than non-expansion-state CHCs to provide additional oral surgery services in 2016 (IRR = 0.865; P = 0.06) and 14.7% less likely in 2017 (IRR = 0.853; P = 0.02). All else equal, and relative to non-expansion-state CHCs, expansion-state CHCs included in the analytic sample were 8.7% less likely to provide oral surgery services in all post-expansion years pooled together (IRR = 0.913; P = 0.01). CONCLUSIONS: Medicaid expansions can provide CHCs with opportunities to expand their patient revenue and services. However, whether because of known dental treatment capacity limitations, new competition, or coordination with other providers, expansion-state CHCs in our study sample were less likely to provide oral surgery services on the margin relative to non-expansion-state CHCs following Medicaid expansion.

Effectiveness of Medicare cost-sharing elimination for Cancer screening on utilization.

BACKGROUND: The Patient Protection and Affordable Care Act (ACA) eliminated the cost-sharing requirement for several preventive cancer screenings. This study examined the cancer screening utilization of mammogram, Pap smear and colonoscopy in Medicare fee-for-service (FFS) under the ACA. METHODS: The primary data were the 2007-2013 Medicare Current Beneficiary Survey linked to FFS claims. The effect of the cost-sharing removal on the probability of receiving a preventive cancer screening test was estimated using a logistic regression, separately for each screening test, adjusting for the complex survey design. The model was also separately estimated for different socioeconomic and race/ethnic groups. The study sample included beneficiaries with Part B coverage for the entire calendar year, excluding beneficiaries in Medicaid or Medicare Advantage plans. Beneficiaries with a claims-documented or self-reported history of targeted cancers, who were likely to have diagnostic tests or have surveillance screenings were excluded. The screening measures were constructed separately following Medicare coverage and U.S. Preventive Services Task Force (USPSTF) recommendations. We measured the screening utilization outcome drawing from claims data, as well as using the self-reported survey data. RESULTS: After the cost-sharing removal policy, we found no statistically significant difference in a beneficiary's probability of receiving a colonoscopy (transition period: OR = 1.08, 95% CI = 0.90-1.29; post-policy period: OR = 1.08, 95% CI = 0.83-1.42), a mammogram (transition period: OR = 1.03, 95% CI = 0.91-1.17; post-policy period: OR = 1.07, 95% CI = 0.88-1.30), or a biennial Pap smear (transition period: OR = 0.87, 95% CI = 0.69-1.09; post-policy period: OR = 0.72, 95% CI = 0.51-1.03) in claims-based measures following Medicare coverage. Similarly, we found null effects of the policy change on utilization of colonoscopy among enrollees 50-75 years old, biennial mammograms by women 50-74, and triennial Pap smear tests among women 21-65 in claims-based measures according to USPSTF. The findings from survey-based measures were consistent with the estimates from claims-based measures, except that the use of Pap smear declined since 2011. Further, the policy change did not increase utilization in patients with disadvantaged socioeconomic characteristics. Yet the disparate patterns in adjusted screening rates by socioeconomic status and race/ethnicity persisted over time. CONCLUSIONS: Removing out-of-pocket costs for screenings did not provide enough incentives to increase the screening rates among Medicare beneficiaries.

Medicare Advantage Disenrollment Patterns Among Beneficiaries With Multiple Chronic Conditions.

This study examines whether Medicare Advantage (MA) enrollees with more chronic conditions were more likely to disenroll when MA enrollment grew rapidly from 2009 to 2019.

High-Tech Versus High-Touch: Components of Hospital Costs Vary Widely.

EXECUTIVE SUMMARY: The recent release by the Centers for Medicare & Medicaid Services of hospital charge and payment data to the public has renewed a national dialogue on hospital costs and prices. However, to better understand the driving force of hospital pricing and to develop strategies for controlling expenditures, it is important to understand the underlying costs of providing hospital services. We use Medicare Provider and Analysis Review inpatient claims data and Medicare cost report data for fiscal years 2008 and 2012 to examine variations in the contribution of "high-tech" resources (i.e., technology/medical device-intensive resources) versus "high-touch" resources (i.e., labor-intensive resources) to the total costs of providing two common services, as well as assess how these costs have changed over time. We found that high-tech inputs accounted for a greater proportion of the total costs of surgical service, whereas medical service costs were primarily attributable to high-touch inputs. Although the total costs of services did not change significantly over time, the distribution of high-tech, high-touch, and other costs for each service varied considerably across hospitals. Understanding resource inputs and the varying contribution of these inputs by clinical condition is an important first step in developing effective cost control strategies.

Rural-urban differences in out-of-network treatment initiation and engagement rates for substance use disorders.

OBJECTIVE: To examine rural-urban disparities in substance use disorder treatment access and continuation. DATA SOURCES AND STUDY SETTING: We analyzed a 2016-2018 U.S. national secondary dataset of commercial insurance claims. STUDY DESIGN: This cross-sectional study examined individuals with a new episode of opioid, alcohol, or other drug use disorders. Treatment initiation and engagement rates, and rates of using out-of-network providers for these services, were compared between rural and urban patients. DATA COLLECTION: We included individuals 18-64 years old with continuous employer-sponsored insurance. PRINCIPAL FINDINGS: Patients in rural settings experienced lower treatment initiation rates for alcohol (36.6% vs. 38.0%, p < 0.001), opioid (41.2% vs. 44.2%, p < 0.001), and other drug (37.7% vs. 40.1%, p < 0.001) use disorders, relative to those in urban areas. Similarly, rural patients had lower treatment engagement rates for alcohol (15.1% vs. 17.3%, p < 0.001), opioid (21.0% vs. 22.6%, p < 0.001), and other drug (15.5% vs. 17.5%, p < 0.001) use disorders. Rural patients had higher out-of-network rates for treatment initiation for other drug use disorders (20.4% vs. 17.2%, p < 0.001), and for treatment engagement for alcohol (27.6% vs. 25.2%, p = 0.006) and other drug (36.1% vs. 31.1%, p < 0.001) use disorders. CONCLUSIONS: These findings indicate that individuals with substance use disorders in rural areas have lower rates of initial and ongoing treatment, and are more likely to seek care out-of-network.

Provider directory inaccuracy and timely access for mental health care.

OBJECTIVES: To evaluate the accuracy of provider directories for mental health providers and network adequacy, defined as timely access to urgent and general care appointments in California. STUDY DESIGN: We assessed provider directory accuracy and timely access using a novel, comprehensive, and representative data set of mental health providers for all plans regulated by the California Department of Managed Health Care with 1,146,954 observations (480,013 for 2018 and 666,941 for 2019). METHODS: We used descriptive statistics to assess provider directory accuracy and network adequacy assessed via access to timely appointments. We used t tests to make comparison across markets. RESULTS: We found that mental health provider directories are highly inaccurate. Commercial plans were consistently more accurate than both Covered California marketplace and Medi-Cal plans. Moreover, plans were highly limited in providing timely access to urgent care and general appointments, although Medi-Cal plans outperformed plans from both other markets when it came to timely access. CONCLUSIONS: These findings are concerning from both the consumer and regulatory perspectives and provide further evidence of the tremendous challenge that consumers face in accessing mental health care. Although California's laws and regulations are some of the strongest in the country, they are still falling short, indicating the need to further expand efforts to protect consumers.

Examining trends in health care access measures among low-income adult smokers in Ohio: 2012-2019.

Smokers are more likely to be low-income with limited access to health services. Although Medicaid expansion under the Patient Protection and Affordable Care Act improved access to care for low-income adults, long-term trends in health care access among low-income smokers remain uncharacterized. The study evaluated changes in five access measures among low-income nonelderly (19-64) adults (N = 28976) across smoking status using pooled data from a statewide survey in Ohio covering pre- (i.e., 2012) and post-Medicaid expansion periods (2015, 2017, and 2019) guided by a comprehensive framework of health care access. We found improvements in some, but not all, health care access measures among low-income smokers in the post-Medicaid-expansion period compared to the pre-expansion period. Compared to 2012, the odds for unmet dental care needs declined in 2015 (aOR = 0.67, 95 % CI = 0.45-1.01), 2017 (aOR = 0.53, 95 % CI = 0.35-0.81), and 2019 (aOR = 0.65, 95 % CI = 0.40-1.05) (p trend < 0.001). Similarly, the odds for unmet other health care needs (i.e., medical exams and supplies) were lower in 2015 (aOR = 0.64, 95 % CI = 0.39-1.06), 2017 (aOR = 0.56, 95 % CI = 0.34-0.93), and 2019 (aOR = 0.47, 95 % CI = 0.27-0.83) (p trend < 0.001). Difficulty paying medical bills was also significantly lower in 2015 (aOR = 0.62, 95 % CI = 0.43-0.89), 2017 (aOR = 0.57, 95 % CI = 0.39-0.83) and 2019 (aOR = 0.57, 95 % CI = 0.37-0.87) (p trend < 0.001). While there was notable progress in measures of affordability (i.e., paying medical bills) as well as care availability and accommodation (i.e., unmet needs), there were no meaningful changes in the approachability of care (i.e., having a usual source of care).

Comparison of thromboembolism outcomes in patients with sickle cell disease prescribed hormonal contraception.

Patients with sickle cell disease (SCD) are at a risk of thromboembolism (TE), and use of hormonal contraception can further increase that risk. This study aims to assess patterns of hormonal contraceptive use and compare risk of contraception-related TE between combined hormonal contraceptives (CHCs) and progestin-only contraceptives (POCs). Patients with SCD aged between 12 and 44 years with a new prescription of a hormonal contraceptive in the Centers for Medicare and Medicaid Services Medicaid Analytic eXtract database (2006-2018) were followed up to 1 year. We identified 7173 new users: 44.6% initiated CHC and 55.4% initiated POC. Combined oral contraceptive pills (OCPs; 36.5%) and progestin-only depot medroxyprogesterone acetate (33.9%) were the most frequently prescribed agents. A total of 1.8% of contraception users had a new diagnosis of TE within 1 year of the first identified contraception prescription. There were no significant differences in TE event rates between CHC and POC users (17.2 and 24.7 events per 1000 person-years, respectively). In patients prescribed OCP, there were no differences in TE event rates based on estrogen dose or progestin generation. Transdermal patch had a 2.4-fold increased risk of TE as compared with that of OCP. Although limited by the retrospective study design and use of administrative claims data, this study found no significant differences in TE rates between new users of CHC and POC in patients with SCD. Careful evaluation of underlying TE risk factors should be considered for each patient with SCD before initiation of hormonal contraception.

Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria.

Mitochondria are critical to cellular and organismal health. To prevent damage, mitochondria have evolved protein quality control machines to survey and maintain the mitochondrial proteome. SKD3, also known as CLPB, is a ring-forming, ATP-fueled protein disaggregase essential for preserving mitochondrial integrity and structure. SKD3 deficiency causes 3-methylglutaconic aciduria type VII (MGCA7) and early death in infants, while mutations in the ATPase domain impair protein disaggregation with the observed loss-of-function correlating with disease severity. How mutations in the non-catalytic N-domain cause disease is unknown. Here, we show that the disease-associated N-domain mutation, Y272C, forms an intramolecular disulfide bond with Cys267 and severely impairs SKD3Y272C function under oxidizing conditions and in living cells. While Cys267 and Tyr272 are found in all SKD3 isoforms, isoform-1 features an additional α-helix that may compete with substrate-binding as suggested by crystal structure analyses and in silico modeling, underscoring the importance of the N-domain to SKD3 function.

Apobec-Mediated Retroviral Hypermutation In Vivo is Dependent on Mouse Strain.

Replication of the complex retrovirus mouse mammary tumor virus (MMTV) is antagonized by murine Apobec3 (mA3), a member of the Apobec family of cytidine deaminases. We have shown that MMTV-encoded Rem protein inhibits proviral mutagenesis by the Apobec enzyme, activation-induced cytidine deaminase (AID) during viral replication in BALB/c mice. To further study the role of Rem in vivo , we have infected C57BL/6 (B6) mice with a superantigen-independent lymphomagenic strain of MMTV (TBLV-WT) or a mutant strain (TBLV-SD) that is defective in Rem and its cleavage product Rem-CT. Unlike MMTV, TBLV induced T-cell tumors in µMT mice, indicating that mature B cells, which express the highest AID levels, are not required for TBLV replication. Compared to BALB/c, B6 mice were more susceptible to TBLV infection and tumorigenesis. The lack of Rem expression accelerated B6 tumorigenesis at limiting doses compared to TBLV-WT in either wild-type B6 or AID-deficient mice. However, unlike proviruses from BALB/c mice, high-throughput sequencing indicated that proviral G-to-A or C-to-T changes did not significantly differ in the presence and absence of Rem expression. Ex vivo stimulation showed higher levels of mA3 relative to AID in B6 compared to BALB/c splenocytes, but effects of agonists differed in the two strains. RNA-Seq revealed increased transcripts related to growth factor and cytokine signaling in TBLV-SD-induced tumors relative to those from TBLV-WT, consistent with a third Rem function. Thus, Rem-mediated effects on tumorigenesis in B6 mice are independent of Apobec-mediated proviral hypermutation.

Comparative Effectiveness of 2 Interventions to Increase Breast, Cervical, and Colorectal Cancer Screening Among Women in the Rural US: A Randomized Clinical Trial.

Importance: Women living in rural areas have lower rates of breast, cervical, and colorectal cancer screening compared with women living in urban settings. Objective: To assess the comparative effectiveness of (1) a mailed, tailored digital video disc (DVD) intervention; (2) a DVD intervention plus telephonic patient navigation (DVD/PN); and (3) usual care with simultaneously increased adherence to any breast, cervical, and colorectal cancer screening that was not up to date at baseline and to assess cost-effectiveness. Design, Setting, and Participants: This randomized clinical trial recruited and followed up women from rural Indiana and Ohio (community based) who were not up to date on any or all recommended cancer screenings. Participants were randomly assigned between November 28, 2016, and July 1, 2019, to 1 of 3 study groups (DVD, DVD/PN, or usual care). Statistical analyses were completed between August and December 2021 and between March and September 2022. Intervention: The DVD interactively assessed and provided messages for health beliefs, including risk of developing the targeted cancers and barriers, benefits, and self-efficacy for obtaining the needed screenings. Patient navigators counseled women on barriers to obtaining screenings. The intervention simultaneously supported obtaining screening for all or any tests outside of guidelines at baseline. Main Outcomes and Measures: Receipt of any or all needed cancer screenings from baseline through 12 months, including breast, cervical, and colorectal cancer, and cost-effectiveness of the intervention. Binary logistic regression was used to compare the randomized groups on being up to date for all and any screenings at 12 months. Results: The sample included 963 women aged 50 to 74 years (mean [SD] age, 58.6 [6.3] years). The DVD group had nearly twice the odds of those in the usual care group of obtaining all needed screenings (odds ratio [OR], 1.84; 95% CI, 1.02-3.43; P = .048), and the odds were nearly 6 times greater for DVD/PN vs usual care (OR, 5.69; 95% CI, 3.24-10.5; P < .001). The DVD/PN intervention (but not DVD alone) was significantly more effective than usual care (OR, 4.01; 95% CI, 2.60-6.28; P < .001) for promoting at least 1 (ie, any) of the needed screenings at 12 months. Cost-effectiveness per woman who was up to date was $14 462 in the DVD group and $10 638 in the DVD/PN group. Conclusions and Relevance: In this randomized clinical trial of rural women who were not up to date with at least 1 of the recommended cancer screenings (breast, cervical, or colorectal), an intervention designed to simultaneously increase adherence to any or all of the 3 cancer screening tests was more effective than usual care, available at relatively modest costs, and able to be remotely delivered, demonstrating great potential for implementing an evidence-based intervention in remote areas of the midwestern US. Trial Registration: ClinicalTrials.gov Identifier: NCT02795104.

Accelerating Colorectal Cancer Screening and Follow-up through Implementation Science (ACCSIS) in Appalachia: protocol for a group randomized, delayed intervention trial.

Appalachian regions of Kentucky and Ohio are hotspots for colorectal cancer (CRC) mortality in the USA. Screening reduces CRC incidence and mortality; however, screening uptake is needed, especially in these underserved geographic areas. Implementation science offers strategies to address this challenge. The aim of the current study was to conduct multi-site, transdisciplinary research to evaluate and improve CRC screening processes using implementation science strategies. The study consists of two phases (Planning and Implementation). In the Planning Phase, a multilevel assessment of 12 health centers (HC) (one HC from each of the 12 Appalachian counties) was conducted by interviewing key informants, creating community profiles, identifying HC and community champions, and performing HC data inventories. Two designated pilot HCs chose CRC evidence-based interventions to adapt and implement at each level (i.e., patient, provider, HC, and community) with evaluation relative to two matched control HCs. During the Implementation Phase, study staff will repeat the rollout process in HC and community settings in a randomized, staggered fashion in the remaining eight counties/HCs. Evaluation will include analyses of electronic health record data and provider and county surveys. Rural HCs have been reluctant to participate in research because of concerns about capacity; however, this project should demonstrate that research does not need to be burdensome and can adapt to local needs and HC abilities. If effective, this approach could be disseminated to HC and community partners throughout Appalachia to encourage the uptake of effective interventions to reduce the burden of CRC.

We conducted a multi-site study to evaluate and improve CRC screening processes using implementation science strategies at multiple levels including the patient, provider, health center, and community. Our goals were to increase rates of guideline-recommended CRC screening, follow-up, and referral-to-care in an Appalachian, medically underserved population.