Provider reported implementation barriers to hepatitis C elimination in Washington State.

BACKGROUND: Despite curative treatment options since 2014, only 12% of individuals in Washington State diagnosed with Hepatitis C (HCV) received treatment in 2018. Washington State agencies launched an elimination plan in 2019 to promote access to and delivery of HCV screening and treatment. The purpose of this study is to evaluate provider and health system barriers to successful implementation of HCV screening and treatment across Washington State. METHODS: This is a cross-sectional online survey of 547 physicians, nurse practitioners, physician assistants, and clinical pharmacists who provide care to adult patients in Washington State conducted in 2022. Providers were eligible if they worked in a primary care, infectious disease, gastroenterology, or community health settings. Questions assessed HCV screening and treating practices, implementation barriers, provider knowledge, observed stigma, and willingness to co-manage HCV and substance use disorder. Chi-squared or fishers exact tests compared characteristics of those who did and did not screen or treat. RESULTS: Provider adoption of screening for HCV was high across the state (96%), with minimal barriers identified. Fewer providers reported treating HCV themselves (28%); most (71%) referred their patients to another provider. Barriers identified by those not treating HCV included knowledge deficit (64%) and lack of organizational support (24%). The barrier most identified in those treating HCV was a lack of treating clinicians (18%). There were few (< 10%) reports of observed stigma in settings of HCV treatment. Most clinicians (95%) were willing to prescribe medication for substance use disorders to those that were using drugs including alcohol. CONCLUSION: Despite widespread screening efforts, there remain barriers to implementing HCV treatment in Washington State. Lack of treating clinicians and clinician knowledge deficit were the most frequently identified barriers to treating HCV. To achieve elimination of HCV by 2030, there is a need to grow and educate the clinician workforce treating HCV.

Patient Out-of-Pocket Costs for Type 2 Diabetes Medications When Aging Into Medicare.

Importance: For people with type 2 diabetes (T2D), out-of-pocket medication costs may influence medication choice, adherence, and overall diabetes management and progression. Little is known about how these costs change as insured people enter Medicare at age 65 years, when coinsurance in the coverage gap and catastrophic phases of Part D coverage can be increased greatly by use of insulin and newer, branded medications (eg, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 agonists, and sodium-glucose cotransporter 2 inhibitors). Objective: To identify whether reaching age 65 years is associated with T2D medication out-of-pocket costs and utilization. Design, Setting, and Participants: This retrospective cohort study (2012-2020) featuring 7 years of follow-up used prescription drug claims data from the TriNetX Diamond Network. Participants included people in the US with diagnosed T2D, and claims for T2D medications were observed both before and after age 65 years. Data analysis was performed from October 2022 to September 2023. Exposure: Reaching age 65 years, according to participants' year of birth. Main Outcomes and Measures: The primary outcome was patient out-of-pocket costs for T2D drugs per quarter (inflation adjusted to 2020 dollars). Utilization, measured as binary utilization of specific classes, and the number of claims for mutually exclusive classes and combinations of classes were also examined. All outcomes were examined using regression discontinuity design. Results: In claims data for 129 997 individuals with T2D diagnosed at ages 58 to 72 years (mean [SD] age, 65.50 [2.95] years; 801 235 female [50.9%]), reaching age 65 years was associated with an increase of $23.04 (95% CI, $19.86-$26.22) in mean quarterly out-of-pocket costs for T2D drugs, and an increase of $56.36 (95% CI, $51.48-$61.23) at the 95th percentile of spending, after utilization adjustment. Utilization decreased by 5.3% at age 65 years, from 3.40 claims per quarter (95% CI, 3.38-3.42 claims per quarter) to 3.22 claims per quarter (95% CI, 3.21-3.24 claims per quarter), but a shift in composition of utilization, including increased insulin use, was associated with additional increases in patient costs. Conclusions and Relevance: In this cohort study of individuals with T2D, the increase in spending upon reaching age 65 years (when most people enroll in Medicare) was associated with patient coinsurance in the coverage gap and catastrophic coverage phases of Medicare Part D. The increased patient cost burden at age 65 years and a modest reduction in overall T2D drug utilization suggest that as people with T2D age into Medicare, there is potentially an increase in nonadherence and diabetes complications.

Utilization of low- and high-value health care by individuals with and without cognitive impairment.

OBJECTIVES: Cognitive impairment and dementia have rising prevalence and impact the health care utilization and lives of older adults. Receipt of low-value (LV) care and underutilization of high-value (HV) care by individuals with these cognitive disorders may have negative consequences for patient health, health system efficiency, and societal welfare. Evidence on health care value among cognitively impaired individuals is limited; we thus ascertained receipt of LV and HV health care in older adults with normal cognition, cognitive impairment without dementia (CIND), and dementia. STUDY DESIGN: Retrospective cohort study of Health and Retirement Study data linked to Medicare claims (1996-2018). METHODS: We examined the association between cognitive decline and the receipt of 5 LV and 7 HV services vs individuals with no change in cognition. RESULTS: Receipt of LV care ranged from 4% to 13% regardless of cognitive status. Cognitive decline (from unimpaired to either CIND or dementia) was associated with decreased probability of receipt of 1 LV service (colorectal cancer screening at 85 years and older [5-percentage-point reduction; P = .047]) and 3 HV services (glucose-lowering drugs [7-percentage-point reduction; P = .029], statins [32-percentage-point reduction; P = .045], and antiresorptive therapy [61-percentage-point reduction; P = .019]). CONCLUSIONS: LV service receipt is wasteful and may be harmful, but it was not consistently associated with cognitive status. Lack of HV care for those with cognitive impairment could be a missed opportunity to improve well-being or reduce preventable adverse events. Our results suggest opportunities for improving the quality of care received by all older adults, including those with cognitive impairment.

Short-chain fatty acids abrogate Japanese encephalitis virus-induced inflammation in microglial cells via miR-200a-3p/ZBTB20/IKßα axis.

Japanese encephalitis virus (JEV), a member of the Flaviviridae family, is a leading cause of viral encephalitis in humans. Survivors of this infection often develop lifelong neurological sequelae. Short-chain fatty acids (SCFAs) produced in the gut are vital mediators of the gut-brain axis. We aimed to study microRNA-based mechanisms of SCFAs in an in vitro model of JEV infection. N9 microglial cells were pretreated with SCFA cocktail before JEV infection. Cytokine bead analysis, immunoblotting, and PCR were performed to analyze relevant inflammatory markers. microRNA sequencing was performed using Illumina Hiseq, and bioinformatics tools were used for differentially expressed (DE) miRNAs and weighted gene co-expression network analysis (WGCNA). microRNA mimic/inhibitor experiments and luciferase assay were performed to study miRNA-target interaction. A significant reduction in monocyte chemoattractant protein (MCP1) and tumor necrosis factor alpha (TNFα) along with reduced expression of phospho-nuclear factor kappa B (phospho-NF-κB) was observed in SCFA conditions. Significant attenuation of histone deacetylase activity and protein expression was recorded. miRNA sequencing revealed 160 DE miRNAs in SCFA + JEV-treated cells at 6 h post-infection. WGCNA revealed miR-200a-3p, a hub miRNA significantly upregulated in SCFA conditions. Transcription factor ZBTB20 was bioinformatically predicted and validated as a gene target for miR-200a-3p. Further miRNA mimic/inhibitor assay demonstrated that miR-200-3p regulated ZBTB20 along with Iκßα that possibly dampened NF-κB signal activation downstream. IMPORTANCE: The gut-brain axis plays a pivotal role in the physiological state of an organism. Gut microbiota-derived metabolites are known to play a role in brain disorders including neuroviral infections. Short-chain fatty acids (SCFAs) appear to quench inflammatory markers in Japanese encephalitis virus-infected microglial cells in vitro. Mechanistically, we demonstrate the interaction between miR-200a-3p and ZBTB20 in regulating the canonical nuclear factor kappa B (NF-κB) signaling pathway via transcriptional regulation of Iκßα. Findings of this study pave the way to a better understanding of SCFA mechanisms that can be used to develop strategies against viral neuroinflammation.

Comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus: emulation of a target trial using routinely collected health data.

OBJECTIVE: To compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in routine clinical practice. DESIGN: Cohort study emulating a comparative effectiveness trial (target trial). SETTING: Linked primary care, hospital, and death data in England, 2015-21. PARTICIPANTS: 75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin. MAIN OUTCOME MEASURES: Primary outcome was absolute change in glycated haemoglobin A1c (HbA1c) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures. RESULTS: 75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA1c change between baseline and one year were -2.5 mmol/mol (95% confidence interval (CI) -3.7 to -1.3) for SGLT-2 inhibitors versus sulfonylureas and -3.2 mmol/mol (-4.6 to -1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking-the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43). CONCLUSIONS: This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA1c, BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure (v DPP-4 inhibitors) and kidney disease progression (v sulfonylureas), with no evidence of differences in other clinical endpoints.

Insights into the interaction and inhibitory action of palmatine on lysozyme fibrillogenesis: Spectroscopic and computational studies.

Interaction under amyloidogenic condition between naturally occurring protoberberine alkaloid palmatine and hen egg white lysozyme was executed by adopting spectrofluorometric and theoretical molecular docking and dynamic simulation analysis. In spetrofluorometric method, different types of experiments were performed to explore the overall mode and mechanism of interaction. Intrinsic fluorescence quenching of lysozyme (Trp residues) by palmatine showed effective binding interaction and also yielded different binding parameters like binding constant, quenching constant and number of binding sites. Synchronous fluorescence quenching and 3D fluorescence map revealed that palmatine was able to change the microenvironment of the interacting site. Fluorescence life time measurements strongly suggested that this interaction was basically static in nature. Molecular docking result matched with fluorimetric experimental data. Efficient drug like interaction of palmatine with lysozyme at low pH and high salt concentration prompted us to analyze its antifibrillation potential. Different assays and microscopic techniques were employed for detailed analysis of lysozyme amyloidosis.Thioflavin T(ThT) assay, Congo Red (CR) assay, 8-anilino-1-naphthalenesulfonic acid (ANS) assay, Nile Red (NR) assay, anisotropy and intrinsic fluorescence measurements confirmed that palmatine successfully retarded and reduced lysozyme fibrillation. Dynamic light scattering (DLS) and atomic force microscopy (AFM) further reiterated the excellent antiamyloidogenic potency of palmatine.

Prophylactic Administration of Gut Microbiome Metabolites Abrogated Microglial Activation and Subsequent Neuroinflammation in an Experimental Model of Japanese Encephalitis.

Short-chain fatty acids (SCFAs) are gut microbial metabolic derivatives produced during the fermentation of ingested complex carbohydrates. SCFAs have been widely regarded to have a potent anti-inflammatory and neuro-protective role and have implications in several disease conditions, such as, inflammatory bowel disease, type-2 diabetes, and neurodegenerative disorders. Japanese encephalitis virus (JEV), a neurotropic flavivirus, is associated with life threatening neuro-inflammation and neurological sequelae in infected hosts. In this study, we hypothesize that SCFAs have potential in mitigating JEV pathogenesis. Postnatal day 10 BALB/c mice were intraperitoneally injected with either a SCFA mixture (acetate, propionate, and butyrate) or PBS for a period of 7 days, followed by JEV infection. All mice were observed for onset and progression of symptoms. The brain tissue was collected upon reaching terminal illness for further analysis. SCFA-supplemented JEV-infected mice (SCFA + JEV) showed a delayed onset of symptoms, lower hindlimb clasping score, and decreased weight loss and increased survival by 3 days (p < 0.0001) upon infection as opposed to the PBS-treated JEV-infected animals (JEV). Significant downregulation of inflammatory cytokines TNF-α, MCP-1, IL-6, and IFN-Υ in the SCFA + JEV group relative to the JEV-infected control group was observed. Inflammatory mediators, phospho-NF-kB (P-NF-kB) and iba1, showed 2.08 ± 0.1 and 3.132 ± 0.43-fold upregulation in JEV versus 1.19 ± 0.11 and 1.31 ± 0.11-fold in the SCFA + JEV group, respectively. Tissue section analysis exhibited reduced glial activation (JEV group─42 ± 2.15 microglia/ROI; SCFA + JEV group─27.07 ± 1.8 microglia/ROI) in animals that received SCFA supplementation prior to infection as seen from the astrocytic and microglial morphometric analysis. Caspase-3 immunoblotting showed 4.08 ± 1.3-fold upregulation in JEV as compared to 1.03 ± 0.14-fold in the SCFA + JEV group and TUNEL assay showed a reduced cellular death post-JEV infection (JEV-6.4 ± 1.5 cells/ROI and SCFA + JEV-3.7 ± 0.73 cells/ROI). Our study critically contributes to the increasing evidence in support of SCFAs as an anti-inflammatory and neuro-protective agent, we further expand its scope as a potential supplementary intervention in JEV-mediated neuroinflammation.

Universal Free School Meals Policy and Childhood Obesity.

BACKGROUND AND OBJECTIVES: The Community Eligibility Provision (CEP), a universal free school meals policy, increases school meal participation by allowing schools in low-income areas to provide free breakfast and lunch to all students; however, its impact on obesity remains uncertain. The objective of this study is to estimate the association of CEP with child obesity. METHODS: School obesity prevalence was calculated using BMI measurements collected annually between 2013 and 2019 from students in California public schools in grades 5, 7, and 9. To estimate the association of CEP with obesity, we used a difference-in-differences approach for staggered policy adoption with an outcome regression model conditional on covariates, weighted by student population size. RESULTS: The analysis included 3531 CEP-eligible schools using school-level obesity prevalence calculated from 3 546 803 BMI measurements. At baseline, on average, 72% of students identified as Hispanic, 11% identified as white, 7% identified as Black, and 80% were eligible for free or reduced-price meals. Baseline obesity prevalence was 25%. Schools that participated in CEP were associated with a 0.60-percentage-point net decrease in obesity prevalence after policy adoption (95% confidence interval: -1.07 to -0.14 percentage points, P = .01) compared with eligible, nonparticipating schools, corresponding with a 2.4% relative reduction, given baseline prevalence. Meals served increased during this period in CEP-participating schools only. CONCLUSIONS: In a balanced sample of California schools, CEP participation was associated with a modest net decrease in obesity prevalence compared with eligible, nonparticipating schools. These findings add to the growing literature revealing potential benefits of universal free school meals for children's well-being.

Tackling Challenges in Assessing the Economic Value of Tumor-Agnostic Therapies: A Cost-Effectiveness Analysis of Pembrolizumab as a Case Study.

OBJECTIVES: Assessing the value of tumor-agnostic drugs (TAD) is challenging given the potential variability in treatment effects, trials with small sample sizes, different standards of care (SoC), and lack of comparative data from single-arm basket trials. Our study developed and applied novel methods to assess the value of pembrolizumab compared with SoC to inform coverage decisions. METHODS: We developed a partitioned survival model to evaluate the cost-utility of pembrolizumab for previously treated patients with 8 advanced or metastatic microsatellite instability-high or mismatch repair-deficient cancers from a US commercial payer perspective. Efficacy of pembrolizumab was based on data from trials directly or with adjustment using Bayesian hierarchical models. Eight chemotherapy-based external control arms were constructed from the TriNetX electronic health record databases. Tumor-specific health-state utility values were applied. All costs were adjusted to 2022 US dollars. RESULTS: At a lifetime horizon, pembrolizumab was associated with increased effectiveness compared with chemotherapies in colorectal (quality-adjusted life years [QALYs]: +0.64, life years [LYs]: +0.64), endometrial (QALYs: +3.79, LYs: +5.47), and small intestine cancers (QALYs: +1.73, LYs: +2.48), but not for patients with metastatic gastric, cholangiocarcinoma, pancreatic, ovarian, and brain cancers. Incremental cost-effectiveness ratios varied substantially across tumor types. Pembrolizumab was found to be cost-effective in treating colorectal and endometrial cancers (incremental cost-effectiveness ratios: $121 967 and $139 257, respectively), and not cost-effective for other assessed cancers at a $150 000 willingness-to-pay/QALY threshold, compared with SoC chemotherapies. CONCLUSIONS: The cost-effectiveness of TADs can vary by cancers. Using analytic tools such as external controls and Bayesian hierarchical models can tackle several challenges in assessing the value of TADs and uncertainties from basket trials.

Regulation of Onecut2 by miR-9-5p in Japanese encephalitis virus infected neural stem/progenitor cells.

Japanese encephalitis virus (JEV) is one of the major neurotropic viral infections that is known to dysregulate the homeostasis of neural stem/progenitor cells (NSPCs) and depletes the stem cell pool. NSPCs are multipotent stem cell population of the central nervous system (CNS) which are known to play an important role in the repair of the CNS during insults/injury caused by several factors such as ischemia, neurological disorders, CNS infections, and so on. Viruses have evolved to utilize host factors for their own benefit and during JEV infection, host factors, including the non-coding RNAs such as miRNAs, are reported to be affected, thereby cellular processes regulated by the miRNAs exhibit perturbed functionality. Previous studies from our laboratory have demonstrated the role of JEV infection in dysregulating the function of neural stem cells (NSCs) by altering the cell fate and depleting the stem cell pool leading to a decline in stem cell function in CNS repair mechanism post-infection. JEV-induced alteration in miRNA expression in the NSCs is one of the major interest to us. In prior studies, we have observed an altered expression pattern of certain miRNAs following JEV infection. In this study, we have validated the role of JEV infection in NSCs in altering the expression of miR-9-5p, which is a known regulator of neurogenesis in NSCs. Furthermore, we have validated the interaction of this miRNA with its target, Onecut2 (OC2), in primary NSCs utilizing miRNA mimic and inhibitor transfection experiments. Our findings indicate a possible role of JEV mediated dysregulated interaction between miR-9-5p and its putative target OC2 in NSPCs. IMPORTANCE: MicroRNAs have emerged as key disease pathogenic markers and potential therapeutic targets. In this study, we solidify this concept by studying a key miRNA, miR-9-5p, in Japanese encephalitis virus infection of neural stem/progenitor cells. miRNA target Onecut2 has a possible role in stem cell pool biology. Here, we show a possible mechanistic axis worth investing in neurotropic viral biology.

Evaluating Policies of Expanding Versus Restricting First-Line Treatment Choices: A Cost-Effectiveness Analysis Framework.

OBJECTIVES: Healthcare payers often implement coverage policies that restrict the utilization of costly new first-line treatments. Cost-effectiveness analysis can be conducted to inform these decisions by comparing the new treatment with an existing one. However, this approach may overlook important factors such as treatment effect heterogeneity and endogenous treatment selection, policy implementation costs, and diverse patient preferences across multiple treatment options. We aimed to develop a cost-effectiveness analysis framework that considers these real-world factors, facilitating the evaluation of alternative policies related to expanding or restricting first-line treatment choices. METHODS: We introduced a metric of incremental cost-effectiveness ratio (ICER) that compares an expanded choice set (CS) including the new first-line treatment with a restricted CS excluding the new treatment. ICER(CS) accounts for treatment selection influenced by heterogeneous treatment effects and policy implementation costs. We examined a basic scenario with 2 standard first-line treatment choices and a more realistic scenario involving diverse preferences toward multiple choices. To illustrate the framework, we conducted a retrospective evaluation of including versus excluding abiraterone acetate plus prednisone (AAP) (androgen deprivation therapy [ADT] + AAP) as a first-line treatment for metastatic hormone-sensitive prostate cancer. RESULTS: The traditional ICERs for ADT + AAP versus ADT alone and ADT+ docetaxel were $104 269 and $206 324/quality-adjusted life-year, respectively. The ICER(CS) for comparing an expanded CS with ADT + AAP with a restricted CS without ADT + AAP was $123 179/quality-adjusted life-year. CONCLUSIONS: The proposed framework provides decision makers with policy-relevant tools, enabling them to assess the cost-effectiveness of alternative policies of expanding versus restricting patients' and physicians' first-line treatment choices.

Interaction of food colorant indigo carmine with human and bovine serum albumins: A multispectroscopic, calorimetric, and theoretical investigation.

In this work we have studied the interaction of the food dye Indigo-Carmine (IndC) with the most studied model transport proteins i.e. human and bovine serum albumin (HSA & BSA). A multispectroscopic approach was used to analyze the details of the binding process. The intrinsic fluorescence of both the albumins was significantly quenched by IndC and the quenching was both static and dynamic in nature with the former being dominant. The HSA-lndC and BSA-IndC distance after complexation was determined by Förster resonance energy transfer (FRET) method which suggested efficient energy transfer from the albumins to IndC. Thermodynamics of serum protein-IndC complexation was estimated by isothermal titration calorimetry (ITC) which revealed that the binding was enthalpy driven. Circular dichroism (CD) and FTIR spectroscopy revealed that the binding of IndC induced secondary structural changes in both the serum proteins. Synchronous and 3D fluorescence spectroscopy revealed that the binding interaction caused microenvironmental changes of protein fluorophores. Molecular docking analysis suggested that hydrogen bonding and hydrophobic interactions are the major forces involved in the complexation process.

Isolating the Drivers of Racial Inequities in Prostate Cancer Treatment.

BACKGROUND: Black individuals in the United States are less likely than White individuals to receive curative therapies despite a 2-fold higher risk of prostate cancer death. While research has described treatment inequities, few studies have investigated underlying causes. METHODS: We analyzed a cohort of 40,137 Medicare beneficiaries (66 and older) linked to the Surveillance Epidemiology and End Results (SEER) cancer registry who had clinically significant, non-metastatic (cT1-4N0M0, grade group 2-5) prostate cancer (diagnosed 2010-2015). Using the Kitagawa-Oaxaca-Blinder decomposition, we assessed the contributions of patient health and health care delivery on the racial difference in localized prostate cancer treatments (radical prostatectomy or radiation). Patient health consisted of comorbid diagnoses, tumor characteristics, SEER site, diagnosis year, and age. Health care delivery was captured as a prediction model with these health variables as predictors of treatment, reflecting current treatment patterns. RESULTS: A total of 72.1% and 78.6% of Black and White patients received definitive treatment, respectively, a difference of 6.5 percentage points. An estimated 15% [95% confidence interval (CI): 6-24] of this treatment difference was explained by measured differences in patient health, leaving the remaining estimated 85% (95% CI: 74-94) attributable to a potentially broad range of health care delivery factors. Limitations included insufficient data to explore how specific health care delivery factors, including structural racism and social determinants, impact differential treatment. CONCLUSIONS: Our results show the inadequacy of patient health differences as an explanation of the treatment inequity. IMPACT: Investing in studies and interventions that support equitable health care delivery for Black individuals with prostate cancer will contribute to improved outcomes.

Gene Therapy Versus Common Care for Eligible Individuals With Sickle Cell Disease in the United States : A Cost-Effectiveness Analysis.

BACKGROUND: Sickle cell disease (SCD) and its complications contribute to high rates of morbidity and early mortality and high cost in the United States and African heritage community. OBJECTIVE: To evaluate the cost-effectiveness of gene therapy for SCD and its value-based prices (VBPs). DESIGN: Comparative modeling analysis across 2 independently developed simulation models (University of Washington Model for Economic Analysis of Sickle Cell Cure [UW-MEASURE] and Fred Hutchinson Institute Sickle Cell Disease Outcomes Research and Economics Model [FH-HISCORE]) using the same databases. DATA SOURCES: Centers for Medicare & Medicaid Services claims data, 2008 to 2016; published literature. TARGET POPULATION: Persons eligible for gene therapy. TIME HORIZON: Lifetime. PERSPECTIVE: U.S. health care sector and societal. INTERVENTION: Gene therapy versus common care. OUTCOME MEASURES: Incremental cost-effectiveness ratios (ICERs), equity-informed VBPs, and price acceptability curves. RESULTS OF BASE-CASE ANALYSIS: At an assumed $2 million price for gene therapy, UW-MEASURE and FH-HISCORE estimated ICERs of $193 000 per QALY and $427 000 per QALY, respectively, under the health care sector perspective. Corresponding estimates from the societal perspective were $126 000 per QALY and $281 000 per QALY. The difference in results between models stemmed primarily from considering a slightly different target population and incorporating the quality-of-life (QOL) effects of splenic sequestration, priapism, and acute chest syndrome in the UW model. From a societal perspective, acceptable (>90% confidence) VBPs ranged from $1 million to $2.5 million depending on the use of alternative effective metrics or equity-informed threshold values. RESULTS OF SENSITIVITY ANALYSIS: Results were sensitive to the costs of myeloablative conditioning before gene therapy, effect on caregiver QOL, and effect of gene therapy on long-term survival. LIMITATION: The short-term effects of gene therapy on vaso-occlusive events were extrapolated from 1 study. CONCLUSION: Gene therapy for SCD below a $2 million price tag is likely to be cost-effective when applying a societal perspective at an equity-informed threshold for cost-effectiveness analysis. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Correction: Bispidine-Amino Acid Conjugates Act as a Novel Scaffold for the Design of Antivirals That Block Japanese Encephalitis Virus Replication.

[This corrects the article DOI: 10.1371/journal.pntd.0002005.].

Acceptance of Insurance by Psychiatrists and Other Physicians, 2007-2016.

OBJECTIVE: The authors aimed to analyze psychiatrists' and other physicians' acceptance of insurance and the associations between insurance acceptance and specific physician- and practice-level characteristics. METHODS: Using the restricted version of the National Ambulatory Medical Care Survey, January 2007-December 2016, the authors analyzed acceptance of private insurance, public insurance, and any insurance among psychiatrists compared with nonpsychiatrist physicians. Because data were considered restricted, all analyses were conducted at federal Research Data Center facilities. RESULTS: The unweighted sample included an average of 4,725 physicians per 2-year time grouping between 2007 and 2016, with an average of 7% being psychiatrists. Nonpsychiatrists participated in all insurance networks at higher rates than did psychiatrists, and the acceptance gap was wider for public (Medicare and Medicaid) than private (noncapitated and capitated) insurance. Among psychiatrists, those practicing in metropolitan statistical areas and those in solo practices were significantly less likely than their peers in other locations and treatment settings to accept private, public, or any insurance. These findings were also observed among nonpsychiatrists, although to a lesser extent. CONCLUSIONS: In addition to general policy interventions to improve insurance network adequacy for psychiatric care, additional measures or incentives to promote insurance network participation should be considered for psychiatrists in solo practices and those in metropolitan areas.

Contribution of arsenic and uranium in private wells and community water systems to urinary biomarkers in US adults: The Strong Heart Study and the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Chronic exposure to inorganic arsenic (As) and uranium (U) in the United States (US) occurs from unregulated private wells and federally regulated community water systems (CWSs). The contribution of water to total exposure is assumed to be low when water As and U concentrations are low. OBJECTIVE: We examined the contribution of water As and U to urinary biomarkers in the Strong Heart Family Study (SHFS), a prospective study of American Indian communities, and the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of racially/ethnically diverse urban U.S. communities. METHODS: We assigned residential zip code-level estimates in CWSs (µg/L) and private wells (90th percentile probability of As >10 µg/L) to up to 1485 and 6722 participants with dietary information and urinary biomarkers in the SHFS (2001-2003) and MESA (2000-2002; 2010-2011), respectively. Urine As was estimated as the sum of inorganic and methylated species, and urine U was total uranium. We used linear mixed-effects models to account for participant clustering and removed the effect of dietary sources via regression adjustment. RESULTS: The median (interquartile range) urine As was 5.32 (3.29, 8.53) and 6.32 (3.34, 12.48) µg/L for SHFS and MESA, respectively, and urine U was 0.037 (0.014, 0.071) and 0.007 (0.003, 0.018) µg/L. In a meta-analysis across both studies, urine As was 11% (95% CI: 3, 20%) higher and urine U was 35% (5, 73%) higher per twofold higher CWS As and U, respectively. In the SHFS, zip-code level factors such as private well and CWS As contributed 46% of variation in urine As, while in MESA, zip-code level factors, e.g., CWS As and U, contribute 30 and 49% of variation in urine As and U, respectively. IMPACT STATEMENT: We found that water from unregulated private wells and regulated CWSs is a major contributor to urinary As and U (an estimated measure of internal dose) in both rural, American Indian populations and urban, racially/ethnically diverse populations nationwide, even at levels below the current regulatory standard. Our findings indicate that additional drinking water interventions, regulations, and policies can have a major impact on reducing total exposures to As and U, which are linked to adverse health effects even at low levels.

An RBM10 and NF-κB interacting host lncRNA promotes JEV replication and neuronal cell death.

IMPORTANCE: Central nervous system infection by flaviviruses such as Japanese encephalitis virus, Dengue virus, and West Nile virus results in neuroinflammation and neuronal damage. However, little is known about the role of long non-coding RNAs (lncRNAs) in flavivirus-induced neuroinflammation and neuronal cell death. Here, we characterized the role of a flavivirus-induced lncRNA named JINR1 during the infection of neuronal cells. Depletion of JINR1 during virus infection reduces viral replication and cell death. An increase in GRP78 expression by JINR1 is responsible for promoting virus replication. Flavivirus infection induces the expression of a cellular protein RBM10, which interacts with JINR1. RBM10 and JINR1 promote the proinflammatory transcription factor NF-κB activity, which is detrimental to cell survival.

Temporal effect of imatinib adherence on time to remission in chronic myeloid leukemia patients.

INTRODUCTION: Adherence to imatinib in chronic myeloid leukemia (CML) patients is estimated to be as low as 70% despite its clinical benefit, and our understanding of the impact of nonadherence in this population is limited. This study presents a novel application of the Alternating Conditional Estimation (ACE) algorithm in newly diagnosed CML patients to map the full dose-response curve (DRC) and determine how the strength of this curve varies over time. METHODS: We applied the ACE algorithm alongside a backward elimination procedure to detect the presence of time dependence and nonlinearity in the relationship between imatinib adherence and time-to-remission. An extended Cox model allowing for the flexible modeling of identified effects via unpenalized B-splines was subsequently fit and assessed. RESULTS: The substantial improvement in model fit associated with the extended Cox approach suggests that traditional Cox proportional hazards model assumptions do not hold in this setting. Results indicate that the DRC for imatinib is non-linearly increasing, with an attenuated effect above a 74% adherence rate. The strength of this effect on remission varied over time and was strongest in the initial months of treatment, reaching a peak around 90 days post-initiation (log hazard ratio: 2.12, 95% confidence interval: 1.47 to 2.66). CONCLUSION: Most patients that achieved remission did so by 4 months (120 days) with consistently high adherence, suggesting that this could be a critical time and duration for realizing treatment benefit and patient monitoring. Findings regarding the relationship between adherence and remission can additionally help guide the design of future studies.