Changes in Use of Hepatitis C Direct-Acting Antivirals After Access Restrictions Were Eased by State Medicaid Programs.

Importance: Direct-acting antivirals (DAAs) are safe and highly effective for curing hepatitis C virus (HCV) infection, but their high cost led certain state Medicaid programs to impose coverage restrictions. Since 2015, many of these restrictions have been lifted voluntarily in response to advocacy or because of litigation. Objective: To estimate how the prescribing of DAAs to Medicaid patients changed after states eased access restrictions. Design, Setting, and Participants: This modified difference-in-differences analysis of 39 state Medicaid programs included Medicaid beneficiaries who were prescribed a DAA from January 1, 2015, to December 31, 2019. DAA coverage restrictions were measured based on a series of cross-sectional assessments performed from 2014 through 2022 by the US National Viral Hepatitis Roundtable and the Center for Health Law and Policy Innovation. Exposure: Calendar quarter when states eased or eliminated 3 types of DAA coverage restrictions: limiting treatment to patients with severe liver disease, restricting use among patients with active substance use, and requiring prescriptions to be written by or in consultation with specialists. States with none of these restrictions at baseline were excluded. Main Outcomes and Measures: Quarterly number of HCV DAA treatment courses per 100 000 Medicaid beneficiaries. Results: Of 39 states, 7 (18%) eliminated coverage restrictions, 25 (64%) eased restrictions, and 7 (18%) maintained the same restrictions from 2015 to 2019. During this period, the average quarterly use of DAAs increased from 669 to 3601 treatment courses per 100 000 Medicaid beneficiaries. After states eased or eliminated restrictions, the use of DAAs increased by 966 (95% CI, 409-1523) treatment courses per 100 000 Medicaid beneficiaries each quarter compared with states that did not ease or eliminate restrictions. Conclusions and Relevance: The results of this study suggest that there was greater use of DAAs after states relaxed coverage restrictions related to liver disease severity, sobriety, or prescriber specialty. Further reductions or elimination of these rules may improve access to a highly effective public health intervention for patients with HCV.

Incorporating the benefits of vegetative filter strips into risk assessment and risk management of pesticides.

The pesticide registration process in North America, including the USA and Canada, involves conducting a risk assessment based on relatively conservative modeling to predict pesticide concentrations in receiving waterbodies. The modeling framework does not consider some commonly adopted best management practices that can reduce the amount of pesticide that may reach a waterbody, such as vegetative filter strips (VFS). Currently, VFS are being used by growers as an effective way to reduce off-site movement of pesticides, and they are being required or recommended on pesticide labels as a mitigation measure. Given the regulatory need, a pair of multistakeholder workshops were held in Raleigh, North Carolina, to discuss how to incorporate VFS into pesticide risk assessment and risk management procedures within the North American regulatory framework. Because the risk assessment process depends heavily on modeling, one key question was how to quantitatively incorporate VFS into the existing modeling approach. Key outcomes from the workshops include the following: VFS have proven effective in reducing pesticide runoff to surface waterbodies when properly located, designed, implemented, and maintained; Vegetative Filter Strip Modeling System (VFSMOD), a science-based and widely validated mechanistic model, is suitable for further vetting as a quantitative simulation approach to pesticide mitigation with VFS in current regulatory settings; and VFSMOD parametrization rules need to be developed for the North American aquatic exposure assessment. Integr Environ Assess Manag 2024;20:454-464. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome.

The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that preferentially occurs at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.

Top-Down Holography in an Asymptotically Flat Spacetime.

We propose a holographic duality for a four dimensional Wess-Zumino-Witten model with target manifold SO(8), coupled to scalar-flat Kähler gravity on an asymptotically flat, four dimensional background known as the Burns metric. The holographic dual is a two dimensional chiral algebra built out of gauged ß-γ systems with SO(8) flavor. We test the duality by matching two-point correlators of soft gluon currents with two-point gluon amplitudes, and their leading operator product expansion coefficients with collinear limits of three-point gluon amplitudes.

Associativity of One-Loop Corrections to the Celestial Operator Product Expansion.

There has been recent interest in the question of whether QCD collinear singularities can be viewed as the operator product expansion of a two-dimensional conformal field theory. We analyze a version of this question for the self-dual limit of pure gauge theory (incorporating states of both helicities). We show that the known one-loop collinear singularities do not form an associative chiral algebra. The failure of associativity can be traced to a novel gauge anomaly on twistor space. We find that associativity can be restored for certain gauge groups if we introduce an unusual axion, which cancels the twistor space anomaly by a Green-Schwarz mechanism. Alternatively, associativity can be restored for some gauge groups with carefully chosen matter.

Sequence features of retrotransposons allow for epigenetic variability.

Transposable elements (TEs) are mobile genetic elements that make up a large fraction of mammalian genomes. While select TEs have been co-opted in host genomes to have function, the majority of these elements are epigenetically silenced by DNA methylation in somatic cells. However, some TEs in mice, including the Intracisternal A-particle (IAP) subfamily of retrotransposons, have been shown to display interindividual variation in DNA methylation. Recent work has revealed that IAP sequence differences and strain-specific KRAB zinc finger proteins (KZFPs) may influence the methylation state of these IAPs. However, the mechanisms underlying the establishment and maintenance of interindividual variability in DNA methylation still remain unclear. Here, we report that sequence content and genomic context influence the likelihood that IAPs become variably methylated. IAPs that differ from consensus IAP sequences have altered KZFP recruitment that can lead to decreased KAP1 recruitment when in proximity of constitutively expressed genes. These variably methylated loci have a high CpG density, similar to CpG islands, and can be bound by ZF-CxxC proteins, providing a potential mechanism to maintain this permissive chromatin environment and protect from DNA methylation. These observations indicate that variably methylated IAPs escape silencing through both attenuation of KZFP binding and recognition by ZF-CxxC proteins to maintain a hypomethylated state.

Chern-Simons Origin of Superstring Integrability.

We derive the AdS_{5}×S^{5} Green-Schwarz superstring from four-dimensional Beltrami-Chern-Simons theory reduced on a manifold with singular boundary conditions. In this construction, the Lax connection and spectral parameter of the integrable superstring have a simple geometric origin in four dimensions as gauge connection and reduction coordinate. κ symmetry arises as a certain class of singular gauge transformations, while the world-sheet metric comes from complex-structure-changing Beltrami differentials. Our approach offers the possibility of investigating integrable holography using traditional field theory methods.

Empowering Patients with Alzheimer's Disease To Avoid Unwanted Medical Care: A Look At The Dementia Care Triad.

Patients with Alzheimer's disease and other types of dementia with acute medical problems, who have lost capacity and are without advance directives, are at risk of being over treated inhospitals. To deal with this growing demographic and ethical crisis, patients with dementia need to plan for their future medical care while they have capacity to do so. This article will examine the role of each member of the dementia care triad and how to empower the patient to participate in planning future medical care. A case will be made that physicians have the same professional disclosure obligations to dementia patients as they do to all other capable patients with terminal illnesses. Because there is little consensus about what facts should be included in a diagnostic disclosure, this article will offer a proposal to empower newly diagnosed patients with dementia with capacity to plan for their future medical care.

LTRs activated by Epstein-Barr virus-induced transformation of B cells alter the transcriptome.

Endogenous retroviruses (ERVs) are ancient viral elements that have accumulated in the genome through retrotransposition events. Although they have lost their ability to transpose, many of the long terminal repeats (LTRs) that originally flanked full-length ERVs maintain the ability to regulate transcription. While these elements are typically repressed in somatic cells, they can function as transcriptional enhancers and promoters when this repression is lost. Epstein-Barr virus (EBV), which transforms primary B cells into continuously proliferating cells, is a tumor virus associated with lymphomas. We report here that transformation of primary B cells by EBV leads to genome-wide activation of LTR enhancers and promoters. The activation of LTRs coincides with local DNA hypomethylation and binding by transcription factors such as RUNX3, EBF1, and EBNA2. The set of activated LTRs is unique to transformed B cells compared with other cell lines known to have activated LTRs. Furthermore, we found that LTR activation impacts the B cell transcriptome by up-regulating transcripts driven by cryptic LTR promoters. These transcripts include genes important to oncogenesis of Hodgkin lymphoma and other cancers, such as HUWE1/HECTH9 These data suggest that the activation of LTRs by EBV-induced transformation is important to the pathology of EBV-associated cancers. Altogether, our results indicate that EBV-induced transformation of B cells alters endogenous retroviral element activity, thereby impacting host gene regulatory networks and oncogenic potential.

Chromatin modifications in metabolic disease: Potential mediators of long-term disease risk.

Metabolic diseases such as obesity and diabetes are complex diseases resulting from multiple genetic and environmental factors, such as diet and activity levels. These factors are well known contributors to the development of metabolic diseases. One manner by which environmental factors can influence metabolic disease progression is through modifications to chromatin. These modifications can lead to altered gene regulatory programs, which alters disease risk. Furthermore, there is evidence that parents exposed to environmental factors can influence the metabolic health of offspring, especially if exposures are during intrauterine growth periods. In this review, we outline the evidence that chromatin modifications are associated with metabolic diseases, including diabetes and obesity. We also consider evidence that these chromatin modifications can lead to long-term disease risk and contribute to disease risk for future generations. This article is categorized under: Biological Mechanisms > Metabolism Developmental Biology > Developmental Processes in Health and Disease Physiology > Organismal Responses to Environment.

Effects of the ResQPOD on Kinetics, Hemodynamics of Vasopressin, and Survivability in a Porcine Cardiac Arrest Model.

BACKGROUND: Ventilation through an impedance threshold device (ITD) purportedly improves hemodynamics and survivability and is given a Class IIb recommendation by the American Heart Association/American College of Cardiology for adult cardiac arrest. No studies have investigated the effects of an ITD with vasopressin. METHODS AND RESULTS: This study compared return of spontaneous circulation (ROSC), time to ROSC, hemodynamics, and pharmacokinetics with and without the use of a ResQPOD ITD. Swine were randomized to three groups: cardiopulmonary resuscitation and defibrillation alone, vasopressin with ResQPOD, and vasopressin without ResQPOD. Survival differences between the cardiopulmonary resuscitation and defibrillation group versus with and without ResQPOD groups were found (p = 0.001, FET; p = 0.021, FET, respectively) but no differences between with and without ResQPOD groups (p = 0.462). A test of Cmax between the IV and IV/ResQPOD group provided limited evidence that the IV/ResQPOD group attained higher Cmax than then IV only group (U = 11.00, p = 0.097). Median Tmax and ROSC were not statistically different between the groups (U = 11.00, p = 0.314). CONCLUSIONS: Our data suggest that there is no difference in drug kinetics or clinical outcomes in terms of survivability with or without the ResQPOD.

Effect of acellular human dermis buttress on laparoscopic hiatal hernia repair.

PURPOSE: The objective of this study was to evaluate the performance of acellular human dermis reinforcement during laparoscopic hiatal hernia repair. METHODS: A prospective non-randomized, single institution study enrolled patients undergoing laparoscopic hiatal hernia repair. Acellular human dermis, FlexHD (Musculoskeletal Transplant Foundation, Edison, NJ) or AlloDerm (LifeCell Inc., Branchburg, NJ) were used to buttress the repair after primary closure. A protocol barium swallow (BAS) was performed at 6 months and then as needed due to clinical indications. Primary outcome measure was recurrence. Patients completed preoperative and postoperative GERD symptom questionnaires and quality of life surveys (SF-36). Kruskal-Wallis ANOVA, Student's t test, Fisher's exact test, or Wilcoxon signed-rank test were utilized as appropriate (p < 0.05 considered statistically significant). RESULTS: Fifty-four patients (10 men and 44 women) with a mean age of 62 ± 10 years underwent laparoscopic hiatal hernia repair using Flex HD (n = 37) or AlloDerm (n = 17). Both groups were similar with respect to gender, age, hiatus size, hernia type [sliding/Type I (n = 14) or paraesophageal/Type III/IV (n = 40)], esophageal motor function (manometry), preoperative SF-36 quality of life surveys, and GERD symptom questionnaires. Forty-seven patients (87 %) completed the BAS at 6 months; each group had two recurrences (p = 0.597). At median follow-up of 33 months, there were 3 recurrences (18 %) in the AlloDerm group and 5 recurrences (14 %) in the Flex HD group (p = 0.365). Minimal differences in GERD symptoms or SF-36 scores were detected between groups. However, anti-reflux medication usage, GERD symptoms, and quality of life significantly improved for both groups after laparoscopic hiatal hernia repair. CONCLUSIONS: Laparoscopic hiatal hernia repair with acellular human dermis reinforcement results in improvement of GERD-related symptoms and quality of life without mesh-associated complications. The type of acellular human dermis did not influence recurrence rate.

Fractured OG tip: a case report.

This case report describes a complication from use of an orogastric tube not previously described in the literature. An OG tube was placed and removed non-traumatically for the anesthetic management for an anterior-posterior cervical spinal fusion. Despite smooth placement and removal, the patient coughed up the tip of the OG tube while in the post anesthesia care unit. Orogastric (OG) and nasogastric (NG) tubes are routinely used in anesthesia as well as many other fields of medicine. OG and NG tubes leading to morbidity are rare; however, this report describes a new potential adverse event that clinicians should be aware of.

Laparoscopic fixation of biologic mesh at the hiatus with fibrin or polyethylene glycol sealant in a porcine model.

BACKGROUND: The objective of this study was to determine the acute and chronic fixation strengths achieved by fibrin or polyethylene glycol (PEG) sealants to secure biologic mesh at the esophageal hiatus in a porcine model. METHODS: For this study, 32 female domestic pigs were divided into four groups of 8 each. The four groups respectively received acute fibrin sealant, acute PEG sealant, chronic fibrin sealant, and chronic PEG sealant. Laparoscopically, a 5.5 × 8.5-cm piece of Biodesign Surgisis Hiatal Hernia Graft (porcine small intestine submucosa) was oriented with the U-shaped cutout around the gastroesophageal junction and the short axis in the craniocaudal direction to simulate hiatal reinforcement with a biologic mesh. The mesh then was secured with 2 ml of either fibrin sealant or PEG sealant. The pigs in the acute groups were maintained alive for 2 h to allow for complete polymerization of the sealants, and the pigs in the chronic group were maintained alive for 14 days. After the pigs were euthanized, specimens of the mesh-tissue interface were subjected to lap shear testing to determine fixation strength, and hematoxylin and eosin (H&E) stained slides were evaluated for evidence of remodeling. RESULTS: No significant differences were observed between the acute and chronic fixation strengths or the remodeling characteristics of the two sealants. However, fixation strength increased significantly over time for both types of sealant. Evidence of remodeling also was significantly more pronounced in the chronic specimens than in the acute specimens. CONCLUSIONS: This study demonstrated the feasibility of using fibrin or PEG sealants to secure biologic mesh at the hiatus in a porcine model.