Policies for Expanding Hepatitis C Testing and Treatment in United States Prisons and Jails

Hepatitis C virus (HCV) is highly prevalent in United States prisons and jails. In prisons and jails, rates of infection are ten to twenty times greater than national levels. And, more than thirty percent of all people living with HCV in the United States will spend time in prisons and jails in any given year. Rates are especially high among people who inject drugs (PWID), a population whose members are also likely to move between carceral settings and the community. Thus, addressing HCV among incarcerated populations would have a significant effect on the virus’s transmission both in and out of confinement and is a crucial part of any HCV elimination strategy. Safe and effective HCV treatment is available. Direct-acting antivirals (DAAs) offered in an eight to twelve week course of oral treatment cure HCV in more than ninety percent of cases. Widespread testing and treatment in prisons and widespread testing and treatment or linkage to community care in jails are essential public health approaches. But testing and treatment in confinement lags behind medical guidance and public health recommendations. People incarcerated in prisons and detained in jails are entitled to adequate health care, and the U.S. Constitution prohibits deliberate indifference to their serious medical needs. In recent years, lawsuits filed by people with HCV in carceral facilities across the country have alleged violations of federal law for failure to provide DAA treatment. Although litigation results have been mixed, settlement agreements in states across the country have expanded HCV testing and broadened access to DAA treatment. These settlement agreements reflect a growing understanding that widespread testing and treatment is cost-effective, avoid the harmful health consequences of disease progression, and meaningfully reduce community transmission. This paper recommends model policies for prisons and jails to expand HCV testing and DAA treatment. The policy recommendations draw from relevant settlement agreements and current medical guidelines, supplemented by input from public health experts, medical professionals, and advocates. The paper proceeds as follows: • Part I describes the HCV epidemic in United States prisons and jails, the recent sea change in treatment protocols, and relevant clinical guidance and public health recommendations. • Part II sets out the legal landscape, including governing federal law and judicial decisions interpreting that law in this context, and describes settlement agreements in class action lawsuits addressing DAA access. • Finally, Part III offers model policies for prisons and jails to expand testing and treatment and to support successful outcomes for people with HCV in their custody

Large-scale discovery of enhancers from human heart tissue.

Development and function of the human heart depend on the dynamic control of tissue-specific gene expression by distant-acting transcriptional enhancers. To generate an accurate genome-wide map of human heart enhancers, we used an epigenomic enhancer discovery approach and identified ∼6,200 candidate enhancer sequences directly from fetal and adult human heart tissue. Consistent with their predicted function, these elements were markedly enriched near genes implicated in heart development, function and disease. To further validate their in vivo enhancer activity, we tested 65 of these human sequences in a transgenic mouse enhancer assay and observed that 43 (66%) drove reproducible reporter gene expression in the heart. These results support the discovery of a genome-wide set of noncoding sequences highly enriched in human heart enhancers that is likely to facilitate downstream studies of the role of enhancers in development and pathological conditions of the heart

The microRNA-29 family in cartilage homeostasis and osteoarthritis

MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family were also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways

The role of low-income and middle-income country prisons in eliminating Hepatitis C

Hepatitis C virus (HCV) is a global health problem affecting 58 million people, 80% of whom live in low-income and middle-income countries (LMICs). In 2019, 1·5 million new HCV infections and 290 000 HCV-related deaths were estimated worldwide. One in two people who inject drugs has been exposed to HCV, and nearly half of incident HCV infections could be prevented if transmission risk due to injection drug use was removed. Mainly as a result of the criminalisation of substance use and the incarceration of people who use drugs, HCV is the most prevalent infectious disease in carceral settings worldwide. However, HCV-related data from prisons in LMICs are scarce.Research grants from AbbVie, Gilead Sciences, ViiV Healthcare, Merck Canada and Sequiris.www.thelancet.com/public-healthhttps://www.unodc.org/unodc/en/justice-and-prison-reform/NMRules.htmlhttp://www.thelancet.com/public-healtham2023Family Medicin

Unraveling Twisty Linear Polarization Morphologies in Black Hole Images

We investigate general relativistic magnetohydrodynamic simulations (GRMHD) to determine the physical origin of the twisty patterns of linear polarization seen in spatially resolved black hole images and explain their morphological dependence on black hole spin. By characterising the observed emission with a simple analytic ring model, we find that the twisty morphology is determined by the magnetic field structure in the emitting region. Moreover, the dependence of this twisty pattern on spin can be attributed to changes in the magnetic field geometry that occur due to the frame dragging. By studying an analytic ring model, we find that the roles of Doppler boosting and lensing are subdominant. Faraday rotation may cause a systematic shift in the linear polarization pattern, but we find that its impact is subdominant for models with strong magnetic fields and modest ion-to-electron temperature ratios. Models with weaker magnetic fields are much more strongly affected by Faraday rotation and have more complicated emission geometries than can be captured by a ring model. However, these models are currently disfavoured by the recent EHT observations of M87*. Our results suggest that linear polarization maps can provide a probe of the underlying magnetic field structure around a black hole, which may then be usable to indirectly infer black hole spins. The generality of these results should be tested with alternative codes, initial conditions, and plasma physics prescriptions.Comment: 25 pages, 19 figure

Topologically associating domain boundaries are required for normal genome function

Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes1,2,3, but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11–80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening.This work was supported by U.S. National Institutes of Health (NIH) grants to L.A.P. and A.V. (UM1HG009421). Research was conducted at the E.O. Lawrence Berkeley National Laboratory and performed under U.S. Department of Energy Contract DE-AC02-05CH11231, University of California (UC). Phenotyping performed by the UC Davis Mouse Biology Program (MBP) (www.mousebiology.org) was funded by an NIH administrative supplement to the KOMP2 grant, 3UM1OD023221-07S1, for phenotyping non-coding elements. Adyam Akeza was supported by the NIH Bridges to Baccalaureate Program Grant R25GM095401 via UC Berkeley. J.L.-R. is supported by the Spanish Ministerio de Ciencia e Innovacion (PID2020-113497GB-I00).Peer reviewe

ChIP-seq Accurately Predicts Tissue-Specific Activity of Enhancers

A major yet unresolved quest in decoding the human genome is the identification of the regulatory sequences that control the spatial and temporal expression of genes. Distant-acting transcriptional enhancers are particularly challenging to uncover since they are scattered amongst the vast non-coding portion of the genome. Evolutionary sequence constraint can facilitate the discovery of enhancers, but fails to predict when and where they are active in vivo. Here, we performed chromatin immunoprecipitation with the enhancer-associated protein p300, followed by massively-parallel sequencing, to map several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain, and limb tissue. We tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases revealed reproducible enhancer activity in those tissues predicted by p300 binding. Our results indicate that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities and suggest that such datasets will be useful to study the role of tissue-specific enhancers in human biology and disease on a genome-wide scale

Disruption of Rolandic Gamma-Band Functional Connectivity by Seizures is Associated with Motor Impairments in Children with Epilepsy

Although children with epilepsy exhibit numerous neurological and cognitive deficits, the mechanisms underlying these impairments remain unclear. Synchronization of oscillatory neural activity in the gamma frequency range (>30 Hz) is purported to be a mechanism mediating functional integration within neuronal networks supporting cognition, perception and action. Here, we tested the hypothesis that seizure-induced alterations in gamma synchronization are associated with functional deficits. By calculating synchrony among electrodes and performing graph theoretical analysis, we assessed functional connectivity and local network structure of the hand motor area of children with focal epilepsy from intracranial electroencephalographic recordings. A local decrease in inter-electrode phase synchrony in the gamma bands during ictal periods, relative to interictal periods, within the motor cortex was strongly associated with clinical motor weakness. Gamma-band ictal desychronization was a stronger predictor of deficits than the presence of the seizure-onset zone or lesion within the motor cortex. There was a positive correlation between the magnitude of ictal desychronization and impairment of motor dexterity in the contralateral, but not ipsilateral hand. There was no association between ictal desynchronization within the hand motor area and non-motor deficits. This study uniquely demonstrates that seizure-induced disturbances in cortical functional connectivity are associated with network-specific neurological deficits