Safe co-administration of direct-acting antivirals and direct oral anticoagulants among patients with hepatitis C virus infection: An international multicenter retrospective cohort study.

Treatment for hepatitis C virus (HCV) with direct-acting antivirals (DAA) is advantageous over previous treatment options due to high efficacy, short treatment duration, and relatively few drug interactions. Similarly, direct oral anticoagulants (DOAC) are generally preferred over warfarin for the management of thrombosis and atrial fibrillation due to a favourable safety profile. Direct-acting antivirals inhibit DOAC transport through P-glycoprotein inhibition leading to a theoretical increase in bleeding risk. We evaluated the incidence of bleeding in patients who received concurrent DAA and DOAC therapy and stratified the analysis based on the patient's cirrhosis status. We conducted a multicenter, retrospective cohort study to evaluate bleeding in patients with HCV and cirrhosis compared to patients with HCV without cirrhosis. Patients receiving at least 1 month of overlapping DAA and DOAC therapy between May 2017 and August 2020 at 11 medical centers in the United Kingdom and three medical centers in the United States were included. Charts were manually reviewed to identify baseline characteristics as well as thromboembolic or bleeding events. Bleeding events were categorized as major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). Of 204 total patients, 36 patients (18%) had cirrhosis and 168 patients (82%) did not have cirrhosis. The majority of patients were male (79%) and Caucasian (75%). Sofosbuvir/velpatasvir (32%) and rivaroxaban (57%) were the most commonly prescribed DAA and DOAC, respectively. Leading indications for anticoagulation included thrombosis (75%) and atrial fibrillation (21%). There were three MB events (1.5%) all of which occurred in patients with additional risk factors (age over 65 and on antiplatelet therapy) and no CRNMB occurred while on DOAC and DAA therapy. Of the three MB, one occurred in a patient with cirrhosis and two in patients without cirrhosis, RR 1.23 (0.56-2.76). In conclusion, in this multicenter cohort study of concurrent DAA and DOAC use, MB was uncommon and there was no CRNMB. There was no significant difference in bleeding events among patients with cirrhosis compared to those without cirrhosis. These findings support the use of DAA among patients requiring DOAC.

Arduino-based, low-cost imaging incubator for extended live cell imaging.

In order to image live cells for prolonged periods of time, an Arduino-based, low-cost imaging incubator was constructed. The imaging incubator keeps cells viable by controlling for temperature and CO 2 in order to maintain physiological conditions for cells during imaging. All devices and parts employed in the build were typical maker-type components in order to minimize the cost of the imaging incubator. The imaging incubator allows for real-time imaging of live cells exposed to any desired perturbation or stimulus. As a proof of the system's functionality, cells are imaged over 24 hours while remaining viable in the imaging incubator.

Functional diversity of Medicago truncatula RNA polymerase II CTD phosphatase isoforms produced in the Arabidopsis thaliana superexpression platform.

Medicago truncatula is a model system for legume plants, which has substantially expanded the genome relative to the prototypical model dicot plant, Arabidopsis thaliana. An essential transcriptional regulator, FCP1 (transcription factor IIF-interacting RNA polymerase II carboxyl-terminal phosphatase 1) ortholog, is encoded by a single essential gene CPL4 (CTD-phosphatase-like 4), whereas M. truncatula genome contains four genes homologous to FCP1/AtCPL4, and splicing variants of MtCPL4 are observed. Functional diversification of MtCPL4 family proteins was analyzed using recombinant proteins (MtCPL4a1, MtCPL4a2, and MtCPL4b) produced in Arabidopsis cell culture system developed for plant protein overexpression. In vitro CTD phosphatase assay using highly purified MtCPL4 preparations revealed a potent CTD phosphatase activity in MtCPL4b, but not two splicing variants of MtCPL4a. On the other hand, in planta binding assay to RNA polymerase II (pol II) revealed a greater pol II-binding activity of both MtCPL4a variants. Our results indicate functional diversification of MtCPL4 isoforms and suggest the presence of a large number of functionally specialized CTD-phosphatase-like proteins in plants.

Developing a primary care-initiated hepatitis C treatment pathway in Scotland: a qualitative study.

BACKGROUND: The ease of contemporary hepatitis C virus (HCV) therapy has prompted a global drive towards simplified and decentralised treatment pathways. In some countries, primary care has become an integral component of community-based HCV treatment provision. In the UK, however, the role of primary care providers remains largely focused on testing and diagnosis alone. AIM: To develop a primary care-initiated HCV treatment pathway for people who use drugs, and recommend theory-informed interventions to help embed that pathway into practice. DESIGN AND SETTING: A qualitative study informed by behaviour change theory. Semi-structured interviews were undertaken with key stakeholders (n = 38) primarily from two large conurbations in Scotland. METHOD: Analysis was three-stage. First, a broad pathway structure was outlined and then sequential pathway steps were specified; second, thematic data were aligned to pathway steps, and significant barriers and enablers were identified; and, third, the Theoretical Domains Framework and Behaviour Change Wheel were employed to systematically develop ideas to enhance pathway implementation, which stakeholders then appraised. RESULTS: The proposed pathway structure spans broad, overarching challenges to primary care-initiated HCV treatment. The theory-informed recommendations align with influences on different behaviours at key pathway steps, and focus on relationship building, routinisation, education, combating stigmas, publicising the pathway, and treatment protocol development. CONCLUSION: This study provides the first practicable pathway for primary care-initiated HCV treatment in Scotland, and provides recommendations for wider implementation in the UK. It positions primary care providers as an integral part of community-based HCV treatment, providing workable solutions to ingrained barriers to care.

Application of compression bandaging post-osteotomy results in altered pain profile; results of a single-centre randomised controlled trial.

PURPOSE: To assess if application of dual-layer compression bandage to osteotomy patients post-surgery can positively influence levels of post-operative pain and swelling. PATIENTS & METHODS: Prospective, single-centre, randomised controlled trial comparing standard care, non-compression bandaging, versus Coban™ 2 (3M). Seven day application of the latter to index leg of osteotomy patients. RESULTS: Primary outcome data was available for 36 out of 49 study subjects (18 standard care versus 18 Coban™ 2 subjects). Median 10-cm scale pain levels showed a statistically non-significant difference at day 5 and day 12 post-surgery between standard care and Coban™ 2 respectively: 5.5 cm vs 2.5 cm (p-value 0.068) and 4.0 cm vs 2.3 cm (p-value 0.39). However, on day 12 (p-value 0.029) and week 6 (p-value 0.027), 'throbbing pain' was significantly higher for Coban™ 2 patients. Changes in limb swelling measures, comparing before and after the surgical procedure, did not differ between treatment arms. Compression led to more patients reporting bandage-related discomfort (6% standard care versus 63% Coban™ 2 patients). CONCLUSION: Compression bandaging changes the post-surgery pain profile in osteotomy patients, but does not reduce leg swelling. Any subsequent leg compression trials must take into account patient comfort and titrate intervention length and compression rates.

Recommendations for Dosing of Repurposed COVID-19 Medications in Patients with Renal and Hepatic Impairment.

INTRODUCTION: In December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began, resulting in a number of antivirals and immune modulators being repurposed to treat the associated coronavirus disease 2019 (COVID-19). Many patients requiring treatment for COVID-19 may have either pre-existing renal or hepatic disease or experience acute renal/hepatic injury as a result of the acute infection. Altered renal or hepatic function can significantly affect drug concentrations of medications due to impaired drug metabolism and excretion, resulting in toxicity or reduced efficacy. The aim of this paper is to review the pharmacokinetics and available study data for the experimental COVID-19 therapies in patients with any degree of renal or hepatic impairment to make recommendations for dosing. METHODS: COVID-19 agents included in these recommendations were listed as primaries on the University of Liverpool COVID-19 drug interaction website ( www.covid19-druginteractions.org ), initially identified from Clinicialtrials.gov and ChicCTR.org.cn. A literature search was performed using PubMed and EMBASE as well as product licences and pharmacokinetic databases. FINDINGS: Remdesivir, dexamethasone, azithromycin, favipiravir, lopinavir/ritonavir, atazanavir, hydroxychloroquine, interferon beta, ribavirin, tocilizumab, anakinra and sarilumab were identified as experimental drugs being used in COVID-19 trials as of November 2020. Limited study data was found for these drugs in patients with renal or hepatic impairment for COVID-19 or other indications. Recommendations were made based on available data, consideration of pharmacokinetic properties (including variability), the dosing and anticipated treatment duration of each regimen in COVID-19 and known toxicities. CONCLUSION: Dosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment is complex. These recommendations were produced to provide guidance to clinicians worldwide who are treating patients with COVID-19, many of whom will have some degree of acute or chronic renal or hepatic impairment.

Provider-related barriers and enablers to the provision of hepatitis C treatment by general practitioners in Scotland: A behaviour change analysis.

The ease of direct-acting antiviral (DAA) medications for hepatitis C virus (HCV) has provided an opportunity to decentralize HCV treatment into community settings. However, the role of non-specialist clinicians in community-based pathways has received scant attention to date. This study examined barriers and enablers to expanding the role of general practitioners (GPs) in HCV treatment provision, using simple behaviour change theory as a conceptual framework. A maximum variation sample of 22 HCV treatment providers, GPs and HCV support workers participated in semi-structured interviews. Data were inductively coded, and the resulting codes deductively mapped into three principal components of behaviour change: capability, opportunity and motivation (COM-B). By this process, a number of provider- and systemic-level barriers and enablers were identified. Key barriers included the pre-treatment assessment of liver fibrosis, GP capacity and the 'speciality' of HCV care. Enablers included the simplicity of the drugs, existing GP/patient relationships and the provision of holistic care. In addition to these specific factors, the data also exposed an overarching provider understanding of 'HCV treatment' as triumvirate in nature, incorporating the assessment of liver fibrosis, the provision of holistic support and the treatment of disease. This understanding imposes a further fundamental barrier to GP-led treatment as each of these three components needs to be individually addressed. To enable sustainable models of HCV treatment provision by GPs, a pragmatic re-examination of the 'HCV treatment triumvirate' is required, and a paradigm shift from the 'refer and treat' status quo.

Uptake and Engagement of Activities to Promote Native Species in Private Gardens.

Activities undertaken by householders in their gardens have huge potential to enhance city-wide biodiversity, but programs aimed at activating householders require an understanding of the factors encouraging or acting as barriers to the uptake of different kinds of activities. We provided 42 householders with two species-enhancing activities, selected from six possibilities, free-of-charge (to remove the barrier of initial cost). We collected socio-demographic data as well as information on knowledge of common urban species, pro-environmental behaviors and nature connectedness. We monitored ongoing engagement at two time points: 1 and 6 months. Characteristics of householders opting for different activities varied in terms of their degree of environmental engagement, their knowledge about common species, and the size of their gardens; e.g., bird feeders and bee planters were popular with people who did not know the names of common species and were not particularly engaged in pro-environmental activities respectively, whereas lizard habitat creation was attractive to people who were already engaged in wildlife gardening activities. Cost to continue with activities was a significant barrier for some people, but most householders were willing to practice relatively inexpensive activities in small spaces. Esthetics was an important factor to be considered when enhancing invertebrate habitat (e.g., bug hotels are more attractive than log piles, and planters for bees contain colorful flowers). A commonly cited barrier was lack of information about wildlife-friendly activities, despite much being available online. Most participants (85%) talked about their activities with others, potentially acting as influencers and shifting social norms.

DNA methylation patterns in ulcerative colitis-associated cancer: a systematic review.

BACKGROUND: Evidence points to the role of DNA methylation in ulcerative colitis (UC)-associated cancer (UCC), the most serious complication of ulcerative colitis. A better understanding of the etiology of UCC may facilitate the development of new therapeutic targets and help to identify biomarkers of the disease risk. METHODS: A search was performed in three databases following PRISMA protocol. DNA methylation in UCC was compared with sporadic colorectal cancer (SCRC), and individual genes differently methylated in UCC identified. RESULTS: While there were some similarities in the methylation patterns of UCC compared with SCRC, generally lower levels of hypermethylation in promoter regions of individual genes was evident in UCC. Certain individual genes are, however, highly methylated in colitis-associated cancer: RUNX3, MINT1, MYOD and p16 exon1 and the promoter regions of EYA4 and ESR. CONCLUSION: Patterns of DNA methylation differ between UCC and SCRC. Seven genes appear to be promising putative biomarkers.

Higher body mass index associated with severe early childhood caries.

BACKGROUND: Severe Early Childhood Caries (S-ECC) is an aggressive form of tooth decay in preschool children affecting quality of life and nutritional status. The purpose was to determine whether there is an association between Body Mass Index (BMI) and S-ECC. METHODS: Children with S-ECC were recruited on the day of their slated dental surgery under general anesthesia. Age-matched, caries-free controls were recruited from the community. All children were participating in a larger study on nutrition and S-ECC. Analysis was restricted to children ≥ 24 months of age. Parents completed a questionnaire and heights and weights were recorded. BMI scores and age and gender adjusted BMI z-scores and percentiles were calculated. A p-value ≤ 0.05 was significant. RESULTS: Two hundred thirty-five children were included (141 with S-ECC and 94 caries-free). The mean age was 43.3 ± 12.8 months and 50.2 % were male. Overall, 34.4 % of participants were overweight or obese. Significantly more children with S-ECC were classified as overweight or obese when compared to caries-free children (p = 0.038) and had significantly higher mean BMI z-scores than caries-free children (0.78 ± 1.26 vs. 0.22 ± 1.36, p = 0.002). Those with S-ECC also had significantly higher BMI percentiles (69.0 % ± 29.2 vs. 56.8 % ± 31.7, p = 0.003). Multiple linear regression analyses revealed that BMI z-scores were significantly and independently associated with S-ECC and annual household income as were BMI percentiles. CONCLUSIONS: Children with S-ECC in our sample had significantly higher BMI z-scores than caries-free peers.

Increased production of retinoic acid by intestinal macrophages contributes to their inflammatory phenotype in patients with Crohn's disease.

BACKGROUND & AIMS: Reduced generation of all-trans retinoic acid (RA) by CD103(+) intestinal dendritic cells (DCs) is linked to intestinal inflammation in mice. However, the role of RA in intestinal inflammation in humans is unclear. We investigated which antigen-presenting cells (APCs) produce RA in the human intestine and whether generation of RA is reduced in patients with Crohn's disease (CD). METHODS: Ileal and colonic tissues were collected from patients with CD during endoscopy or surgery, and healthy tissues were collected from subjects who were undergoing follow-up because of rectal bleeding, altered bowel habits, or cancer (controls). Cells were isolated from the tissue samples, and APCs were isolated by flow cytometry. Retinaldehyde dehydrogenase (RALDH) activity was assessed by Aldefluor assay, and ALDH1A expression was measured by quantitative real-time polymerase chain reaction. Macrophages were derived by incubation of human blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF). RESULTS: CD103(+) and CD103(-) DCs and CD14(+) macrophages from healthy human intestine had RALDH activity. Although ALDH1A1 was not expressed by DCs, it was the predominant RALDH enzyme isoform expressed by intestinal CD14(+) macrophages and their putative precursors, CD14(+) monocytes. RALDH activity was up-regulated in all 3 populations of APCs from patients with CD; in CD14(+) macrophages, it was associated with local induction of ALDH1A1 expression. Blocking of RA receptor signaling during GM-CSF-mediated differentiation of monocytes into macrophages down-regulated CD14 and HLA-DR expression and reduced the development of tumor necrosis factor α-producing inflammatory macrophages. CONCLUSIONS: RA receptor signaling promotes differentiation of human tumor necrosis factor α-producing inflammatory macrophages in vitro. In vivo, more CD14(+) macrophages from the intestinal mucosa of patients with CD than from controls are capable of generating RA, which might increase the inflammatory phenotype of these cells. Strategies to reduce the generation of RA by CD14(+) macrophages could provide new therapeutic options for patients with CD.