Implementation of a Pharmacist-Driven Aspirin Deprescribing Protocol Among Older Veterans in a Primary Care Setting.

Background Recent cardiovascular guideline updates recommend against the use of aspirin for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in older people. However, aspirin use remains common in this population. Objective To implement and evaluate the benefit of a pharmacist-driven aspirin deprescribing protocol compared with primary care provider (PCP) education-only in a primary care setting. Methods This prospective, cohort project targeted deprescribing for patients prescribed aspirin for primary prevention of ASCVD. Patients were included if they received primary care services at the Milwaukee Veterans Health Administration Medical Center (VHA) and were 70 years of age or older. Criteria for exclusion were aspirin obtained outside the VHA system, aspirin prescribed for a non-ASCVD-related condition, and/or a history of ASCVD. Active deprescribing by pharmacists and PCP education took place in the intervention group with PCP education only in the standard-of-care group. The primary outcome was the proportion of patients who had aspirin deprescribed in each group. Secondary outcomes included patient acceptability of the intervention and barriers to implementation. Results A total of 520 patients were prescribed aspirin in the intervention group versus 417 in the education-only group. Sixty-five patients met intervention criteria and were contacted for aspirin deprescribing. The pharmacist-led active deprescribing group led to a higher rate of aspirin deprescriptions versus the education-only group (54% vs 18%; P = 0.0001) for patients who met criteria. Conclusion A pharmacist-led aspirin deprescribing protocol within a primary care setting significantly decreased the number of aspirin prescriptions compared with PCP education only.

Pharmacist Interventions in a Palliative PLUS Program at a Veterans Affairs Medical Center.

Background: Palliative PLUS (PP) at the Minneapolis Veterans Affairs Health Care System (MVAHCS) is an interdisciplinary team that seeks to improve veteran access to palliative and hospice resources. Palliative care pharmacists were incorporated to increase patient access to palliative specialties. Objective: To identify and categorize pharmacist interventions within an outpatient PP team at the MVAHCS. Methods: This quality improvement project was a retrospective analysis of the electronic health record. Results: A total of 84 patients were participating in the PP program over 13 months. Among those patients, 25 had pharmacist involvement and a total of 56 interventions were identified. Of those interventions, 29 (51.8%) were direct interventions and 27 (48.2%) were curbside consults. Most interventions involved medication counseling and medication adherence. Conclusion: Pharmacists made an impact on the PP team through direct patient interventions involving medication counseling and aided the interdisciplinary team by facilitating patient medication adherence.

CTCF regulates hepatitis B virus cccDNA chromatin topology.

Hepatitis B Virus (HBV) is a small DNA virus that replicates via an episomal covalently closed circular DNA (cccDNA) that serves as the transcriptional template for viral mRNAs. The host protein, CCCTC-binding factor (CTCF), is a key regulator of cellular transcription by maintaining epigenetic boundaries, nucleosome phasing, stabilisation of long-range chromatin loops and directing alternative exon splicing. We previously reported that CTCF binds two conserved motifs within Enhancer I of the HBV genome and represses viral transcription, however, the underlying mechanisms were not identified. We show that CTCF depletion in cells harbouring cccDNA-like HBV molecules and in de novo infected cells resulted in an increase in spliced transcripts, which was most notable in the abundant SP1 spliced transcript. In contrast, depletion of CTCF in cell lines with integrated HBV DNA had no effect on the abundance of viral transcripts and in line with this observation there was limited evidence for CTCF binding to viral integrants, suggesting that CTCF-regulation of HBV transcription is specific to episomal cccDNA. Analysis of HBV chromatin topology by Assay for Transposase Accessible Chromatin Sequencing (ATAC-Seq) revealed an accessible region spanning Enhancers I and II and the basal core promoter (BCP). Mutating the CTCF binding sites within Enhancer I resulted in a dramatic rearrangement of chromatin accessibility where the open chromatin region was no longer detected, indicating loss of the phased nucleosome up- and down-stream of the HBV enhancer/BCP. These data demonstrate that CTCF functions to regulate HBV chromatin conformation and nucleosomal positioning in episomal maintained cccDNA, which has important consequences for HBV transcription regulation.

Lead Time to Recurrence After Posttreatment Plasma and Saliva HPV DNA Testing in Patients With Low-Risk HPV Oropharynx Cancer.

Importance: Head and neck squamous cell carcinoma is a highly lethal cancer that is often associated with human papillomavirus (HPV). Recent studies have shown promise in the use of HPV DNA detection in salivary rinses and plasma as a factor associated with a future diagnosis of HPV-positive oropharynx cancer (HPVOPC). However, the use of plasma and salivary HPV DNA detection in defining risk for recurrence in the context of a prospective, phase 3, clinical trial coupled with standardized clinical surveillance has not been reported. Objective: To identify patients with low-risk HPVOPC at risk for recurrence by detection of HPV16 DNA in plasma and salivary rinses. Design, Setting, and Participants: In this cohort study, 233 low-risk patients were recruited from 32 head and neck treatment centers in Ireland (1 [3.1%]), the Netherlands (1 [3.1%]), and the UK (30 [93.8%]) as part of the DE-ESCALATE HPV trial, an open-label, phase 3 randomized clinical trial examining treatment with cetuximab vs cisplatin for HPVOPC. Patients were assayed for the presence of HPV16 DNA in plasma and salivary rinse via a quantitative polymerase chain reaction-based assay. Main Outcomes and Measures: Assay results were associated with risk of recurrence and lead time from HPV16 DNA detection to recurrence. Results: Of 233 patients, 45 (19.3%) were women, and the mean (SD) age was 57.01 (8.45) years. A total 1040 salivary or blood samples were collected during the course of the study. With a median follow-up of 760 days, the sensitivity and specificity of combined plasma and salivary rinse HPV DNA assays for detecting recurrence were 65% and 87%, respectively. There was a median lead time of positive test to event/recurrence date of 19 days (range, 0-536 days) and mean (SD) of 122 (169.8) days. Conclusion and Relevance: The results of this cohort study suggest that in the setting of a randomized, prospective, phase 3 trial for low-risk patients with HPVOPC, posttreatment presence of HPV DNA in plasma and salivary rinses is associated with recurrence; a lead time between test positivity and clinical recurrence offers a potential opportunity for earlier detection of recurrence.

Lying low-chromatin insulation in persistent DNA virus infection.

Persistent virus infections are achieved when the intricate balance of virus replication, host-cell division and successful immune evasion is met. The genomes of persistent DNA viruses are either maintained as extrachromosomal episomes or can integrate into the host genome. Common to both these strategies of persistence is the chromatinisation of viral DNA by cellular histones which, like host DNA, are subject to epigenetic modification. Epigenetic repression of viral genes required for lytic replication occurs, while genes required for latent or persistent infection are maintained in an active chromatin state. Viruses utilise host-cell chromatin insulators, which function to maintain epigenetic boundaries and enforce this strict transcriptional programme. Here, we review insulator protein function in virus transcription control, focussing on CCCTC-binding factor (CTCF) and cofactors. We describe CTCF-dependent activities in virus transcription regulation through epigenetic and promoter-enhancer insulation, three-dimensional chromatin looping and manipulation of transcript splicing.

Aortic Endarterectomy for Aortic Occlusive Disease: An Old Operation With a Re-emerging Role.

INTRODUCTION: Descending aortic complex atheromatous plaques can cause claudication, critical lower limb ischaemia (CLI), and are an independent risk factor for systemic embolization. Current practice involves dealing with most cases using endovascular techniques. However, open repair remains superior in terms of the patency rates and may be the only valid option in a subgroup of patients who are unsuitable for endovascular treatments. Most of the current data investigating open procedures are now historic. The aim of this study is to determine whether it is a feasible option in the current day practice. PATIENTS AND METHODS: Ten years data from 2010 to 2020 were collected retrospectively from the hospital records. Clinic letters, radiologic scans, operative records and discharge letters were reviewed. Death records were reviewed to identify patients who survived. RESULTS: Ten cases were identified. The average age was 55 and the mean BMI was 29.4. The mean hospital stay in days was 12 (range: 4 to 22). The mean follow-up period was 147 days (range: 30 to 360 days). Four of the patients were TASC B, four were TASC C and two were TASC D. Two cases had to return to theatres. One patient had transient post-op AF and another had transient post-op ileus. One patient was readmitted within 30 days of discharge for urosepsis. All cases are alive to date except one case which only survived three years after procedure. CONCLUSION: AE is a procedure that should be considered in selected cases where endovascular approach is not feasible. There is a trend towards lower mortality than the historic data available in literature. Larger case series or registry data may be required to accurately estimate the current day mortality and morbidity figures.

First impressions of the foundation interim year 1 postings: positives, pitfalls, and perils.

COVID-19 has placed an increased burden on the NHS. Changes were made to expand patient capacity including hospital restructuring, cancellation of most elective surgeries and early graduation of final year medical students. 1 The UK foundation programme (UKFP) curated a new training position for graduates as foundation interim year 1 (FiY1) doctors, where they voluntarily work in paid positions prior to entering formal foundation year 1 (FY1) roles. 2 Expediting the process of fulfilling these positions, the General Medical Council facilitated early provisional registration of doctors. We discuss the positives, pitfalls, and perils of the new roles and the first impressions of three newly qualified FiY1 s in medical, obstetrics and gynaecology and surgical posts, a surgical FY1 doctor and a clinical supervisor in surgery.

Author Correction: Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGFß, JAK/STAT and senescence signalling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.

Deafening decreases neuronal incorporation in the zebra finch caudomedial nidopallium (NCM).

New neurons formed in the adult brain are incorporated into existing circuits. However, the number of new neurons recruited into a given brain region varies widely depending on the experience of the animal. An emerging general principle is that recruitment and early neuronal survival may be correlated with activity or use of the brain region. Here we show that use-dependent neuronal survival also occurs in the higher order auditory processing region of the songbird caudomedial nidopallium (NCM). We suggest that retention of young neurons may in part be influenced by use of the system without an increased demand for learning or behavioral plasticity.