Defining Interactions Between the Genome, Epigenome, and the Environment in Inflammatory Bowel Disease: Progress and Prospects.

Recent advances in our understanding of the pathogenesis of inflammatory bowel disease (IBD) have highlighted the complex interplay between the genome, the epigenome, and the environment. Despite the exciting advances in genomics that have enabled the identification of over 200 susceptibility loci, these only account for a small proportion of the disease variance and the estimated heritability in IBD. It is likely that gene-environment (GxE) interactions contribute to "missing heritability" and these may act through epigenetic mechanisms. Several environmental factors, such as the microbiome, nutrition, and tobacco smoking, induce alterations in the epigenome of children and adults, which may impact disease susceptibility. Other mechanisms for GxE interactions are also directly pertinent in early life. We discuss a model in which environmental factors imprint disease risk in a window of susceptibility during infancy that may contribute to later disease onset, whereas other elements of the exposome act later in life and contribute directly to the pathogenesis and course of the disease. Understanding the mechanisms underlying GxE interactions may provide the basis for new therapeutic targets or preventative strategies for IBD.

Pharmacist Prescribing Models for HIV Pre-exposure and Post-exposure Prophylaxis.

State strategies for pharmacist prescribing exist on a continuum from most restrictive to least restrictive. Using human immunodeficiency virus (HIV) pre-exposure prophylaxis and post-exposure prophylaxis as a case study, there are 3 viable pharmacist prescribing models: (1) population-based collaborative practice agreements; (2) government protocols; and (3) standard of care prescribing. The advantages and disadvantages of these 3 models are reviewed.

How to implement a "standard of care" regulatory model for pharmacists.

National pharmacy associations have increasingly explored regulation according to a "standard of care." In such a model, pharmacists can provide a wide range of clinical services aligned with their education and training. Based on Idaho's experience implementing this model, there are five critical steps states must take to enact a standard of care: 1) Adopt a broad definition of "practice of pharmacy;" 2) Allow elasticity for practice innovation over time; 3) Decide which limited instances still necessitate prescriptive regulation; 4) Eliminate all unnecessary regulations; and 5) Strengthen accountability for deviations from the standard of care. States wishing to adopt a standard of care approach can follow this five-step process to enhance patient care and mitigate the lag that is otherwise constant between laws and practice.

Tiered Licensure for Pharmacy Technicians: Is the Advanced Pharmacy Technician (APhT) License the Model for State Regulators?

Two states-Connecticut and New Hampshire-have created or attempted to create advanced pharmacy technician (APhT) licenses. Both licenses, proposed and actual, have high barriers to entry, such as requiring 1 to 3 years of prior technician experience and passage of various assessments or trainings, such as a state-specific jurisprudence exam. Those obtaining APhT licensure are granted additional authority, such as performing final product verification (e.g., tech-check-tech) and vaccine administration. Compared with practices in other states, the APhT role in CT and NH provides minimal scope gains relative to the requirements imposed; as a result, there has been limited uptake (<1%) among current technicians. As such, it appears unlikely that tiered licensure for technicians will be the preferred mechanism for states to expand the role of pharmacy technicians in the future.

Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response.

OBJECTIVES: We aimed to determine whether changes in acute severe colitis (ASC) management have translated to improved outcomes and to develop a simple model predicting steroid non-response on admission. DESIGN: Outcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015 and 2019 were compared with data from 1992 to 1993. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)). Steroid non-response was defined as receiving medical rescue therapy or surgery. A predictive model developed in the Oxford cohort was validated in Australia and India (Gold Coast University Hospital 2015-2020, n=110; All India Institute of Medical Sciences, New Delhi 2018-2020, n=62). RESULTS: In the 2015-2019 Oxford cohort, 15% required colectomy during admission vs 29% in 1992-1993 (p=0.033), while 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-tumour necrosis factor, compared with 27% ciclosporin in 1992-1993 (p=0.0015). Admission C reactive protein (CRP) (false discovery rate, p=0.00066), albumin (0.0066) and UCEIS scores (0.015) predicted steroid non-response. A four-point model was developed involving CRP of ≥100 mg/L (one point), albumin of ≤25 g/L (one point), and UCEIS score of ≥4 (1 point) or ≥7 (2 points). Patients scoring 0, 1, 2, 3 and 4 in the validation cohorts had steroid response rates of 100, 75.0%, 54.9%, 18.2% and 0%, respectively. Scoring of ≥3 was 84% (95% CI 0.70 to 0.98) predictive of steroid failure (OR 11.9, 95% CI 10.8 to 13.0). Colectomy rates in the validation cohorts were were 8%-11%. CONCLUSIONS: Emergency colectomy rates for ASC have halved in 25 years to 8%-15% worldwide. Patients who will not respond to corticosteroids are readily identified on admission and may be prioritised for early intensification of therapy.

The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants.

Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a molecular classification for 59 reported rare IL6ST pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of IL6ST variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian IL6ST coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights IL6ST as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations.

Facilitating multistate pharmacy practice: Streamlining continuing pharmacy education requirements.

A major regulatory impediment to achieving multistate pharmacist licensure is state-specific Continuing Pharmacy Education (CPE) mandates. States vary on CPE requirements in 6 key domains, presenting a potentially significant administrative burden for multistate pharmacists. In the short term, replicating the nursing compact model of CPE regulation is the most viable model for the pharmacy profession. In this model, a pharmacist would have to follow just the CPE requirements for the state where the pharmacist maintains primary residence, and maintenance of this home state license would be automatically recognized by other states in which the pharmacist practices.

Revisiting the continuum of pharmacist prescriptive authority.

Pharmacists in all states have prescriptive authority in some form. We identify two broad categories of pharmacist prescribing: dependent and independent. There are gradients within these broad categories that allow us to chart pharmacist prescribing on a continuum from most restrictive to least restrictive. Independent prescribing has seen the most innovation in recent years at the state level, with at least three states adopting a "standard of care" prescribing framework that allows pharmacists to exercise broad prescriptive authority including for conditions that require a diagnosis. Each of the approaches to pharmacist prescriptive authority have perceived advantages and disadvantages as it relates to improving patient care.

Opportunities for pharmacist prescriptive authority of buprenorphine following passage of the Mainstreaming Addiction Treatment (MAT) Act.

In December 2022, Congress passed the Mainstreaming Addiction Treatment Act, which removed the federal legal barrier to pharmacist buprenorphine prescribing. As a result, each state can now decide whether or not to allow pharmacists to prescribe buprenorphine as an additional access point to reduce fatal opioid overdoses. At least 10 states allow pharmacists to prescribe controlled substances under collaborative practice agreements. Two states (California and Idaho) have also created pathways for independent prescribing of buprenorphine by pharmacists. Additional states should seek to enable pharmacists to prescribe buprenorphine to increase access to a proven beneficial treatment and help reduce fatal opioid overdoses.

Pediatric Diving-Related Injuries in Swimming Pools Presenting to US Emergency Departments: 2008-2020.

OBJECTIVES: Recreational swimming/diving is among the most common physical activities in US children and a significant cause of morbidity across the United States. This study updates the national epidemiology of diving-related injuries. METHODS: The Consumer Product Safety Commission's National Electronic Injury Surveillance System database was queried for patients aged 0 to 19 from 2008 to 2020 who presented to any of the 100 National Electronic Injury Surveillance System-participating emergency departments for a diving-related injury. Dive characteristics such as dive height, dive skill, dive direction, and dive sequence were determined from case narratives. RESULTS: A total of 1202 cases were identified for analysis corresponding to a total national estimate of 37,387 diving related injuries during the period from 2008 to 2020 and a national incidence of 3.6 injuries per 100,000 population. Males accounted for 64% of injuries. The average yearly incidences of injury in the 10 to 14 and 15 to 19 age groups were identical at 5.8 per 100,000. Contact with the diving board or platform was the most common cause of injury (34%). Diving backwards or attempting a flip or handstand dive were associated with increased odds of sustaining an injury resulting from contact with the diving board or platform (odds ratio, 16.0 and 6.9, respectively). In 2020, the incidence of diving-related injury fell to 1.6 per 100,000 population. CONCLUSIONS: Diving injuries are common in children and adolescents, especially in boys aged 10 to 19. There was a significant reduction in diving-related injury corresponding with the COVID-19 pandemic.

Extending COVID-19 Pharmacy Technician Duties: Impact on Safety and Pharmacist Jobs.

Background: The 2019 coronavirus pandemic (COVID-19) led to an expanded scope of practice for pharmacy technicians. As the pandemic wanes, state governments are faced with the decision of whether or not to make permanent the authority of pharmacy technicians to perform extended duties. Objective: Determine the impacts on patient safety and job market demands preadoption and postadoption of Idaho's expanded technician duties in 2017 as a natural experiment for expanded technician duties. Methods: Data from the National Practitioner Data Bank (NPDB) is used to explore patient safety outcomes in Idaho preadoption and postadoption and as compared with its border states. Data from Pharmacy Demand Reports is used to compare job postings in Idaho and its border state, and National Association of Boards of Pharmacy census data are used to compare growth in the number of pharmacists and technicians in Idaho and its border states over time. Results: For Idaho pharmacists, the average number of disciplinary actions reported against both pharmacists and technicians dropped after implementation of expanded technician duties. Idaho also had a lower rate of discipline for pharmacists and technicians than its border states. Idaho had the third highest job postings for pharmacists and the second highest for technicians among its border states. Idaho also had the largest growth in the number of licensed pharmacists and technicians of the observed states in the study period. Conclusion: Available statewide data from Idaho as compared with its border states suggests that expanded technician duties did not adversely impact patient safety outcomes or the pharmacist job market. Additional states may wish to expand pharmacy technician duties in the years ahead.

Systemic Inflammation in Preclinical Ulcerative Colitis.

BACKGROUND & AIMS: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. METHODS: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. RESULTS: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1ß, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. CONCLUSIONS: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.

Pharmacy technician-administered immunizations: A five-year review.

In October 2020, the U.S. Department of Health and Human Services (HHS) issued guidance authorizing trained pharmacy technicians in all states to administer immunizations. Given that this action is temporary, it will be necessary for states to adopt their own legislation or regulations to sustain these efforts beyond the coronavirus pandemic. At least 11 different immunization administration training programs have emerged for pharmacy technicians. An increasing number of publications have emerged on pharmacy technician immunization administration, demonstrating the ability to train technicians and have them safely administer immunizations in practice. Supervising pharmacists reported initial hesitancy but strong acceptance of delegating this task after experience in practice. States should look to expand and make permanent the authority of pharmacy technicians to ensure these benefits can continue to be realized after the HHS guidance expires.

Immune cell-specific smoking-related expression characteristics are revealed by re-analysis of transcriptomes from the CEDAR cohort.

Introduction: Smoking is known to affect whole-blood expression and methylation profiles. Although whole-genome methylation studies indicated that effects observed in blood may be driven by changes within leukocyte subtypes, these phenomena have not been explored using expression profiling. Material and methods: This study reanalyzed data from the Correlated Expression and Disease Association Research (CEDAR) patient cohort recruited by Momozawa et al. (E-MTAB-6667). Data from gene expression profiling of immunomagnetically sorted CD4+, CD8+, CD14+, CD15+, and CD19+ cells were processed. Differential expression analyses were conducted in each immune cell type, followed by gene ontology analysis and supplementary investigations. Results: Ninety-four differentially expressed genes were found (CD8+ n = 58, CD14+ n = 20, CD4+ n = 14, CD19+ n = 2). Two key smoking-related genes were overexpressed in specific cell types: LRRN3 (CD4+, CD8+) and MMP25 (CD8+, CD14+). In CD4+ cells smoking was associated with reduced expression of the NK cell receptor KLRB1, suggesting CD4+ subpopulation shifts and differences in interferon signaling (reduced IRF1 and IL18RAP in smokers). Key results and their integration with an immune protein-protein interaction network revealed that smoking influences integrins in CD8+ cells (ITGB7, ITGAL, ITGAM, ITGB2). C-type lectin CLEC4A was reduced in CD8+ cells and CLEC10A was increased in CD14+ cells from smokers; moreover, CLEC5A (CD8+), CLEC7A (CD8+) and CLEC9A (CD19+) were related to smoking in supplementary analyses. CD14+ cells from smokers exhibited overexpression of LDLR and the formyl peptide receptor FPR3. Conclusions: Smoking specifically alters vital immune regulation genes in lymphocyte subtypes, especially CD4+, CD8+ and CD14+ cells.

Waiting in the wings: RUNX3 reveals hidden depths of immune regulation with potential implications for inflammatory bowel disease.

BACKGROUND: Complex interactions between the environment and the mucosal immune system underlie inflammatory bowel disease (IBD). The involved cytokine signalling pathways are modulated by a number of transcription factors, one of which is runt-related transcription factor 3 (RUNX3). OBJECTIVE: To systematically review the immune roles of RUNX3 in immune regulation, with a focus on the context of IBD. METHODS: Relevant articles and reviews were identified through a Scopus search in April 2020. Information was categorized by immune cell types, analysed and synthesized. IBD transcriptome data sets and FANTOM5 regulatory networks were processed in order to complement the literature review. RESULTS: The available evidence on the immune roles of RUNX3 allowed for its description in twelve cell types: intraepithelial lymphocyte, Th1, Th2, Th17, Treg, double-positive T, cytotoxic T, B, dendritic, innate lymphoid, natural killer and macrophages. In the gut, the activity of RUNX3 is multifaceted and context-dependent: it may promote homeostasis or exacerbated reactions via cytokine signalling and regulation of receptor expression. RUNX3 is mostly engaged in pathways involving ThPOK, T-bet, IFN-γ, TGF-ß/IL-2Rß, GATA/CBF-ß, SMAD/p300 and a number of miRNAs. RUNX3 targets relevant to IBD may include RAG1, OSM and IL-17B. Moreover, in IBD RUNX3 expression correlates positively with GZMM, and negatively with IFNAR1, whereas in controls, it strongly associates with TGFBR3. CONCLUSIONS: Dysregulation of RUNX3, mostly in the form of deficiency, likely contributes to IBD pathogenesis. More clinical research is needed to examine RUNX3 in IBD.

Toward Multistate Pharmacy Practice: Enhancing Mobility and Portability of Pharmacist Licensure.

Pharmacists are licensed in all 50 states. As society becomes increasingly mobile and interconnected, several models of cross-state pharmacy practice have emerged, straining the current state-based system of licensure. The nursing profession has provided a model for license portability that offers 3 primary advantages over the current pharmacist licensure model while still protecting safety: (1) faster speed, (2) lower cost, and (3) reduced administrative burden. A hybrid approach for the pharmacy profession that builds off of the expedited license transfer model and adds a mutual recognition model is ideal.

Pharmacists' Patient Care Process: State "Scope of Practice" Priorities for Action.

To fully engage in the Pharmacists' Patient Care Process, pharmacists must be able to (1) participate in a Collaborative Practice Agreement, (2) order and interpret laboratory tests, (3) prescribe certain medications, (4) adapt medications, (5) administer medications, and (6) effectively delegate tasks to support staff. Each of these activities is dependent on state scope of practice laws, but these laws are not binary. Various state-level restrictions allow us to view these activities on a continuum from more restrictive to less restrictive. This continuum will allow pharmacy and public health stakeholders to identify priorities for action in their states.

Pharmacy Regulatory Innovation Index: Benchmarking the regulatory environment in 10 western states.

BACKGROUND: Pharmacy is among the most regulated of health professions on the basis of both word count and restrictions. State-level restrictions limit the ability of pharmacists to be fully engaged as members of the health care team. OBJECTIVE: This paper aimed to create a simple benchmark-the Pharmacy Regulatory Innovation Index (PRII)-that takes into account the scope-of-practice allowances that a state provides to pharmacists and the overall regulatory burden for the pharmacy profession using 10 western states as a sample. METHODS: A scorecard was developed on the basis of the activities reported as necessary for pharmacists to fully engage in the Pharmacists' Patient Care Process (PPCP). The laws and regulations of 10 western states were analyzed using plain-text interpretation. RESULTS: The 10 western states fall into 3 of 4 distinct quadrants. Three states appear in the highly regulated, low-innovation quadrant (Oregon, California, and Nevada), and 2 states appear in the low-regulated, high-innovation quadrant (Idaho and Washington). The remaining 5 states fall in the low-regulated, low-innovation quadrant (Alaska, Hawaii, Montana, Utah, and Wyoming). CONCLUSION: The PRII has been created to assess a state's regulatory burden and its scope-of-practice allowances, using the PPCP as a guide for innovation. States can use the PRII tool to benchmark their regulations in comparison with those of peer states and identify opportunities for improvement.

Rethinking pharmacy regulation: Core elements of Idaho's transition to a "Standard of Care" approach.

The National Association of Boards of Pharmacy recently established a task force to explore the feasibility of developing regulations based on "standards of care" rather than "prescriptive rule-based regulation." The Board sought to update its professional practice standards by transitioning from prescriptive regulations to a "standard of care" model that harmonizes pharmacists education and training with their legal scope of practice. In doing so, the Board expanded practice authority to include prescription adaptation services and independent prescribing of certain drug classes. As the Board approached how to update its facility standards, it pursued 2 primary goals: (1) Make the regulations practice- and technology-agnostic; and (2) Enable decentralization of pharmacy functions to offsite locations. The Board achieved its goal of reducing overall word count and restrictions in its laws. The Board also created a more permissive professional practice standard rooted in a "standard of care" approach that is more closely aligned with the regulatory model employed by the medical and nursing professions.

Pharmacy Technicians Are People, Too! Let's Consider Their Personal Outcomes Along With Other Pharmacy Outcomes.

Studies have found that expanded pharmacy technician roles can help "free up" pharmacist time, leading to role optimization. However, these studies and the positions taken by many are quite pharmacist-centric. We seem to have underestimated the importance of support staff in pharmacy operations. If research demonstrates that technicians can perform a function safely and effectively, that alone should compel the function's allowance in practice. Freeing up pharmacist time for higher-order care is a positive corollary to technician advancement, but it need not be a precondition for it.