Are x-waiver trainings enough? Facilitators and barriers to buprenorphine prescribing after x-waiver trainings.

BACKGROUND: In the United States, an x-waiver credential is necessary to prescribe buprenorphine medication treatment for opioid use disorder (B-MOUD). Historically, this process has required certified training, which could be a barrier to obtaining an x-waiver and subsequently prescribing. To address this barrier, the US recently removed the training requirement for some clinicians. We sought to determine if clinicians who attended x-waiver training went on to obtain an x-waiver and prescribe B-MOUD, and to examine what facilitated or impeded B-MOUD prescribing. METHODS: In September 2020, we conducted a cross-sectional, electronic survey of attendees of 15 in-person x-waiver pieces of training from June 2018 to January 2020 within the Veterans Health Administration (VHA). Of the attendees (n = 321), we surveyed current VHA clinicians who recalled taking the training. The survey assessed whether clinicians obtained the x-waiver, had prescribed B-MOUD, and barriers or facilitators that influenced B-MOUD prescribing. RESULTS: Of 251 eligible participants, 62 (24.7%) responded to the survey, including 27 (43.5%) physicians, 16 (25.8%) advanced practice clinicians, and 12 (19.4%) pharmacists. Of the 43 clinicians who could prescribe, 29 (67.4%) had obtained their x-waiver and 16 (37.2%) had reported prescribing B-MOUD. Prominent barriers to prescribing B-MOUD included a lack of supporting clinical staff and competing demands on time. The primary facilitator to prescribing was leadership support. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Nine months after x-waiver training, two-thirds of clinicians with prescribing credentials had obtained their x-waiver and one-third were prescribing B-MOUD. Removing the x-waiver training may not have the intended policy effect as other barriers to B-MOUD prescribing persist.

Aims, development, and early results of an interdisciplinary primary care initiative to address patient vulnerabilities.

Addressing substance use disorders and social determinants of poor health at a population level is a major national healthcare priority. One promising model to improve healthcare outcomes for patients with these conditions is the Vulnerable Veteran Innovative Patient-Aligned Care Team (PACT) Initiative, or VIP - an interdisciplinary, team-based primary care delivery model designed to address the needs of vulnerable patients in the Veterans Health Administration. VIP establishes a single, integrated primary care environment for the management of substance use disorders, mental illness, social determinants of poor health, and complexities in care resulting from the co-occurrence of these conditions. We describe the origination, goals, and evolution of VIP to provide an example of how clinics and health systems can address vulnerable patient populations within a primary care clinic framework. While ongoing evaluation will be essential to understand its impact on patient outcomes and its sustainability and scalability in the future, VIP holds promise as a novel model to improve care for patients with addiction and other vulnerabilities.

Stepped Care for Opioid Use Disorder Train the Trainer (SCOUTT) initiative: Expanding access to medication treatment for opioid use disorder within Veterans Health Administration facilities.

The US is confronted with a rise in opioid use disorder (OUD), opioid misuse, and opioid-associated harms. Medication treatment for opioid use disorder (MOUD)-including methadone, buprenorphine and naltrexone-is the gold standard treatment for OUD. MOUD reduces illicit opioid use, mortality, criminal activity, healthcare costs, and high-risk behaviors. The Veterans Health Administration (VHA) has invested in several national initiatives to encourage access to MOUD treatment. Despite these efforts, by 2017, just over a third of all Veterans diagnosed with OUD received MOUD. VHA OUD specialty care is often concentrated in major hospitals throughout the nation and access to this care can be difficult due to geography or patient choice. Recognizing the urgent need to improve access to MOUD care, in the Spring of 2018, the VHA initiated the Stepped Care for Opioid Use Disorder, Train the Trainer (SCOUTT) Initiative to facilitate access to MOUD in VHA non-SUD care settings. The SCOUTT Initiative's primary goal is to increase MOUD prescribing in VHA primary care, mental health, and pain clinics by training providers working in those settings on how to provide MOUD and to facilitate implementation by providing an ongoing learning collaborative. Thirteen healthcare providers from each of the 18 VHA regional networks across the VHA were invited to implement the SCOUTT Initiative within one facility in each network. We describe the goals and initial activities of the SCOUTT Initiative leading up to a two-day national SCOUTT Initiative conference attended by 246 participants from all 18 regional networks in the VHA. We also discuss subsequent implementation facilitation and evaluation plans for the SCOUTT Initiative. The VHA SCOUTT Initiative could be a model strategy to implement MOUD within large, diverse health care systems.

What Does "Successful Aging" Mean to you? - Systematic Review and Cross-Cultural Comparison of Lay Perspectives of Older Adults in 13 Countries, 2010-2020.

Successful aging is a concept that has gained popularity and relevance internationally among gerontologists in recent decades. Examining lay older adults' perspectives on successful aging can enhance our understanding of what successful aging means. We conducted a systematic review of peer reviewed studies from multiple countries published in 2010-2020 that contained qualitative responses of lay older adults to open-ended questions such as "What does successful aging mean to you?" We identified 23 studies conducted in 13 countries across North America, Western Europe, the Middle East, Asia, and Oceania. We identified no studies meeting our criteria in Africa, South America, Eastern Europe, North Asia, or Pacific Islands. Across all regions represented in our review, older adults most commonly referred to themes of social engagement and positive attitude in their own lay definitions of successful aging. Older adults also commonly identified themes of independence and physical health. Least mentioned were themes of cognitive health and spirituality. Lay definitions of successful aging varied by country and culture. Our findings suggest that gerontology professionals in fields including healthcare, health psychology, and public health may best serve older adults by providing services that align with older adults' priority of maintaining strong social engagement as they age. Lay perspectives on successful aging acknowledge the importance of positive attitude, independence, and spirituality, in addition to physical and cognitive functioning.

Inflammation Resolution in the Cardiovascular System: Arterial Hypertension, Atherosclerosis, and Ischemic Heart Disease.

Significance: Chronic inflammation has emerged as a major underlying cause of many prevalent conditions in the Western world, including cardiovascular diseases. Although targeting inflammation has emerged as a promising avenue by which to treat cardiovascular disease, it is also associated with increased risk of infection. Recent Advances: Though previously assumed to be passive, resolution has now been identified as an active process, mediated by unique immunoresolving mediators and mechanisms designed to terminate acute inflammation and promote tissue repair. Recent work has determined that failures of resolution contribute to chronic inflammation and the progression of human disease. Specifically, failure to produce pro-resolving mediators and the impaired clearance of dead cells from inflamed tissue have been identified as major mechanisms by which resolution fails in disease. Critical Issues: Drawing from a rapidly expanding body of experimental and clinical studies, we review here what is known about the role of inflammation resolution in arterial hypertension, atherosclerosis, myocardial infarction, and ischemic heart disease. For each, we discuss the involvement of specialized pro-resolving mediators and pro-reparative cell types, including T regulatory cells, myeloid-derived suppressor cells, and macrophages. Future Directions: Pro-resolving therapies offer the promise of limiting chronic inflammation without impairing host defense. Therefore, it is imperative to better understand the mechanisms underlying resolution to identify therapeutic targets. Antioxid. Redox Signal. 40, 292-316.

Selection on plastic adherence leads to hyper-multicellular strains and incidental virulence in the budding yeast.

Many disease-causing microbes are not obligate pathogens; rather, they are environmental microbes taking advantage of an ecological opportunity. The existence of microbes whose life cycle does not require a host and are not normally pathogenic, yet are well-suited to host exploitation, is an evolutionary puzzle. One hypothesis posits that selection in the environment may favor traits that incidentally lead to pathogenicity and virulence, or serve as pre-adaptations for survival in a host. An example of such a trait is surface adherence. To experimentally test the idea of 'accidental virulence', replicate populations of Saccharomyces cerevisiae were evolved to attach to a plastic bead for hundreds of generations. Along with plastic adherence, two multicellular phenotypes- biofilm formation and flor formation- increased; another phenotype, pseudohyphal growth, responded to the nutrient limitation. Thus, experimental selection led to the evolution of highly-adherent, hyper-multicellular strains. Wax moth larvae injected with evolved hyper-multicellular strains were significantly more likely to die than those injected with evolved non-multicellular strains. Hence, selection on plastic adherence incidentally led to the evolution of enhanced multicellularity and increased virulence. Our results support the idea that selection for a trait beneficial in the open environment can inadvertently generate opportunistic, 'accidental' pathogens.

Yeast are microscopic fungi that are found on many plants, in the soil and in other environments around the world. But, when given the chance, some yeasts are also good at infecting human and other animals and causing disease. It has been proposed that some opportunistic microbes may have dual-use traits that evolved for one purpose in their natural environment but also incidentally allow them to infect animals. For example, a toxin that helps the opportunistic microbe compete against neighboring microbes may also weaken an animal. Or the ability of many individual microbe cells to clump together into structures known as biofilms on solid surfaces, or floating mats called flors on liquids, helps them to survive in harsh environments, whether in the soil or in the body of an animal. To investigate this possibility, Ekdahl, Salcedo et al. examined whether artificially selecting yeast with a specific trait ­ the ability to stick to plastic beads ­ in the absence of any host animals would inadvertently also select for yeast that were good at causing disease. This trait was selected because it has not been previously linked to opportunistic yeast infections. The team grew the yeast for 400 generations in tubes that each contained a plastic bead. At every generation, only yeast that stuck to the plastic bead were transferred to a fresh tube to grow the next generation. The experiments found that, not only did the ability of the yeast to stick to the plastic increase over time, but the yeast also evolved the ability to form biofilms and flors. Furthermore, the sticky yeast killed an insect host known as wax moth larvae more quickly than non-sticky yeast. Together, these findings demonstrate that when microbes evolve in an environment that is devoid of any host animals, selection can inadvertently favor dual-use traits that also help the yeast to infect animals. Opportunistic yeast infections are of increasing concern in human patients, particularly those with weakened immune systems. Understanding which yeast traits are dual-use will help guide future efforts in combatting yeast and other opportunistic microbes.

Regulation of expansion of CD11c+ B cells and anti-viral immunity by epithelial V-like antigen.

Prior work demonstrated that epithelial V-like antigen (EVA), a cell surface adhesion molecule, is expressed in B lymphocytes and is necessary for the efficacy of anti-alpha4 integrin treatment of experimental autoimmune encephalomyelitis (EAE), the mouse model of human multiple sclerosis. EVA deficiency is associated with a severe clinical phenotype of EAE in the presence or absence of treatment. Histological analysis revealed enhanced B cell-mediated autoimmunity and deposition of antibody and complement within the brain and spinal cord. Here our goal was to determine the molecular mechanism of EVA regulation of B lymphocyte function. Analysis of bone marrow from MOG-immunized mice revealed increased expansion of CD11c+ B cells in EVA-deficient mice as compared to wild type controls. In vitro studies of mouse bone marrow B lymphocytes revealed enhanced proliferation of the CD11c+ population in response to the Tlr7/8 agonist R848. An increase in R848-induced proliferation of CD11c+ B cells was also seen in vitro in Daudi cells, a human B cell line, following knockdown of the mpzl2 gene that encodes EVA. These mechanisms were characterized further by global expression analysis of bone marrow from immunized EVA-deficient and wild type control mice. These data revealed increased expression of B cell associated genes and decreased expression of the anti-viral oligoadenylate synthase genes, Oas1 and Oas2, in the knockout condition. In Daudi cells, R848 treatment induced an increase in Oas2 expression in control cells that was not observed in EVA-deficient cells. EVA deficiency also was associated with increased transcription of an Epstein-Barr virus gene during lytic replication. These results suggest EVA expression and signaling prevent expansion of CD11c+ B lymphocytes, a cellular phenotype associated with autoimmunity, increase expression of anti-viral oligoadenylate synthase genes, and reduce replication of a DNA virus.

Activation of human macrophage sodium channels regulates RNA processing to increase expression of the DNA repair protein PPP1R10.

Prior work demonstrated that a splice variant of SCN5A, a voltage-gated sodium channel gene, acts as a cytoplasmic sensor for viral dsRNA in human macrophages. Expression of this channel also polarizes macrophages to an anti-inflammatory phenotype in vitro and in vivo. Here we utilized global expression analysis of splice variants to identify novel channel-dependent signaling mechanisms. Pharmacological activation of voltage-gated sodium channels in human macrophages, but not treatment with cytoplasmic poly I:C, was associated with splicing of a retained intron in transcripts of PPP1R10, a regulator of phosphatase activity and DNA repair. Microarray analysis also demonstrated expression of a novel sodium channel splice variant, human macrophage SCN10A, that contains a similar exon deletion as SCN5A. SCN10A localizes to cytoplasmic and nuclear vesicles in human macrophages. Simultaneous expression of human macrophage SCN5A and SCN10A was required to decrease expression of the retained intron and increase protein expression of PPP1R10. Channel activation also increased protein expression of the splicing factor EFTUD2, and knockdown of EFTUD2 prevented channel dependent splicing of the retained PPP1R10 intron. Knockdown of the SCN5A and SCN10A variants in human macrophages reduced the severity of dsDNA breaks induced by treatment with bleomycin and type 1 interferon. These results suggested that human macrophage SCN5A and SCN10A variants mediate an innate immune signaling pathway that limits DNA damage through increased expression of PPP1R10. The functional significance of this pathway is that it may prevent cytotoxicity during inflammatory responses.