Test of a Workforce Development Intervention to Expand Opioid Use Disorder Treatment Pharmacotherapy Prescribers: Protocol for a Cluster Randomized Trial

Background: Overdoses due to non-medical use of prescription opioids and other opiates have become the leading cause of accidental deaths in the USA. Buprenorphine and extended-release naltrexone are key evidence-based pharmacotherapies available to addiction treatment providers to address opioid use disorder (OUD) and prevent overdose deaths. Treatment organizations’ efforts to provide these pharmacotherapies have, however, been stymied by limited success in recruiting providers (physicians, nurse practitioners, and physician assistants) to prescribe these medications. Historically, the addiction treatment field has not attracted physicians, and many barriers to implementing OUD pharmacotherapy exist, ranging from lack of confidence in treating OUD patients to concerns regarding reimbursement. Throughout the USA, the prevalence of OUD far exceeds the capacity of the OUD pharmacotherapy treatment system. Poor access to OUD pharmacotherapy prescribers has become a workforce development need for the addiction treatment field and a significant health issue. Methods: This cluster randomized controlled trial (RCT) is designed to increase buprenorphine and extended-release naltrexone treatment capacity for OUD. The implementation intervention to be tested is a bundle of OUD pharmacotherapy capacity building practices called the Prescriber Recruitment Bundle (PRB), which was developed and piloted in a previous statewide buprenorphine implementation study. For this cluster RCT, organizational sites will be recruited and then randomized into one of two arms: (1) control, with treatment as usual and access to a website with PRB resources, or (2) intervention, with organizations implementing the PRB using the Network for the Improvement of Addiction Treatment organizational change model over a 24-month intervention period and a 10-month sustainability period. The primary treatment outcomes for each organizational site are self-reported monthly counts of buprenorphine slots, extended-release naltrexone capacity, number of buprenorphine patients, and number of extended-release naltrexone patients. This trial will be conducted in Florida, Ohio, and Wisconsin, resulting in 35 sites in each arm, for a total sample size of 70 organizations. Discussion: This study addresses three issues of substantial public health significance: (1) the pressing opioid misuse epidemic, (2) the low uptake of OUD treatment pharmacotherapies, and (3) the need to increase prescriber participation in the addiction treatment workforce. Trial Registration: ClinicalTrials.gov NCT02926482

Surgical versus nonsurgical treatment for lumbar degenerative spondylolisthesis.

BACKGROUND: Management of degenerative spondylolisthesis with spinal stenosis is controversial. Surgery is widely used, but its effectiveness in comparison with that of nonsurgical treatment has not been demonstrated in controlled trials. METHODS: Surgical candidates from 13 centers in 11 U.S. states who had at least 12 weeks of symptoms and image-confirmed degenerative spondylolisthesis were offered enrollment in a randomized cohort or an observational cohort. Treatment was standard decompressive laminectomy (with or without fusion) or usual nonsurgical care. The primary outcome measures were the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) bodily pain and physical function scores (100-point scales, with higher scores indicating less severe symptoms) and the modified Oswestry Disability Index (100-point scale, with lower scores indicating less severe symptoms) at 6 weeks, 3 months, 6 months, 1 year, and 2 years. RESULTS: We enrolled 304 patients in the randomized cohort and 303 in the observational cohort. The baseline characteristics of the two cohorts were similar. The one-year crossover rates were high in the randomized cohort (approximately 40% in each direction) but moderate in the observational cohort (17% crossover to surgery and 3% crossover to nonsurgical care). The intention-to-treat analysis for the randomized cohort showed no statistically significant effects for the primary outcomes. The as-treated analysis for both cohorts combined showed a significant advantage for surgery at 3 months that increased at 1 year and diminished only slightly at 2 years. The treatment effects at 2 years were 18.1 for bodily pain (95% confidence interval [CI], 14.5 to 21.7), 18.3 for physical function (95% CI, 14.6 to 21.9), and -16.7 for the Oswestry Disability Index (95% CI, -19.5 to -13.9). There was little evidence of harm from either treatment. CONCLUSIONS: In nonrandomized as-treated comparisons with careful control for potentially confounding baseline factors, patients with degenerative spondylolisthesis and spinal stenosis treated surgically showed substantially greater improvement in pain and function during a period of 2 years than patients treated nonsurgically. (ClinicalTrials.gov number, NCT00000409 [ClinicalTrials.gov].)

EPEN-11. TUMOR DIFFERENTIATION IMPACTS THE BIOLOGY OF RECURRENCE IN CHILDHOOD POSTERIOR FOSSA EPENDYMOMA

Ependymoma (EPN) of childhood is curable in only 50% of cases, with recurrences in the remainder that are refractory to treatment. In recent years significant advances have been made in understanding the molecular and cellular biology of EPN. Recent studies show that PFA subgroup EPN are comprised of multiple neoplastic subpopulations that show undifferentiated, differentiated and mesenchymal characteristics. These studies focused on tumor at presentation, with recurrent EPN being less well understood. In the present longitudinal study we examine changes in neoplastic cell heterogeneity in serial presentations of PFA EPN using deconvolution (Cibersort) of bulk RNAseq data. Analysis of a cohort of 48 PFA EPN presenting at Children’s Colorado showed survival and PFA1/PFA2 subtype assignment was associated with the proportion of individual neoplastic subpopulations as determined by deconvolution. Tumors that subsequently regrew had a significantly higher estimated proportion of undifferentiated EPN cells (UEC) at presentation, than those that were non-recurrent after 5 years follow-up. This outcome association potentially age related, as UEC proportions are significantly higher in PFA arising in children < 1 year old who have a particularly poor prognosis. Changes in PFA neoplastic subpopulations at recurrence was performed in two cohorts of patients from Children’s Colorado (n=23) and Nottingham, UK (n=15). As a whole, no subpopulation proportion was significantly changed at recurrence. However, separation of PFA into subtypes PFA1 and PFA2 revealed an increase in the proportion of the cilia-differentiated EPN cell subpopulation is more frequent event in PFA1 (15/24), and rare in PFA2 (2/11). Changes in other neoplastic subpopulations at recurrence were smaller and only seen in PFA1, both UEC and mesenchymal subpopulations being lower at recurrence. In summary, only PFA1 showed dynamic changes in neoplastic subpopulation proportions at recurrence, with potential impacts on transcriptomic based-subgroup assignment, whereas PFA2 proportions remained largely stable

Defining Ecological Drought for the Twenty-First Century

THE RISING RISK OF DROUGHT. Droughts of the twenty-first century are characterized by hotter temperatures, longer duration, and greater spatial extent, and are increasingly exacerbated by human demands for water. This situation increases the vulnerability of ecosystems to drought, including a rise in drought-driven tree mortality globally (Allen et al. 2015) and anticipated ecosystem transformations from one state to another—for example, forest to a shrubland (Jiang et al. 2013). When a drought drives changes within ecosystems, there can be a ripple effect through human communities that depend on those ecosystems for critical goods and services (Millar and Stephenson 2015). For example, the “Millennium Drought” (2002–10) in Australia caused unanticipated losses to key services provided by hydrological ecosystems in the Murray–Darling basin—including air quality regulation, waste treatment, erosion prevention, and recreation. The costs of these losses exceeded AUD $800 million, as resources were spent to replace these services and adapt to new drought-impacted ecosystems (Banerjee et al. 2013). Despite the high costs to both nature and people, current drought research, management, and policy perspectives often fail to evaluate how drought affects ecosystems and the “natural capital” they provide to human communities. Integrating these human and natural dimensions of drought is an essential step toward addressing the rising risk of drought in the twenty-first century

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

Local Control Following Stereotactic Body Radiation Therapy for Liver Oligometastases: Lessons from a Quarter Century

The utilization of stereotactic body radiation therapy for the treatment of liver metastasis has been widely studied and has demonstrated favorable local control outcomes. However, several predictive factors play a crucial role in the efficacy of stereotactic body radiation therapy, such as the number and size (volume) of metastatic liver lesions, the primary tumor site (histology), molecular biomarkers (e.g., KRAS and TP53 mutation), the use of systemic therapy prior to SBRT, the radiation dose, and the use of advanced technology and organ motion management during SBRT. These prognostic factors need to be considered when clinical trials are designed to evaluate the efficacy of SBRT for liver metastases

A nomenclature for restriction enzymes, DNA methyltransferases, homing endonucleases and their genes

A nomenclature is described for restriction endonucleases, DNA methyltransferases, homing endonucleases and related genes and gene products. It provides explicit categories for the many different Type II enzymes now identified and provides a system for naming the putative genes found by sequence analysis of microbial genome

The ‘affect tagging and consolidation’ (ATaC) model of depression vulnerability

Since the 1960’s polysomnographic sleep research has demonstrated that depressive episodes are associated with REM sleep alterations. Some of these alterations, such as increased REM sleep density, have also been observed in first-degree relatives of patients and remitted patients, suggesting that they may be vulnerability markers of major depressive disorder (MDD), rather than mere epiphenomena of the disorder. Neuroimaging studies have revealed that depression is also associated with heightened amygdala reactivity to negative emotional stimuli, which may also be a vulnerability marker for MDD. Several models have been developed to explain the respective roles of REM sleep alterations and negatively-biased amygdala activity in the pathology of MDD, however the possible interaction between these two potential risk-factors remains uncharted. This paper reviews the roles of the amygdala and REM sleep in the encoding and consolidation of negative emotional memories, respectively. We present our ‘affect tagging and consolidation’ (ATaC) model, which argues that increased REM sleep density and negatively-biased amygdala activity are two separate, genetically influenced risk-factors for depression which interact to promote the development of negative memory bias – a well-known cognitive vulnerability marker for depression. Predictions of the ATaC model may motivate research aimed at improving our understanding of sleep dependent memory consolidation in depression aetiology

High-Frequency Dynamics of Ocean pH: A Multi-Ecosystem Comparison

The effect of Ocean Acidification (OA) on marine biota is quasi-predictable at best. While perturbation studies, in the form of incubations under elevated pCO2, reveal sensitivities and responses of individual species, one missing link in the OA story results from a chronic lack of pH data specific to a given species' natural habitat. Here, we present a compilation of continuous, high-resolution time series of upper ocean pH, collected using autonomous sensors, over a variety of ecosystems ranging from polar to tropical, open-ocean to coastal, kelp forest to coral reef. These observations reveal a continuum of month-long pH variability with standard deviations from 0.004 to 0.277 and ranges spanning 0.024 to 1.430 pH units. The nature of the observed variability was also highly site-dependent, with characteristic diel, semi-diurnal, and stochastic patterns of varying amplitudes. These biome-specific pH signatures disclose current levels of exposure to both high and low dissolved CO2, often demonstrating that resident organisms are already experiencing pH regimes that are not predicted until 2100. Our data provide a first step toward crystallizing the biophysical link between environmental history of pH exposure and physiological resilience of marine organisms to fluctuations in seawater CO2. Knowledge of this spatial and temporal variation in seawater chemistry allows us to improve the design of OA experiments: we can test organisms with a priori expectations of their tolerance guardrails, based on their natural range of exposure. Such hypothesis-testing will provide a deeper understanding of the effects of OA. Both intuitively simple to understand and powerfully informative, these and similar comparative time series can help guide management efforts to identify areas of marine habitat that can serve as refugia to acidification as well as areas that are particularly vulnerable to future ocean change