Chronic Overlapping Pain Conditions and Long-Term Opioid Treatment

OBJECTIVES: One in 5 people in the United States lives with chronic pain. Many patients with chronic pain experience a subset of specific co-occurring pain conditions that may share a common pain mechanism and that have been designated as chronic overlapping pain conditions (COPCs). Little is known about chronic opioid prescribing patterns among patients with COPCs in primary care settings, especially among socioeconomically vulnerable patients. This study aims to evaluate opioid prescribing among patients with COPCs in US community health centers and to identify individual COPCs and their combinations that are associated with long-term opioid treatment (LOT). STUDY DESIGN: Retrospective cohort study. METHODS: We conducted analyses of more than 1 million patients 18 years and older based on electronic health record data from 449 US community health centers across 17 states between January 1, 2009, and December 31, 2018. Logistic regression models were used to assess the relationship between COPCs and LOT. RESULTS: Individuals with COPCs were prescribed LOT 4 times more often than individuals without a COPC (16.9% vs 4.0%). The presence of chronic low back pain, migraine headache, fibromyalgia, or irritable bowel syndrome combined with any of the other COPCs increased the odds of LOT prescribing compared with the presence of a single COPC. CONCLUSIONS: Although LOT prescribing has declined over time, it remains relatively high among patients with certain COPCs and for those with multiple COPCs. These study findings suggest target populations for future interventions to manage chronic pain among socioeconomically vulnerable patients

The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: Too big to fail?

Objective: To examine the pricing trajectories in the United States of disease-modifying therapies (DMT) for multiple sclerosis (MS) over the last 20 years and assess the influences on rising prices. Methods: We estimated the trend in annual drug costs for 9 DMTs using published drug pricing data from 1993 to 2013. We compared changes in DMT costs to general and prescription drug inflation during the same period. We also compared the cost trajectories for first-generation MS DMTs interferon (IFN)–β-1b, IFN-β-1a IM, and glatiramer acetate with contemporaneously approved biologic tumor necrosis factor (TNF) inhibitors. Results: First-generation DMTs, originally costing $8,000 to$11,000, now cost about $60,000 per year. Costs for these agents have increased annually at rates 5 to 7 times higher than prescription drug inflation. Newer DMTs commonly entered the market with a cost 25%–60% higher than existing DMTs. Significant increases in the cost trajectory of the first-generation DMTs occurred following the Food and Drug Administration approvals of IFN-β-1a SC (2002) and natalizumab (reintroduced 2006) and remained high following introduction of fingolimod (2010). Similar changes did not occur with TNF inhibitor biologics during these time intervals. DMT costs in the United States currently are 2 to 3 times higher than in other comparable countries. Conclusions: MS DMT costs have accelerated at rates well beyond inflation and substantially above rates observed for drugs in a similar biologic class. There is an urgent need for clinicians, payers, and manufacturers in the United States to confront the soaring costs of DMTs.CORRECTIONS: In the article “The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: Too big to fail?” by D.M. Hartung et al. (Neurology® 2015;84:2185–2192), there is an error in table 1. Columns 5–7 should have been labeled “cumulative percent change per year” rather than “annualized changes.” The authors regret the error. Correction is attached as a separate pdf. This is the publisher’s final pdf. The article is published by Lippincott, Williams & Wilkins and copyrighted by American Academy of Neurology. The published article can be found at: http://www.neurology.org

Changes in Long-acting β-agonist Utilization After the FDA’s 2010 Drug Safety Communication

PURPOSE: In February 2010, the US Food and Drug Administration (FDA) issued new recommendations for the safe use of long-acting beta agonists (LABA) in those with asthma. The objective of this study was to determine the impact of the FDA’s 2010 LABA advisory on LABA utilization. METHODS: Using administrative data from the state of Oregon Medicaid program we performed an interrupted time series regression to evaluate changes in the trend in new LABA prescriptions before and after the FDA’s 2010 advisory. Trends in incident fills were examined among those with and without an asthma diagnosis code, prior respiratory controller medication use, and by age. FINDINGS: Of the 8646 study patients, 53% had a diagnosis of asthma, 21% of patients had no respiratory diagnosis, and 32% did not use a respiratory controller medication in the recent past. The trend in new LABA prescriptions declined by 0.09 new starts per 10,000 patients per month (95% confidence interval [CI] -0.19 to -0.01) following the FDA’s advisory. Among those with a diagnosis of asthma, there was an immediate drop of 0.48 (95% CI -0.93 to -0.03) and a 0.10 (95% CI -0.13 to -0.06) decline in the monthly rate of new starts per 10,000 patients. Immediately following the FDA’s advisory we observed a statistically significant 4.7% increase (95% CI 0.8% to 8.7%) in the proportion of new LABA starts with history of previous respiratory controller medication use. Utilization of LABAs did not change in those without a diagnosis of asthma. IMPLICATIONS: The FDA’s 2010 advisory was associated with modest reductions in LABA utilization overall and in ways highlighted in their recommendations.This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier and can be found at: http://www.clinicaltherapeutics.com/ This research was presented previously at the 29th International Conference on Pharmacoepidemiology & Therapeutic Risk Management; August 25–28, 2013; Montreal, Quebec, Canada.Keywords: Medicaid, Utilization, United States Food and Drug Administration, Adrenergic beta2-agonists (adrenergic β₂-agonists)Keywords: Medicaid, Utilization, United States Food and Drug Administration, Adrenergic beta2-agonists (adrenergic β₂-agonists

Determining the ability for universal quantum computing: Testing controllability via dimensional expressivity

Operator controllability refers to the ability to implement an arbitrary unitary in SU(N) and is a prerequisite for universal quantum computing. Controllability tests can be used in the design of quantum devices to reduce the number of external controls. Their practical use is hampered, however, by the exponential scaling of their numerical effort with the number of qubits. Here, we devise a hybrid quantum-classical algorithm based on a parametrized quantum circuit. We show that controllability is linked to the number of independent parameters, which can be obtained by dimensional expressivity analysis. We exemplify the application of the algorithm to qubit arrays with nearest-neighbour couplings and local controls. Our work provides a systematic approach to the resource-efficient design of quantum chips

A pilot study evaluating alternative approaches of academic detailing in rural family practice clinics

Background: Academic detailing is an interactive, convenient, and user-friendly approach to delivering non-commercial education to healthcare clinicians. While evidence suggests academic detailing is associated with improvements in prescribing behavior, uncertainty exists about generalizability and scalability in diverse settings. Our study evaluates different models of delivering academic detailing in a rural family medicine setting. Methods: We conducted a pilot project to assess the feasibility, effectiveness, and satisfaction with academic detailing delivered face-to-face as compared to a modified approach using distance-learning technology. The recipients were four family medicine clinics within the Oregon Rural Practice-based Research Network (ORPRN). Two clinics were allocated to receive face-to-face detailing and two received outreach through video conferencing or asynchronous web-based outreach. Surveys at midpoint and completion were used to assess effectiveness and satisfaction. Results: Each clinic received four outreach visits over an eight month period. Topics included treatment-resistant depression, management of atypical antipsychotics, drugs for insomnia, and benzodiazepine tapering. Overall, 90% of participating clinicians were satisfied with the program. Respondents who received in person detailing reported a higher likelihood of changing their behavior compared to respondents in the distance detailing group for five of seven content areas. While 90%-100% of respondents indicated they would continue to participate if the program were continued, the likelihood of participation declined if only distance approaches were offered. Conclusions: We found strong support and satisfaction for the program among participating clinicians. Participants favored in-person approaches to distance interactions. Future efforts will be directed at quantitative methods for evaluating the economic and clinical effectiveness of detailing in rural family practice settings.Keywords: Behavior, Physicians, Randomized trial, Educational outreach, Quality, Care, Industry, DrugsKeywords: Behavior, Physicians, Randomized trial, Educational outreach, Quality, Care, Industry, Drug

The Arabidopsis BLAP75/Rmi1 Homologue Plays Crucial Roles in Meiotic Double-Strand Break Repair

In human cells and in Saccharomyces cerevisiae, BLAP75/Rmi1 acts together with BLM/Sgs1 and TopoIIIα/Top3 to maintain genome stability by limiting crossover (CO) formation in favour of NCO events, probably through the dissolution of double Holliday junction intermediates (dHJ). So far, very limited data is available on the involvement of these complexes in meiotic DNA repair. In this paper, we present the first meiotic study of a member of the BLAP75 family through characterisation of the Arabidopsis thaliana homologue. In A. thaliana blap75 mutants, meiotic recombination is initiated, and recombination progresses until the formation of bivalent-like structures, even in the absence of ZMM proteins. However, chromosome fragmentation can be detected as soon as metaphase I and is drastic at anaphase I, while no second meiotic division is observed. Using genetic and imunolocalisation studies, we showed that these defects reflect a role of A. thaliana BLAP75 in meiotic double-strand break (DSB) repair—that it acts after the invasion step mediated by RAD51 and associated proteins and that it is necessary to repair meiotic DSBs onto sister chromatids as well as onto the homologous chromosome. In conclusion, our results show for the first time that BLAP75/Rmi1 is a key protein of the meiotic homologous recombination machinery. In A. thaliana, we found that this protein is dispensable for homologous chromosome recognition and synapsis but necessary for the repair of meiotic DSBs. Furthermore, in the absence of BLAP75, bivalent formation can happen even in the absence of ZMM proteins, showing that in blap75 mutants, recombination intermediates exist that are stable enough to form bivalent structures, even when ZMM are absent

A High Throughput Genetic Screen Identifies New Early Meiotic Recombination Functions in Arabidopsis thaliana

Meiotic recombination is initiated by the formation of numerous DNA double-strand breaks (DSBs) catalysed by the widely conserved Spo11 protein. In Saccharomyces cerevisiae, Spo11 requires nine other proteins for meiotic DSB formation; however, unlike Spo11, few of these are conserved across kingdoms. In order to investigate this recombination step in higher eukaryotes, we took advantage of a high-throughput meiotic mutant screen carried out in the model plant Arabidopsis thaliana. A collection of 55,000 mutant lines was screened, and spo11-like mutations, characterised by a drastic decrease in chiasma formation at metaphase I associated with an absence of synapsis at prophase, were selected. This screen led to the identification of two populations of mutants classified according to their recombination defects: mutants that repair meiotic DSBs using the sister chromatid such as Atdmc1 or mutants that are unable to make DSBs like Atspo11-1. We found that in Arabidopsis thaliana at least four proteins are necessary for driving meiotic DSB repair via the homologous chromosomes. These include the previously characterised DMC1 and the Hop1-related ASY1 proteins, but also the meiotic specific cyclin SDS as well as the Hop2 Arabidopsis homologue AHP2. Analysing the mutants defective in DSB formation, we identified the previously characterised AtSPO11-1, AtSPO11-2, and AtPRD1 as well as two new genes, AtPRD2 and AtPRD3. Our data thus increase the number of proteins necessary for DSB formation in Arabidopsis thaliana to five. Unlike SPO11 and (to a minor extent) PRD1, these two new proteins are poorly conserved among species, suggesting that the DSB formation mechanism, but not its regulation, is conserved among eukaryotes

SPO11-Independent DNA Repair Foci and Their Role in Meiotic Silencing

In mammalian meiotic prophase, the initial steps in repair of SPO11-induced DNA double-strand breaks (DSBs) are required to obtain stable homologous chromosome pairing and synapsis. The X and Y chromosomes pair and synapse only in the short pseudo-autosomal regions. The rest of the chromatin of the sex chromosomes remain unsynapsed, contains persistent meiotic DSBs, and the whole so-called XY body undergoes meiotic sex chromosome inactivation (MSCI). A more general mechanism, named meiotic silencing of unsynapsed chromatin (MSUC), is activated when autosomes fail to synapse. In the absence of SPO11, many chromosomal regions remain unsynapsed, but MSUC takes place only on part of the unsynapsed chromatin. We asked if spontaneous DSBs occur in meiocytes that lack a functional SPO11 protein, and if these might be involved in targeting the MSUC response to part of the unsynapsed chromatin. We generated mice carrying a point mutation that disrupts the predicted catalytic site of SPO11 (Spo11YF/YF), and blocks its DSB-inducing activity. Interestingly, we observed foci of proteins involved in the processing of DNA damage, such as RAD51, DMC1, and RPA, both in Spo11YF/YFand Spo11 knockout meiocytes. These foci preferentially localized to the areas that undergo MSUC and form the so-called pseudo XY body. In SPO11-deficient oocytes, the number

Switching Multiple Sclerosis Patients with Breakthrough Disease to Second-Line Therapy

BACKGROUND: Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to natalizumab or immunosuppressants. The effect of natalizumab monotherapy in patients with breakthrough disease is unknown. METHODS: This is an open-label retrospective cohort study of 993 patients seen at least four times at the University of California San Francisco MS Center, 95 had breakthrough disease on first-line therapy (60 patients switched to natalizumab, 22 to immunosuppressants and 13 declined the switch [non-switchers]). We used Poisson regression adjusted for potential confounders to compare the relapse rate within and across groups before and after the switch. RESULTS: In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p<0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p<0.001) in switchers to immunosuppressants; relapse rate in non-switchers did not decrease (6%, p =  0.87). Relative to the reduction among non-switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004). CONCLUSIONS: Switching to natalizumab or immunosuppressants in patients with breakthrough disease is effective in reducing clinical activity of relapsing MS. The magnitude of the effect and the risk-benefit ratio should be evaluated in randomized clinical trials and prospective cohort studies

Simulating Microdosimetry in a Virtual Hepatic Lobule

The liver plays a key role in removing harmful chemicals from the body and is therefore often the first tissue to suffer potentially adverse consequences. To protect public health it is necessary to quantitatively estimate the risk of long-term low dose exposure to environmental pollutants. Animal testing is the primary tool for extrapolating human risk but it is fraught with uncertainty, necessitating novel alternative approaches. Our goal is to integrate in vitro liver experiments with agent-based cellular models to simulate a spatially extended hepatic lobule. Here we describe a graphical model of the sinusoidal network that efficiently simulates portal to centrilobular mass transfer in the hepatic lobule. We analyzed the effects of vascular topology and metabolism on the cell-level distribution following oral exposure to chemicals. The spatial distribution of metabolically inactive chemicals was similar across different vascular networks and a baseline well-mixed compartment. When chemicals were rapidly metabolized, concentration heterogeneity of the parent compound increased across the vascular network. As a result, our spatially extended lobule generated greater variability in dose-dependent cellular responses, in this case apoptosis, than were observed in the classical well-mixed liver or in a parallel tubes model. The mass-balanced graphical approach to modeling the hepatic lobule is computationally efficient for simulating long-term exposure, modular for incorporating complex cellular interactions, and flexible for dealing with evolving tissues