Treatment Updates for Pain Management and Opioid Use Disorder.

The medical community has proposed several clinical recommendations to promote patient safety and health amid the opioid overdose public health crisis. For a frontline practicing physician, distilling the evidence and implementing the latest guidelines may prove challenging. This article aims to highlight pertinent updates and clinical care pearls as they relate to primary care management of chronic pain and opioid use disorder.

Induced Fit Describes Ligand Binding to Membrane-Associated Cytochrome P450 3A4.

Cytochrome P450 3A4 (CYP3A4) is the dominant P450 involved in human xenobiotic metabolism. Competition for CYP3A4 therefore underlies several adverse drug-drug interactions. Despite its clinical significance, the mechanisms CYP3A4 uses to bind diverse ligands remain poorly understood. Highly monodisperse CYP3A4 embedded in anionic lipoprotein nanodiscs containing an equal mixture of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) were used to determine which of the limiting kinetic schemes that include protein conformational change, conformational selection (CS) or induced fit (IF), best described the binding of four known irreversible inhibitors. Azamulin, retapamulin, pleuromutilin, and mibrefadil binding to CYP3A4 nanodiscs conformed to a single-site binding model. Exponential fits of stopped-flow UV-visible absorption spectroscopy data supported multiple-step binding mechanisms. Trends in the rates of relaxation to equilibrium with increasing ligand concentrations were ambiguous as to whether IF or CS was involved; however, global fitting and consideration of the rate constants favored an IF mechanism. In the case of mibrefadil, a transient complex was observed in the stopped-flow UV-visible experiment, definitively assigning the presence of IF in ligand binding. While these studies only consider a small region of CYP3A4's vast ligand space, they provide kinetic evidence that CYP3A4 can use an IF mechanism. SIGNIFICANCE STATEMENT: CYP3A4 is capable of oxidizing numerous xenobiotics, including many drugs. Such promiscuity could not be achieved without conformational changes to accommodate diverse substrates. It is unknown whether conformational heterogeneity is present before (conformational selection) or after (induced fit) ligand binding. Stopped-flow measurements of suicide inhibitors binding to nanodisc-embedded CYP3A4 combined with sophisticated numerical analyses support that induced fit better describes ligand binding to this important enzyme.

River Basin Simulations Reveal Wide-Ranging Wetland-Mediated Nitrate Reductions.

River basin-scale wetland restoration and creation is a primary management option for mitigating nitrogen-based water quality challenges. However, the magnitude of nitrogen reduction that will result from adding wetlands across large river basins is uncertain, partly because the areal extent, location, and physical and functional characteristics of the wetlands are unknown. We simulated over 3600 wetland restoration scenarios across the ∼450,000 km2 Upper Mississippi River Basin (UMRB) depicting varied assumptions for wetland areal extent, physical and functional characteristics, and placement strategy. These simulations indicated that restoring wetlands will reduce local nitrate yields and nitrate loads at the UMRB outlet. However, the projected magnitude of nitrate reduction varied widely across disparate scenario assumptions─e.g., restoring 4500 km2 of wetlands (i.e., 1% of UMRB area) decreased mean annual nitrate loads at the UMRB outlet between 3 and 42%. Higher magnitude nitrate reductions correlated with best-case assumptions, particularly for characteristics controlling nitrate loading rates to the wetlands. These results show that simplified claims about basin-scale wetland-mediated water quality improvements discount the breadth of possible wetland impacts across disparate wetland physical and functional conditions and highlight a need for greater clarity regarding the likelihood of these conditions at river basin scales.

Buprenorphine Prescribing and Dosing Limits: Evidence and Policy Goals.

The opioid misuse epidemic is a serious public health crisis. Opioid-involved deaths continue to rise and the potency of illicitly manufactured synthetic opioids has increased, creating challenges for the healthcare system to provide multifaceted specialized care. Elements of the regulation around buprenorphine, 1 of 3 drugs approved to treat opioid use disorder (OUD), constrain treatment options for patients and providers alike. Updates to this regulatory framework, particularly around dosing and access to care, would enable providers to better treat the changing landscape of opioid misuse. Specific actions to this end are to: (1) Increase buprenorphine dosing flexibility based on FDA labeling which drives payor policies; (2) Restrict local government and institutional impositions of arbitrary access and dosing limits for buprenorphine; and (3) Liberalize buprenorphine initiation and maintenance via telemedicine for OUD.

Comprehensive profiling of antibody responses to the human anellome using programmable phage display.

Anelloviruses represent a major constituent of the commensal human virome; however, little is known about their immunobiology. Here, we present "AnelloScan," a T7 phage library representing the open reading frame 1 (ORF1), ORF2, ORF3, and torque teno virus (TTV)-derived apoptosis-inducing protein (TAIP) sequences of more than 800 human anelloviruses and profile the antibody reactivities of serum samples from a cross-sectional cohort of 156 subjects by using phage-immunoprecipitation sequencing (PhIP-Seq). A majority of anellovirus peptides are not reactive in any of the subjects tested (n = ∼28,000; ∼85% of the library). Antibody-reactive peptides are largely restricted to the C-terminal region of the capsid protein ORF1. Moreover, using a longitudinal cohort of matched blood-transfusion donors and recipients, we find that most transmitted anelloviruses do not elicit a detectable antibody reactivity in the recipient and that the remainder elicit delayed responses appearing ∼100-150 days after transfusion.

Trigeminal Zoster with drug-induced labial angioedema leading to necrosis.

Introduction: Zoster is caused by the reactivation of a dormant viral infection, and is characterized by painful, vesicular lesions along a dermatome. Neuritic pain associated with zoster can be treated with anticonvulsant medications. Case Report: An immunocompetent adult physician developed prominent zoster lesions in the trigeminal nerve distribution. Treatment included antiviral therapy for the acute infection, and pharmacotherapy for neuritic pain. Pharmacotherapy included several anticonvulsant agents, with labial angioedema developing after initiation of oxcarbazepine. Discussion: The case is notable for the pictorial timeline of lesion development, as well as the marked incident angioedema following initiation of treatment for neuritis with oxcarbazepine. Conclusions: Clinicians should remain vigilant for drug-induced facial angioedema when treating patients with trigeminal zoster-related neuritis due to the potential for angioedema to aggravate a lesion, resulting in scarring. Angioedema of the head and neck should be closely monitored due to the potential for airway compromise.

Considerations on the use of carbon and nitrogen isotopic ratios for sediment fingerprinting.

Carbon and nitrogen stable isotopic ratios are increasingly used in sediment fingerprinting studies. However, questions remain regarding tracer conservativeness during sediment transport and other error considerations. We investigate conservativeness processes, including carbon oxidation and nitrogen mineralization, using experiments. We also test how other considerations impact the isotopic ratios including algae accrual into temporary sediment deposits in the river, the physical loss of organic matter via disaggregation, concentration dependent mixing, and time-varying isotopic ratios of sediment sources. Results show all processes and considerations can change isotope abundance, however, significance varied. Carbon oxidation, nitrogen mineralization and upland seasonality of sediment sources did not significantly change isotopic ratios. Algae accrual, concentration dependency mixing, physical loss of organic matter during transport, and seasonality of the in-stream sediment source significantly changed the isotopic ratios for the conditions tested. Fertilization significantly impacted the stable carbon isotopic ratio in one case considered. Results from sediment fingerprinting simulations and testing how well the virtual mixture fits the mass balance equation agreed with significance results for tracer changes, and some uncertainty considerations changed fractional contribution of sources by as much as 50%. A noteworthy recommendation is the mean isotopic ratios of sediment sources should be separated by at least 1‰ to lessen tracer conservativeness concerns in fingerprinting simulation. We recommend concentration dependent mixing becomes the accepted practice when using isotopic ratios, however, we warn against using particle size corrections. We recommend the loss of organic matter during disaggregation be accounted for in fingerprinting estimates. We recommend algae accrual in in-stream sediment deposits should either be accounted for or in-stream sediment should be treated as a time-varying source in sediment fingerprinting simulations. Finally, we recommend both the carbon and nitrogen isotopic ratio should be tested as potential tracers because the two tracers performed similarly when testing how well the virtual mixture fits the mass balance equations.

Wetland restoration yields dynamic nitrate responses across the Upper Mississippi river basin.

Wetland restoration is a primary management option for removing surplus nitrogen draining from agricultural landscapes. However, wetland capacity to mitigate nitrogen losses at large river-basin scales remains uncertain. This is largely due to a limited number of studies that address the cumulative and dynamic effects of restored wetlands across the landscape on downstream nutrient conditions. We analyzed wetland restoration impacts on modeled nitrate dynamics across 279 subbasins comprising the ∼0.5 million km2 Upper Mississippi River Basin (UMRB), USA, which covers eight states and houses ∼30 million people. Restoring ∼8,000 km2 of wetlands will reduce mean annual nitrate loads to the UMRB outlet by 12%, a substantial improvement over existing conditions but markedly less than widely cited estimates. Our lower wetland efficacy estimates are partly attributed to improved representation of processes not considered by preceding empirical studies - namely the potential for nitrate to bypass wetlands (i.e., via subsurface tile drainage) and be stored or transformed within the river network itself. Our novel findings reveal that wetlands mitigate surplus nitrogen basin-wide, yet they may not be as universally effective in tiled landscapes and because of river network processing.

Cul4 ubiquitin ligase cofactor DCAF12 promotes neurotransmitter release and homeostatic plasticity.

We genetically characterized the synaptic role of the Drosophila homologue of human DCAF12, a putative cofactor of Cullin4 (Cul4) ubiquitin ligase complexes. Deletion of Drosophila DCAF12 impairs larval locomotion and arrests development. At larval neuromuscular junctions (NMJs), DCAF12 is expressed presynaptically in synaptic boutons, axons, and nuclei of motor neurons. Postsynaptically, DCAF12 is expressed in muscle nuclei and facilitates Cul4-dependent ubiquitination. Genetic experiments identified several mechanistically independent functions of DCAF12 at larval NMJs. First, presynaptic DCAF12 promotes evoked neurotransmitter release. Second, postsynaptic DCAF12 negatively controls the synaptic levels of the glutamate receptor subunits GluRIIA, GluRIIC, and GluRIID. The down-regulation of synaptic GluRIIA subunits by nuclear DCAF12 requires Cul4. Third, presynaptic DCAF12 is required for the expression of synaptic homeostatic potentiation. We suggest that DCAF12 and Cul4 are critical for normal synaptic function and plasticity at larval NMJs.

CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells.

To identify new therapeutic targets in acute myeloid leukemia (AML), we performed small-molecule and small-interfering RNA (siRNA) screens of primary AML patient samples. In 23% of samples, we found sensitivity to inhibition of colony-stimulating factor 1 (CSF1) receptor (CSF1R), a receptor tyrosine kinase responsible for survival, proliferation, and differentiation of myeloid-lineage cells. Sensitivity to CSF1R inhibitor GW-2580 was found preferentially in de novo and favorable-risk patients, and resistance to GW-2580 was associated with reduced overall survival. Using flow cytometry, we discovered that CSF1R is not expressed on the majority of leukemic blasts but instead on a subpopulation of supportive cells. Comparison of CSF1R-expressing cells in AML vs healthy donors by mass cytometry revealed expression of unique cell-surface markers. The quantity of CSF1R-expressing cells correlated with GW-2580 sensitivity. Exposure of primary AML patient samples to a panel of recombinant cytokines revealed that CSF1R inhibitor sensitivity correlated with a growth response to CSF1R ligand, CSF1, and other cytokines, including hepatocyte growth factor (HGF). The addition of CSF1 increased the secretion of HGF and other cytokines in conditioned media from AML patient samples, whereas adding GW-2580 reduced their secretion. In untreated cells, HGF levels correlated significantly with GW-2580 sensitivity. Finally, recombinant HGF and HS-5-conditioned media rescued cell viability after GW-2580 treatment in AML patient samples. Our results suggest that CSF1R-expressing cells support the bulk leukemia population through the secretion of HGF and other cytokines. This study identifies CSF1R as a novel therapeutic target of AML and provides a mechanism of paracrine cytokine/growth factor signaling in this disease.

Single cell RNA-seq reveals profound transcriptional similarity between Barrett's oesophagus and oesophageal submucosal glands.

Barrett's oesophagus is a precursor of oesophageal adenocarcinoma. In this common condition, squamous epithelium in the oesophagus is replaced by columnar epithelium in response to acid reflux. Barrett's oesophagus is highly heterogeneous and its relationships to normal tissues are unclear. Here we investigate the cellular complexity of Barrett's oesophagus and the upper gastrointestinal tract using RNA-sequencing of single cells from multiple biopsies from six patients with Barrett's oesophagus and two patients without oesophageal pathology. We find that cell populations in Barrett's oesophagus, marked by LEFTY1 and OLFM4, exhibit a profound transcriptional overlap with oesophageal submucosal gland cells, but not with gastric or duodenal cells. Additionally, SPINK4 and ITLN1 mark cells that precede morphologically identifiable goblet cells in colon and Barrett's oesophagus, potentially aiding the identification of metaplasia. Our findings reveal striking transcriptional relationships between normal tissue populations and cells in a premalignant condition, with implications for clinical practice.

Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples.

In many malignancies, the tumor microenvironment includes CSF1R-expressing supportive monocyte/macrophages that promote tumor cell survival. For chronic lymphocytic leukemia (CLL), these supportive monocyte/macrophages are known as nurse-like cells (NLCs), although the potential effectiveness of selective small-molecule inhibitors of CSF1R against CLL is understudied. Here, we demonstrate the preclinical activity of two inhibitors of CSF1R, GW-2580 and ARRY-382, in primary CLL patient samples. We observed at least 25% of CLL samples showed sub-micromolar sensitivity to CSF1R inhibitors. This sensitivity was observed in samples with varying genetic and clinical backgrounds, although higher white cell count and monocyte cell percentage was associated with increased sensitivity. Depleting CD14-expressing monocytes preferentially decreased viability in samples sensitive to CSF1R inhibitors, and treating samples with CSF1R inhibitors eliminated the presence of NLCs in long-term culture conditions. These results indicate that CSF1R small-molecule inhibitors target CD14-expressing monocytes in the CLL microenvironment, thereby depriving leukemia cells of extrinsic support signals. In addition, significant synergy was observed combining CSF1R inhibitors with idelalisib or ibrutinib, two current CLL therapies that disrupt tumor cell intrinsic B-cell receptor signaling. These findings support the concept of simultaneously targeting supportive NLCs and CLL cells and demonstrate the potential clinical utility of this combination.

Opioid analgesic dose and the risk of misuse, overdose, and death: A narrative review.

PURPOSE: Despite the rise in serious adverse events paralleling increased prescription opioid analgesic use in the United States over the past 2 decades, the association between opioid analgesic dose and the risk of serious adverse health outcomes is incompletely characterized. We sought to synthesize the medical literature for observational studies examining the association between opioid analgesic dose and the risk of serious adverse health outcomes, with particular attention to the outcomes of misuse, abuse, addiction, overdose, and death. METHODS: Searching MEDLINE using PubMed and bibliography review, we identified 22 observational studies published between 2000 and 2015 that assessed the association between opioid analgesic dose and the risk of serious adverse health outcomes. Some of these studies had significant methodological limitations. Twelve reviewed studies examined the outcomes of misuse, overdose, or death; no studies examining the risk of addiction or abuse met our criteria for inclusion. RESULTS: The results of multiple studies clearly indicate an increasing risk of serious adverse health outcomes associated with increasing opioid analgesic dose. In particular, the risk of misuse, overdose, and death increases with increasing opioid analgesic dose. However, there is no opioid dose inflection point beyond which the risk of these adverse health outcomes increases. No opioid analgesic dose is without risk. CONCLUSIONS: The reviewed studies show an increasing risk of serious adverse health outcomes-including misuse, overdose, and death-associated with increasing opioid analgesic dose. Further research is needed to characterize the relationship between opioid analgesic dose and the risk of addiction and abuse. This analysis could inform policy actions for regulators and clinical decision making for providers.

The Lac-Mégantic Derailment, Corporate Regulation, and Neoliberal Sovereignty.

On July 6, 2013, Montreal, Maine, and Atlantic railcar 5017 hauling 72 tanker cars of Bakken crude oil derailed over the town of Lac-Mégantic, Quebec. The town erupted in a fiery inferno as 5,560,000 liters of highly flammable Bakken crude oil exploded over the town, killing 47 people and contaminating 558,000 tons of soil and local waterways. While Montreal, Maine, and Atlantic Rail Chairman Edward Burkhardt initially blamed the derailment on the lone engineer and local firefighters, this study shows how Transport Canada and the rail industry undermined regulatory and safety measures for several years before the derailment. This study uses a Foucauldian theoretical perspective to conceptualize and explain a new political mentality that transfers existing state regulatory authority to the corporate sector. This new mentality, neoliberal sovereignty, is composed of sovereign and neoliberal logics that monopolize "correct" trajectories of human economic development. This absolute market mentality merges with state sovereignty and eliminates existing safety and regulation frameworks to pursue unregulated corporate profits. Le 6 juillet 2013, un train de 72 wagons-citernes transportant du pétrole brute Bakken a déraillé de la ligne de chemin de fer de la Montréal, Maine et Atlantique, dans la ville de Lac-Mégantic au Québec. La ville c'est transformé en véritable enfer, alors que 5 560 000 litre de pétrole brute Bakken très inflammable ont fait explosé la ville, tuant quarante-sept personnes et contaminant 558 000 tonnes d'eaux et du sol de Lac-Mégantic et ses environs. Alors que le président de la MMA, Edward Burkhart, a d'abord blâmé l'ingénieur et le service d'incendie local, les études montrent que Transport Canada et l'industrie ferroviaire ont amoindrit les mesures de réglementation et de sécurité plusieurs années avant le déraillement. Cette étude utilise une perspective théorique foucauldienne pour conceptualiser et expliquer une nouvelle mentalité politique qui transfère l'autorité de régulations gouvernementales existantes au secteur des entreprises. Cette nouvelle mentalité, souveraines et néo-libérale, est composé de logique souveraines et néo-libérales qui monopolise les trajectoires « respectables ¼ de développement économique humain. Cette mentalité de marché absolu fusionne avec la souveraineté de l'État et élimine les cadres de sécurité et les réglementations existantes pour les bénéfices des entreprises non réglementaires.

Management of late main-body aortic endograft component uncoupling and type IIIa endoleak encountered with the Endologix Powerlink and AFX platforms.

OBJECTIVE: Junctional component separation producing type IIIa endoleak after endovascular abdominal aortic aneurysm repair (EVAR) is an uncommon but serious complication requiring unanticipated reinterventions. This retrospective study analyzed main-body EVAR component uncoupling and type IIIa endoleaks encountered with Powerlink and AFX (Endologix Inc, Irvine, Calif) endografts during an 8-year period. METHODS: Type IIIa endoleaks were identified from a database of secondary interventions and clinical surveillance. Operative reports, medical records, and computed tomography studies were reviewed. Clinical and imaging characteristics were analyzed over time, and differences were compared at appropriate follow-up intervals. RESULTS: Since 2006, 701 patients underwent primary EVAR using Endologix Powerlink (352 patients, 2006-2011) or AFX (349 patients, 2011-2014) endografts. Endoleaks required 32 secondary interventions (4.6%), including type Ia in 4 patients (1 proximal extension and 3 explants); type Ib in 8 patients (all distal extensions for enlarging iliac aneurysms); type II in 1 patient (explant); type IIIa in 17 patients (2.4%), who were the subject of this report; and type IIIb in 2 patients (both EVAR relining). The 17 patients with type IIIa endoleak were an average age of 71 years, and 14 (82%) were men. The mean preoperative abdominal aortic aneurysm (AAA) diameter was 70 ± 18 mm. The repair was elective in 16 patients and an emergency in one. Ten cases were performed with Powerlink and seven with AFX. Analysis of serial computed tomography scans found significant changes in AAA diameter; renal-to-bifurcation straight-line, centerline, and greater curvature lengths; EVAR angulation; and loss of EVAR component overlap. The average time from EVAR to reintervention was 32 months. Three patients returned with a ruptured AAA and three with AAA thrombosis, and three of these patients (18%) died ≤30 days of the emergency reintervention. Secondary procedures included EVAR relining with additional bridging components in 14 patients (82%), explant in 2, and axillobifemoral bypass in 1. No new cases of endograft uncoupling have been identified in patients treated with AFX since December 2012 after adoption of revised instructions for use. CONCLUSIONS: Although a small number of secondary interventions were needed after EVAR with the Endologix Powerlink or AFX endografts, most were undertaken for late main-body component uncoupling and type IIIa endoleak, which can occur after sideways displacement of the endograft in large and angulated AAAs. Patients treated before 2013 under the old instructions for use should be evaluated for signs of impending component separation and monitored annually, noting that expected indicators of endograft failure, such as increasing AAA diameter and endoleak, may be absent.