The bacterial virulence factor NleA undergoes host-mediated O-linked glycosylation.

Enterohaemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) are gastrointestinal pathogens responsible for severe diarrheal illness. EHEC and EPEC form "attaching and effacing" lesions during colonization and, upon adherence, inject proteins directly into host intestinal cells via the type III secretion system (T3SS). Injected bacterial proteins have a variety of functions but generally alter host cell biology to favor survival and/or replication of the pathogen. Non-LEE-encoded effector A (NleA) is a T3SS-injected effector of EHEC, EPEC, and the related mouse pathogen Citrobacter rodentium. Studies in mouse models indicate that NleA has an important role in bacterial virulence. However, the mechanism by which NleA contributes to disease remains unknown. We have determined that the following translocation into host cells, a serine and threonine-rich region of NleA is modified by host-mediated mucin-type O-linked glycosylation. Surprisingly, this region was not present in several clinical EHEC isolates. When expressed in C. rodentium, a non-modifiable variant of NleA was indistinguishable from wildtype NleA in an acute mortality model but conferred a modest increase in persistence over the course of infection in mixed infections in C57BL/6J mice. This is the first known example of a bacterial effector being modified by host-mediated O-linked glycosylation. Our data also suggests that this modification may confer a selective disadvantage to the bacteria during in vivo infection.

Targeting α7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development.

The decades-old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the α7 nicotinic acetylcholine receptor (α7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid ß1-42 (Aß42 ) was shown to bind α7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau-containing tangles. Multiple biopharmaceutical companies explored α7nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting α7nAChR proved to be a drug development challenge. The ultra-high-affinity interaction between Aß42 and α7nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of α7nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug-related toxicities. As alternatives, proteins interacting with α7nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with α7nAChR was shown to be critical to Aß42 's toxic signaling via α7nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A-α7nAChR interaction, reduces Aß42 's high-affinity binding to α7nAChR, and suppresses Aß42 's toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease-modifying treatment for AD.

Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer's Disease.

Simufilam is a novel oral drug candidate in Phase 3 clinical trials for Alzheimer's disease (AD) dementia. This small molecule binds an altered form of filamin A (FLNA) that occurs in AD. This drug action disrupts FLNA's aberrant linkage to the α7 nicotinic acetylcholine receptor (α7nAChR), thereby blocking soluble amyloid beta1-42 (Aß42)'s signaling via α7nAChR that hyperphosphorylates tau. Here, we aimed to clarify simufilam's mechanism. We now show that simufilam reduced Aß42 binding to α7nAChR with a 10-picomolar IC50 using time-resolved fluorescence resonance energy transfer (TR-FRET), a robust technology to detect highly sensitive molecular interactions. We also show that FLNA links to multiple inflammatory receptors in addition to Toll-like receptor 4 (TLR4) in postmortem human AD brains and in AD transgenic mice: TLR2, C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 5 (CCR5), and T-cell co-receptor cluster of differentiation 4 (CD4). These aberrant FLNA linkages, which can be induced in a healthy control brain by Aß42 incubation, were disrupted by simufilam. Simufilam reduced inflammatory cytokine release from Aß42-stimulated human astrocytes. In the AD transgenic mice, CCR5-G protein coupling was elevated, indicating persistent activation. Oral simufilam reduced both the FLNA-CCR5 linkage and the CCR5-G protein coupling in these mice, while restoring CCR5's responsivity to C-C chemokine ligand 3 (CCL3). By disrupting aberrant FLNA-receptor interactions critical to AD pathogenic pathways, simufilam may promote brain health.

Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review.

AIMS: While suboptimal adherence to statin medication has been quantified in real-world patient settings, a better understanding of its impact is needed, particularly with respect to distinct problems of medication taking. Our aim was to synthesize current evidence on the impacts of statin adherence, discontinuation and persistence on cardiovascular disease and mortality outcomes. METHODS: We conducted a systematic review of peer-reviewed studies using a mapped search of Medline, Embase and International Pharmaceutical Abstracts databases. Observational studies that met the following criteria were included: defined patient population;statin adherence exposure; defined study outcome [i.e. cardiovascular disease (CVD), mortality]; and reporting of statin-specific results. RESULTS: Overall, 28 studies were included, with 19 studies evaluating outcomes associated with statin adherence, six with statin discontinuation and three with statin persistence. Among adherence studies, the proportion of days covered was the most widely used measure, with the majority of studies reporting increased risk of CVD (statistically significant risk estimates ranging from 1.22 to 5.26)and mortality (statistically significant risk estimates ranging from 1.25 to 2.54) among non-adherent individuals. There was greater methodological variability in discontinuation and persistence studies. However, findings of increased CVD (statistically significant risk estimates ranging from 1.22 to 1.67) and mortality (statistically significant risk estimates ranging from 1.79 to 5.00) among nonpersistent individuals were also consistently reported. CONCLUSIONS: Observational studies consistently report an increased risk of adverse outcomes associated with poor statin adherence. These findings have important implications for patients and physicians and emphasize the importance of monitoring and encouraging adherence to statin therapy.

Direct evidence of host-mediated glycosylation of NleA and its dependence on interaction with the COPII complex.

Non-LEE-encoded Effector A (NleA) is a type III secreted effector protein of enterohaemorrhagic and enteropathogenic Escherichia coli as well as the related mouse pathogen Citrobacter rodentium. NleA translocation into host cells is essential for virulence. We previously published several lines of evidence indicating that NleA is modified by host-mediated mucin-type O-linked glycosylation, the first example of a bacterial effector protein modified in this way. In this study, we use lectins to provide direct evidence for the modification of NleA by O-linked glycosylation and determine that the interaction of NleA with the COPII complex is necessary for this modification to occur.

Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A.

PTI-125 is a novel compound demonstrating a promising new approach to treating Alzheimer's disease (AD), characterized by neurodegeneration and amyloid plaque and neurofibrillary pathologies. We show that the toxic signaling of amyloid-ß(42) (Aß(42)) by the α7-nicotinic acetylcholine receptor (α7nAChR), which results in tau phosphorylation and formation of neurofibrillary tangles, requires the recruitment of the scaffolding protein filamin A (FLNA). By binding FLNA with high affinity, PTI-125 prevents Aß(42)'s toxic cascade, decreasing phospho-tau and Aß aggregates and reducing the dysfunction of α7nAChRs, NMDARs, and insulin receptors. PTI-125 prevents Aß(42) signaling by drastically reducing its affinity for α7nAChRs and can even dissociate existing Aß(42)-α7nAChR complexes. Additionally, PTI-125 prevents Aß-induced inflammatory cytokine release by blocking FLNA recruitment to toll-like receptor 4, illustrating an anti-inflammatory effect. PTI-125's broad spectrum of beneficial effects is demonstrated here in an intracerebroventricular Aß(42) infusion mouse model of AD and in human postmortem AD brain tissue.

Simufilam suppresses overactive mTOR and restores its sensitivity to insulin in Alzheimer's disease patient lymphocytes.

Introduction: Implicated in both aging and Alzheimer's disease (AD), mammalian target of rapamycin (mTOR) is overactive in AD brain and lymphocytes. Stimulated by growth factors such as insulin, mTOR monitors cell health and nutrient needs. A small molecule oral drug candidate for AD, simufilam targets an altered conformation of the scaffolding protein filamin A (FLNA) found in AD brain and lymphocytes that induces aberrant FLNA interactions leading to AD neuropathology. Simufilam restores FLNA's normal shape to disrupt its AD-associated protein interactions. Methods: We measured mTOR and its response to insulin in lymphocytes of AD patients before and after oral simufilam compared to healthy control lymphocytes. Results: mTOR was overactive and its response to insulin reduced in lymphocytes from AD versus healthy control subjects, illustrating another aspect of insulin resistance in AD. After oral simufilam, lymphocytes showed normalized basal mTOR activity and improved insulin-evoked mTOR activation in mTOR complex 1, complex 2, and upstream and downstream signaling components (Akt, p70S6K and phosphorylated Rictor). Suggesting mechanism, we showed that FLNA interacts with the insulin receptor until dissociation by insulin, but this linkage was elevated and its dissociation impaired in AD lymphocytes. Simufilam improved the insulin-mediated dissociation. Additionally, FLNA's interaction with Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN), a negative regulator of mTOR, was reduced in AD lymphocytes and improved by simufilam. Discussion: Reducing mTOR's basal overactivity and its resistance to insulin represents another mechanism of simufilam to counteract aging and AD pathology. Simufilam is currently in Phase 3 clinical trials for AD dementia.

Dual energy CT in gout: a prospective validation study.

OBJECTIVE: The authors prospectively determined: (1) the specificity and sensitivity of dual energy CT (DECT) for gout; and (2) the interobserver and intraobserver reproducibility for DECT urate volume measurements. METHODS: Forty crystal-proven gout patients (17 tophaceous) and 40 controls with other arthritic conditions prospectively underwent DECT scans of all peripheral joints using a gout protocol that color-codes the composition of tissues. A blinded radiologist identified urate deposition to calculate specificity and sensitivity of DECT for gout. Inter-rater volumetric reproducibility was determined by two independent radiologists on 40 index tophi from the 17 tophaceous gout patients using automated software. RESULTS: The mean age of the 40 gout patients was 62 years, the mean gout duration was 13 years and 87% had a history of urate-lowering therapy (ULT). The specificity and sensitivity of DECT for gout were 0.93 (95% CI, 0.80 to 0.98) and 0.78 (0.62 to 0.89), respectively. When the authors excluded three gout cases with unreadable or incomplete scans, the sensitivity was 0.84 (95% CI, 0.68 to 0.94). The urate volumes of 40 index tophi ranged from 0.06 cm(3) to 18.74 cm(3) with a mean of 2.45 cm(3). Interobserver and intraobserver intraclass correlation coefficients for DECT volume measurements were 1.00 (95% CI, 1.00 to 1.00) and 1.00 (95% CI, 1.00 to 1.00) with corresponding bias estimates (SD) of 0.01 (0.00) cm(3) and 0.01 (0.03) cm(3). CONCLUSIONS: These prospective data indicate high reproducibility of DECT urate volume measures. The specificity was high, but sensitivity was more moderate, potentially due to frequent ULT use in our patients.

Obesity and the risk of psoriatic arthritis: a population-based study.

BACKGROUND: Obesity is associated with an increased risk of psoriasis; however, its potential impact on the risk of psoriatic arthritis (PsA) remains unclear. OBJECTIVES: To evaluate the association between body mass index (BMI) and the risk of PsA among patients with psoriasis from the general population. METHODS: The authors conducted a cohort study using data from The Health Improvement Network, an electronic medical records database representative of the UK general population, collected between 1995 and 2010. The exposure of interest was the first BMI measured after psoriasis diagnosis and endpoints were incident cases of physician-diagnosed PsA. The authors estimated the RR of PsA after adjusting for age, sex, and histories of trauma, smoking and alcohol consumption. RESULTS: Among 75,395 individuals with psoriasis (43% male, mean follow-up of 5 years, and mean age of 52 years), 976 developed PsA (incidence rate, 26.5 per 10,000 person-years). The PsA incidence rates increased with increasing BMI. Compared with psoriasis patients with BMI <25 kg/m(2), the RRs for developing PsA were 1.09 (0.93-1.28) for BMIs from 25.0 to 29.9, 1.22 (1.02-1.47) for BMIs from 30.0 to 34.9 and 1.48 (1.20-1.81) for BMIs ≥35.0. In our secondary analysis among all individuals, regardless of psoriasis (~2 million), the corresponding multivariate RRs tended to be stronger (1.0, 1.17, 1.57, 1.96; p for trend <0.001). CONCLUSIONS: This general population study suggests that obesity is associated with an increased risk of incident PsA and supports the importance of weight reduction among psoriasis patients who often suffer from the metabolic syndrome and obesity.

Differences in body mass index among individuals with PsA, psoriasis, RA and the general population.

OBJECTIVES: To compare obesity among individuals with PsA, psoriasis (PsO), RA and the general population (n), and identify correlates of obesity among individuals with PsO and PsA. METHODS: We compared the BMI of patients with PsA (n = 644), PsO (n = 448), RA (n = 350) and the general population using age- and sex-adjusted linear and logistic regression analyses. We conducted multivariate analyses limited to PsO and PsA to determine correlates of BMI and obesity. RESULTS: The mean BMI (kilogram per square metre) for individuals with PsA, PsO, RA and the general population were 29.6, 27.9, 27.3 and 26.1, respectively. The proportion with obesity was 37, 29, 27 and 18% for individuals with PsA, PsO, RA and the general population, respectively. The differences in BMI were significant between all categories (P < 0.05) except between PsO and RA. Age- and sex-adjusted linear and logistic regression confirmed that these differences were significant. In multivariate logistic regression analyses adjusted for age, sex, smoking, PsO duration, psoriasis area severity index score, use of DMARDs, glucocorticoids and biologics, the odds of obesity were 61% higher for PsA patients than PsO patients (95% CI 1.10, 2.37). When we additionally adjusted for the physical component summary of the short form-36, the association was attenuated and became insignificant. CONCLUSIONS: Individuals with PsA have a higher mean BMI than those with PsO, RA or the general population. The BMI difference between PsA and PsO correlates with physical health.

Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations.

Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. In these patients, the presence of focal cortical malformations is associated with the occurrence of lifelong epilepsy, leading to severe neurological comorbidities. Here, we show that the expression of the actin cross-linking protein filamin A (FLNA) is increased in resected cortical tissue that is responsible for seizures in patients with FCDII and in mice modeling TSC and FCDII with mutations in phosphoinositide 3-kinase (PI3K)-ras homolog enriched in brain (Rheb) pathway genes. Normalizing FLNA expression in these mice through genetic knockdown limited cell misplacement and neuronal dysmorphogenesis, two hallmarks of focal cortical malformations. In addition, Flna knockdown reduced seizure frequency independently of mTOR signaling. Treating mice with a small molecule targeting FLNA, PTI-125, before the onset of seizures alleviated neuronal abnormalities and reduced seizure frequency compared to vehicle-treated mice. In addition, the treatment was also effective when injected after seizure onset in juvenile and adult mice. These data suggest that targeting FLNA with either short hairpin RNAs or the small molecule PTI-125 might be effective in reducing seizures in patients with TSC and FCDII bearing mutations in PI3K-Rheb pathway genes.

Abuse-deterrent properties of REMOXY® ER, a high-viscosity extended-release oxycodone formulation.

OBJECTIVE: These in vitro studies compared abuse-deterrent properties of REMOXY ER (extended-release oxycodone), a novel, high-viscosity gel formulation, versus the two currently marketed ER oxycodone formulations. METHODS: Tampering methods were tailored to each product to maximize oxycodone release with the least complexity, time, and effort, based on the physical/chemical properties of each formulation. Oral abuse was simulated by extracting oxycodone from each manipulated formulation in Common Ingestible Liquids and in Advanced Solvents (not ingestible and requiring additional separation). To simulate injection abuse, oxycodone was extracted from each manipulated formulation in low volumes of injection vehicles, heated or unheated. Inhalation abuse potential was assessed by volatilization. RESULTS: In oral abuse simulations, manipulated REMOXY ER released 2-22 percent of its oxycodone in 20 minutes in five Common Ingestible Liquids, versus 77-85 percent oxycodone released from OxyContin® ER in 5 minutes in four of the five. In six Advanced Solvents, REMOXY ER released 3-37 percent at 20 minutes, versus 55-89 percent released from OxyContin ER at 5 minutes. Minimal oxycodone was extracted from REMOXY ER in five injection vehicles, heated or unheated. In contrast, OxyContin ER released 65-87 percent of its oxycodone within 10 minutes in all vehicles, regardless of heating. Xtampza® ER released 96 percent of its oxycodone in a heated injection vehicle and released 50-60 percent in two unheated injection vehicles. Showing minimal inhalation abuse potential, 9 percent of oxycodone was vaporized from manipulated REMOXY ER at 20 minutes compared to 8.8 percent at 5 minutes for OxyContin ER. CONCLUSIONS: In these studies, REMOXY ER demonstrated robust and meaningful abuse-deterrence relative to OxyContin ER and Xtampza ER. PERSPECTIVE: Abuse-deterrent drugs were intended to help fight opioid abuse. Yet, the persistence of the opioid epidemic indicates that vast improvements in abuse-deterrent technology are sorely needed. A new, high-viscosity, ER oxycodone formulation showed much improved abuse-deterrent properties in simulations of oral, injection, and inhalation abuse, compared to earlier, first-generation formulations.

A nasal abuse potential randomized clinical trial of REMOXY® ER, a high-viscosity extended-release oxycodone formulation.

OBJECTIVE: This study examined the nasal abuse deterrence of REMOXY ER, a novel high-viscosity extended-release oxycodone formulation. DESIGN: An Institutional Review Board-approved, single-center, randomized, double-blind, placebo, and active-controlled, four-way crossover study of intranasal REMOXY ER gel, manipulated or intact, and ground oxycodone immediate-release (IR). An open label extension examined pharmacokinetics of OxyContin® ER in the first 20 subjects. PARTICIPANTS: Healthy, adult nondependent recreational opioid users with a history of intranasal abuse. Thirty-eight subjects enrolled; 36 completed. SETTING: A clinical research in-patient unit. INTERVENTIONS: Cross-over arms included nasal self-administration of the entire contents of REMOXY ER 40 mg capsules (manipulated or intact), ground oxycodone IR 40 mg tablets, and placebo. The open-label arm was ground OxyContin ER. MAIN OUTCOME MEASURES: The primary endpoint was the maximum effect (Emax) of visual analog scale ratings of Drug Liking. Secondary endpoints included Take Drug Again (12 and 24 hours), Drug High Emax, area under effect curves through 12 hours, pupillometry, peak oxycodone concentrations (Cmax), time to maximum concentration (Tmax), and Abuse Quotient (Cmax/Tmax). RESULTS: Intranasal REMOXY ER (manipulated or intact) elicited lower Drug Liking and Drug High compared to ground oxycodone IR. Secondary endpoints also reflected reduced Abuse Potential. Intranasal REMOXY ER (manipulated or intact) led to fourfold lower Cmax, a 57 to 128 percent longer Tmax, a >10-fold lower Abuse Quotient and lower Take Drug Again scores compared to both OxyContin ER and oxycodone IR. CONCLUSION: In this study, REMOXY ER demonstrated significantly lower nasal abuse potential compared to oxycodone IR or OxyContin ER. PERSPECTIVE: Abuse-deterrent drugs are intended to help fight opioid abuse. Yet the persistence of the opioid epidemic indicates that vast improvements in abuse-deterrent technology are needed. A new, high-viscosity, extended-release oxycodone formulation showed robust abuse-deterrence against the nasal route of abuse in an Food and Drug Administration-advised clinical trial in recreational opioid users.

Psychological treatments for the management of postsurgical pain: a systematic review of randomized controlled trials.

BACKGROUND: Inadequately managed pain is a risk factor for chronic postsurgical pain (CPSP), a growing public health challenge. Multidisciplinary pain-management programs with psychological approaches, including cognitive behavioral therapy (CBT), acceptance and commitment therapy (ACT), and mindfulness-based psychotherapy, have shown efficacy as treatments for chronic pain, and show promise as timely interventions in the pre/perioperative periods for the management of PSP. We reviewed the literature to identify randomized controlled trials evaluating the efficacy of these psychotherapy approaches on pain-related surgical outcomes. MATERIALS AND METHODS: We searched Medline, Medline-In-Process, Embase and Embase Classic, and PsycInfo to identify studies meeting our search criteria. After title and abstract review, selected articles were rated for risk of bias. RESULTS: Six papers based on five trials (four back surgery, one cardiac surgery) met our inclusion criteria. Four papers employed CBT and two CBT-physiotherapy variant; no ACT or mindfulness-based studies were identified. Considerable heterogeneity was observed in the timing and delivery of psychological interventions and length of follow-up (1 week to 2-3 years). Whereas pain-intensity reporting varied widely, pain disability was reported using consistent methods across papers. The majority of papers (four of six) reported reduced pain intensity, and all relevant papers (five of five) found improvements in pain disability. General limitations included lack of large-scale data and difficulties with blinding. CONCLUSION: This systematic review provides preliminary evidence that CBT-based psychological interventions reduce PSP intensity and disability. Future research should further clarify the efficacy and optimal delivery of CBT and newer psychological approaches to PSP.

Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with proteopathy characterized by abnormalities in amyloid beta (Aß) and tau proteins. Defective amyloid and tau propagate and aggregate, leading to eventual amyloid plaques and neurofibrillary tangles. New data show that a third proteopathy, an altered conformation of the scaffolding protein filamin A (FLNA), is critically linked to the amyloid and tau pathologies in AD. Altered FLNA is pervasive in AD brain and without apparent aggregation. In a striking interdependence, altered FLNA is both induced by Aß and required for two prominent pathogenic signaling pathways of Aß. Aß monomers or small oligomers signal via the α7 nicotinic acetylcholine receptor (α7nAChR) to activate kinases that hyperphosphorylate tau to cause neurofibrillary lesions and formation of neurofibrillary tangles. Altered FLNA also enables a persistent activation of toll-like-receptor 4 (TLR4) by Aß, leading to excessive inflammatory cytokine release and neuroinflammation. The novel AD therapeutic candidate PTI-125 binds and reverses the altered FLNA conformation to prevent Aß's signaling via α7nAChR and aberrant activation of TLR4, thus reducing multiple AD-related neuropathologies. As a regulator of Aß's signaling via α7nAChR and TLR4, altered FLNA represents a novel AD therapeutic target.

PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis.

We show that amyloid-ß1-42 (Aß42) triggers a conformational change in the scaffolding protein filamin A (FLNA) to induce FLNA associations with α7-nicotinic acetylcholine receptor (α7nAChR) and toll-like receptor 4 (TLR4). These aberrant associations respectively enable Aß42's toxic signaling via α7nAChR to hyperphosphorylate tau protein, and TLR4 activation to release inflammatory cytokines. PTI-125 is a small molecule that preferentially binds altered FLNA and restores its native conformation, restoring receptor and synaptic activities and reducing its α7nAChR/TLR4 associations and downstream pathologies. Two-month oral PTI-125 administration to triple-transgenic (3xTg) Alzheimer's disease (AD) mice before or after apparent neuropathology and to 8-month wildtypes with milder neuropathologies reduced receptor dysfunctions and improved synaptic plasticity, with some improvements in nesting behavior and spatial and working memory in 3xTg AD mice. PTI-125 also reduced tau hyperphosphorylation, aggregated Aß42 deposition, neurofibrillary tangles, and neuroinflammation. Efficacy in postmortem AD and Aß42-treated age-matched control hippocampal slices was concentration-dependent starting at 1 picomolar (pM) concentration. PTI-125 is the first therapeutic candidate to preferentially bind an altered protein conformation and reverse this proteopathy.

The psychology of chronic post-surgical pain: new frontiers in risk factor identification, prevention and management.

In an era of considerable advances in anaesthesiology and pain medicine, chronic pain after major surgery continues to be problematic. This article briefly reviews the known psychological risk and protective factors associated with the development of chronic postsurgical pain (CPSP). We begin with a definition of CPSP and then explain what we mean by a risk/protective factor. Next, we summarize known psychological risk and protective factors for CPSP. Psychological interventions that target risk factors and may impact postsurgical pain are reviewed, including the acceptance and commitment therapy (ACT)-based approach to CPSP prevention and management we use in the Transitional Pain Service (TPS) at the Toronto General Hospital. Finally, we conclude with recommendations for research in risk factor identification and psychological interventions to prevent CPSP. Several pre-surgical psychological risk factors for CPSP have been consistently identified in recent years. These include negative affective constructs, such as anxiety symptoms, depressive symptoms, pain catastrophizing and general psychological distress. In contrast, relatively few studies have examined psychological protective factors for CPSP. Psychological interventions that target known psychological risk factors while enhancing protective psychological factors may reduce new incidence of CPSP. The primary goal of our ACT intervention is to teach patients a mindful way of responding to their postsurgical pain that empowers them to interrupt the negative cycle of pain, distress, behavioural avoidance and escalating opioid use that can limit functioning and quality of life while paradoxically amplifying pain over time. Early clinical outcome data suggest that patients who receive care from TPS physicians reduce their pain and opioid use, yet patients who also receive our ACT intervention have a larger decrease in daily opioid dose while reporting less pain interference and lower depression scores.

Acceptance and Commitment Therapy to manage pain and opioid use after major surgery: Preliminary outcomes from the Toronto General Hospital Transitional Pain Service.

Background: Chronic postsurgical pain (CPSP) and associated long-term opioid use are major public health concerns. Aims: The Toronto General Hospital Transitional Pain Service (TPS) is a multidisciplinary, hospital-integrated program developed to prevent and manage CPSP and support opioid tapering. This clinical practice-based study reports on preliminary outcomes of the TPS psychology program, which provides acceptance and commitment therapy (ACT) to patients at risk for CPSP and persistent opioid use. Methods: Ninety-one patients received ACT, whereas 252 patients did not (no ACT group). Patient outcomes were compared for the two groups at first and last TPS visits. Pain, pain interference, sensitivity to pain traumatization, pain catastrophizing, anxiety, depression, and opioid use were analyzed using two-way (Group [ACT, no ACT] × Time [first, last visit]) analyses of variance (ANOVAs). Results: Patients referred to ACT were more likely to report a mental health condition preoperatively (P < 0.001), had higher opioid use (P < 0.001) at the first postsurgical visit, and reported higher sensitivity to pain traumatization (P < 0.05) and anxiety (P < 0.05) than the no ACT group at both time points. Both groups showed reductions in pain, pain interference, pain catastrophizing, anxiety, and opioid use by the last TPS visit (P < 0.05). The ACT group demonstrated greater reductions in opioid use and pain interference and showed reductions in depressed mood (P = 0.001) by the end of treatment compared to the no ACT group. Conclusion: Preliminary outcomes suggest that ACT was effective in reducing opioid use while pain interference and mood improved.

Contexte: La douleur chronique post-chirurgicale (DCPC) et l'usage à long terme d'opioïdes qui y sont associées sont des préoccupations majeures en santé publique.Objectifs: Le Service de la douleur transitionnelle (STD) de l'Hôpital général de Toronto est un programme multidisciplinaire qui a été mis sur pied au sein même de l'hôpital pour prévenir et prendre en charge la douleur chronique post-chirurgicale et diminuer l'usage d'opioïdes. Cette étude clinique axée sur les pratiques porte sur les résultats préliminaires du programme de psychologie du STD. Ce programme offre une thérapie d'acceptation et d'engagement (ACT) aux patients à risques de douleur post-chirurgicale chronique et d'usage persistant d'opioïdes.Méthodes: Quatre-vingt onze patients ont bénéficié de l'ACT, tandis que deux-cent cinquante-deux patients n'en ont pas bénéficié (groupe sans ACT). Les résultats obtenus ont été comparés pour les patients des deux groupes lors de la première et de la dernière visite d'ACT. Une analyse de variance à deux facteurs (groupe [ACT - sans ACT] x moment [première, dernière visite]) a été effectuée pour la douleur, l'interférence de la douleur, la sensibilité au traumatisme de la douleur, la catastrophisation de la douleur, l'anxiété, la dépression et l'usage d'opioïdes.Résultats: Les résultats suggèrent que les patients référés à l'ACT étaient plus susceptibles de souffrir d'un problème de santé mentale avant l'opération chirurgicale (p < 0,001) et présentaient un plus grand usage d'opioïdes (p < 0,001) au moment de la première visite post-chirurgicale. De plus, ils manifestaient une plus grande prédisposition a la douleur en lien avec un sensibilité au traumatisme (p < 0,05) et à l'anxiété (p < 0,05) comparativement au groupe sans ACT. Une diminution de la douleur, de l'interférence de la douleur, de la catastrophisation en lien à la douleur et de l'usage d'opioïdes au moment de la dernière visite au STD (p < 0,05) a été observée chez les sujets des deux groupes. Une plus grande diminution de l'usage d'opioïdes, de l'interférence de la douleur et de l'humeur dépressive (p = 0,001) ont été observées chez le groupe avec ACT à la fin du traitement, ceci comparativement au groupe sans ACT.Conclusion: Les résultats préliminaires suggèrent que l'ACT a été efficace pour réduire l'usage d'opioïdes tout en diminuant l'interférence de la douleur et en améliorant l'humeur des patients.

A case report on the treatment of complex chronic pain and opioid dependence by a multidisciplinary transitional pain service using the ACT Matrix and buprenorphine/naloxone.

In an era of growing concern about opioid prescribing, the postsurgical period remains a critical window with the risk of significant opioid dose escalation, particularly in patients with a history of chronic pain and presurgical opioid use. The purpose of this case report is to describe the multidisciplinary care of a complex, postsurgical pain patient by an innovative transitional pain service (TPS). A 59-year-old male with complex chronic pain, as well as escalating long-term opioid use, presented with a bleeding duodenal ulcer requiring emergency surgery. After surgery, the TPS provided integrated pharmacological and behavioral treatment, including buprenorphine combined with naloxone and acceptance and commitment therapy (ACT) using the ACT Matrix. The result was dramatic pain reduction and improved functioning and quality of life after 40+ years of chronic pain, thus changing the pain trajectory of a chronic, complex, opioid-dependent patient.

Identification of human short introns.

Canonical pre-mRNA splicing requires snRNPs and associated splicing factors to excise conserved intronic sequences, with a minimum intron length required for efficient splicing. Non-canonical splicing-intron excision without the spliceosome-has been documented; most notably, some tRNAs and the XBP1 mRNA contain short introns that are not removed by the spliceosome. There have been some efforts to identify additional short introns, but little is known about how many short introns are processed from mRNAs. Here, we report an approach to identify RNA short introns from RNA-Seq data, discriminating against small genomic deletions. We identify hundreds of short introns conserved among multiple human cell lines. These short introns are often alternatively spliced and are found in a variety of RNAs-both mRNAs and lncRNAs. Short intron splicing efficiency is increased by secondary structure, and we detect both canonical and non-canonical short introns. In many cases, splicing of these short introns from mRNAs is predicted to alter the reading frame and change protein output. Our findings imply that standard gene prediction models which often assume a lower limit for intron size fail to predict short introns effectively. We conclude that short introns are abundant in the human transcriptome, and short intron splicing represents an added layer to mRNA regulation.