Omega-3 polyunsaturated fatty acid supplementation versus placebo on vascular health, glycaemic control, and metabolic parameters in people with type 1 diabetes: a randomised controlled preliminary trial

Background: The role of omega-3 polyunsaturated fatty acids (n-3PUFA), and the potential impact of n-3PUFA supplementation, in the treatment and management of type 1 diabetes (T1D) remains unclear and controversial. Therefore, this study aimed to examine the efficacy of daily high-dose-bolus n-3PUFA supplementation on vascular health, glycaemic control, and metabolic parameters in subjects with T1D. Methods: Twenty-seven adults with T1D were recruited to a 6-month randomised, double-blind, placebo-controlled trial. Subjects received either 3.3 g/day of encapsulated n-3PUFA or encapsulated 3.0 g/day corn oil placebo (PLA) for 6-months, with follow-up at 9-months after 3-month washout. Erythrocyte fatty acid composition was determined via gas chromatography. Endpoints included inflammation-associated endothelial biomarkers (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], E-selectin, P-selectin, pentraxin-3, vascular endothelial growth factor [VEGF]), and their mediator tumor necrosis factor alpha [TNFα] analysed via immunoassay, vascular structure (carotid intima-media thickness [CIMT]) and function (brachial artery flow mediated dilation [FMD]) determined via ultrasound technique, blood pressure, glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial metabolism. Results: Twenty subjects completed the trial in full. In the n-3PUFA group, the mean ± SD baseline n-3PUFA index of 4.93 ± 0.94% increased to 7.67 ± 1.86% (P  0.05). Conclusions: This study indicates that daily high-dose-bolus of n-3PUFA supplementation for 6-months does not improve vascular health, glucose homeostasis, or metabolic parameters in subjects with T1D. The findings from this preliminary RCT do not support the use of therapeutic n-3PUFA supplementation in the treatment and management of T1D and its associated complications. Trial Registration ISRCTN, ISRCTN40811115. Registered 27 June 2017, http://www.isrctn.com/ISRCTN40811115

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I2-IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases. Keywords Imidazoline I2 receptors (2-imidazolin-4-yl)phosphonates Behavior Cognition Neurodegeneration Neuroprotection Agin

Opioid moderatism and the imperative of rapprochement in pain medicine

Michael E Schatman,1,2 Alexis Vasciannie,3,4 Ronald J Kulich3,5 1Research and Network Development, Boston PainCare, Waltham, MA, USA; 2Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA; 3Department of Diagnostic Sciences, Tufts University School of Dental Medicine, Boston, MA, USA; 4Department of Biological Sciences, Northeastern University, Boston, MA, USA; 5Department of Anesthesia Critical Care and Pain Medicine, Harvard Medical School/Massachusetts General Hospital, Boston, MA, USA   A brief history of the “prescription opioid crisis” Few would deny that the first decade of this millennium was marked by a “prescription opioid crisis” in the United States, characterized by overprescription and frank opiophilia. Although many have attempted to blame this crisis on a single cause, more thoughtful analysis has yielded numerous contributors to the onset and maintenance of the abuse crisis.1 Schatman,2,3 among others, has posited that health insurance carriers’ decision to discontinue coverage of interdisciplinary pain management programs left physicians without the most effective means of treating chronic pain, resulting in the consequence of turning to increased opioid prescribing. Dasgupta et al1 recently suggested that the pharmaceutical industry responded to this void by propagating not only long-acting opioids but forms that were ultra-rapid-acting, including dissolving strips and nasal sprays. They also noted that safety issues associated with non-opioid pain medications such as non-steroidal anti-inflammatory drugs and acetaminophen may have further fueled opioid prescribing. Perhaps the aggressive and fraudulent marketing of OxyContin as “nonaddictive” has been considered the primary culprit in the prescription opioid crisis,4 although other questionable industry behaviors such as kickback schemes,5 lucrative compensation for speaking as an incentive to prescribe,6 and promotion of off-label use7 have also been implicated as contributing to the prescription opioid conflict. In the late 1990s patient advocates began to encourage the assessment of pain as the “fifth vital sign”, and those most vehemently against opioids have gone so far as to suggest that pharmaceutical industry lobbying was responsible for the Joint Commission on Accreditation of Healthcare Organizations’ (JCAHO) advocacy for the institution of such.8 JCAHO’s proclamation has been indicted as creating a culture resulting in a marked increase in opioid prescription.9 Other causes to which the prescription opioid crisis has been attributed include unscrupulous physicians operating “pill mills”,10 unrealistic expectations of patients regarding complete relief of pain,11 state medical boards curtailing restrictions on prescribing opioids for noncancer pain,12 the Affordable Care Act’s provision requiring hospitals’ provision of patient satisfaction surveys that included satisfaction regarding pain relief,13 increased availability of prescription opioids without a prescription over the internet,14 and providers’ failures to adequately identify and monitor misuse and overuse.15 This list is far from exhaustive, with a recent assessment16 reporting that “The root causes of the modern opioid crisis are complex and traceable to at least 30 or more factors” (p. 943)

10 kHz spinal cord stimulation: a retrospective analysis of real-world data from a community-based, interdisciplinary pain facility [Corrigendum]

DiBenedetto DJ, Wawrzyniak KM, Schatman ME, Kulich RJ, Finkelman M. J Pain Res. 2018;11:2929–2941.   On page 2931, Figure 1 was incorrect. The correct figure is included below:   Read the original articl

An investigation of completion times on the Screener and Opioid Assessment for Patients with Pain – revised (SOAPP-R)

Matthew D Finkelman,1 Ronald J Kulich,2,3 Stephen F Butler,4 William C Jackson,3 Franklin D Friedman,5 Niels Smits,6 Scott G Weiner7 1Department of Public Health and Community Service, Tufts University School of Dental Medicine, Boston, MA, USA; 2Craniofacial Pain and Headache Center, Tufts University School of Dental Medicine, Boston, MA, USA; 3Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 4Inflexxion Inc, Newton, MA, USA; 5Department of Emergency Medicine, Tufts Medical Center, Boston, MA, USA; 6Department of Methods and Statistics, Research Institute of Child Development and Education, University of Amsterdam, Amsterdam, the Netherlands; 7Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, USA Background: Respondents’ scores to the Screener and Opioid Assessment for Patients with Pain – revised (SOAPP-R) have been shown to be predictive of aberrant drug-related behavior (ADB). However, research is lacking on whether an individual’s completion time (the amount of time that he/she takes to finish the screener) has utility in predicting ADB, despite the fact that response speed has been useful in predicting behavior in other fields. The purpose of this study was to evaluate the degree to which SOAPP-R completion time is predictive of ADB.Materials and methods: This retrospective study analyzed completion-time data from 82 adult emergency department patients who completed the SOAPP-R on a tablet computer. The utility of SOAPP-R completion times in predicting ADB was assessed via logistic regression and the area under the curve (AUC) statistic. An external measure of ADB using Prescription Drug Monitoring Program data defined ADB to have occurred in individuals with at least four opioid prescriptions and at least four prescribers in 12 months.Results: Although there was a slight trend for individuals with greater completion times to have greater odds of ADB (odds ratio 1.004 in simple logistic regression), the association between SOAPP-R completion time and ADB was not statistically significant in either simple logistic regression (P=0.307) or multiple logistic regression adjusting for SOAPP-R score (P=0.419). AUC values for the prediction of ADB using completion time alone, SOAPP-R score alone, and both completion time and SOAPP-R score were 0.63, 0.64, and 0.65, respectively.Conclusion: There was no significant evidence that SOAPP-R completion times were predictive of ADB among emergency department patients. However, the AUC value for completion times was only slightly less than that for SOAPP-R total scores. Keywords: chronic pain, substance abuse, risk stratification, aberrant drug-related behavior, response times, response latenc

Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis

Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspects (eg, lung function, infection, survival) of cystic fibrosis (CF) in some studies but not others. Inconsistent results may be due to confounding among disease variables that were not fully accounted for in each study. To account for these relationships, we derived a modeling framework incorporating CFTR genotype, age, Pseudomonas aeruginosa (Pa) infection, and lung function from 788 patients in the US CF Twin and Sibling Study. This framework was then used to identify confounding variables when testing the effect of MBL2 variation on specific CF traits. MBL2 genotypes corresponding to low levels of MBL associated with Pa infection 1.94 years earlier than did MBL2 genotypes corresponding to high levels of MBL (P=0.0034). In addition, Pa-infected patients with MBL2 genotypes corresponding to low levels of MBL underwent conversion to mucoid Pa 2.72 years earlier than did patients with genotypes corresponding to high levels of MBL (P=0.0003). MBL2 was not associated with the time to transition from infection to conversion or with lung function. Thus, use of a modeling framework that identified confounding among disease variables revealed that variation in MBL2 associates with age at infection with Pa and age at conversion to mucoid Pa in CF

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10(−11)), chr5p15.3 (SLC9A3; P=6.8 × 10(−12)), chr6p21.3 (HLA Class II; P=1.2 × 10(−8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(−9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10(−10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF