Prolonged opioid use among opioid-naive individuals after prescription for nonspecific low back pain in the emergency department.

ABSTRACT: Low back pain is a leading cause of disability globally. It is a common reason for presentation to the emergency department where opioids are commonly prescribed. This is a retrospective cohort study of opioid-naive adults with low back pain presenting to 1 of 4 emergency departments in Nova Scotia. We use routinely collected administrative clinical and drug-use data (July 2010-November 2017) to investigate the prevalence of prolonged opioid use and associated individual and prescription characteristics. In total, 23,559 eligible individuals presented with nonspecific low back pain, with 84.4% being opioid-naive. Our study population included 4023 opioid-naive individuals who filled a new opioid prescription within 7 days after their index emergency department visit (24.4%). The prevalence of prolonged opioid use after a new opioid prescription for low back pain (filling an opioid prescription 8-90 days after the emergency department visit and filling a subsequent prescription ±30 days of 6 months) was 4.6% (185 individuals). Older age and female sex were associated with clinically important increased odds of prolonged opioid use. First prescription average >90 morphine milligram equivalents/day (odds ratio 1.6, 95% confidence interval 1.0-2.6) and greater than 7-day supply (1.9, 1.1-3.1) were associated with prolonged opioid use in adjusted models. We found evidence of declining opioid prescriptions over the study period, but that 24.3% of first opioid prescriptions in 2016 would not have aligned with current guideline recommendations. Our study provides evidence to support a cautious approach to prescribing in opioid-naive populations.

Total sleep deprivation does not significantly degrade semantic encoding.

Sleep deprivation impairs performance on cognitive tasks, but it is unclear which cognitive processes it degrades. We administered a semantic matching task with variable stimulus onset asynchrony (SOA) and both speeded and self-paced trial blocks. The task was administered at the baseline and 24 hours later after 30.8 hours of total sleep deprivation (TSD) or matching well-rested control. After sleep deprivation, the 20% slowest response times (RTs) were significantly increased. However, the semantic encoding time component of the RTs remained at baseline level. Thus, the performance impairment induced by sleep deprivation on this task occurred in cognitive processes downstream of semantic encoding.

Comparison of a point-of-care analyser for the determination of HbA1c with HPLC method.

AIMS: As the use of Point of Care Testing (POCT) devices for measurement of glycated haemoglobin (HbA1c) increases, it is imperative to determine how their performance compares to laboratory methods. This study compared the performance of the automated Quo-Test POCT device (EKF Diagnostics), which uses boronate fluorescence quenching technology, with a laboratory based High Performance Liquid Chromatography (HPLC) method (Biorad D10) for measurement of HbA1c. METHODS: Whole blood EDTA samples from subjects (n=100) with and without diabetes were assayed using a BioRad D10 and a Quo-Test analyser. Intra-assay variation was determined by measuring six HbA1c samples in triplicate and inter-assay variation was determined by assaying four samples on 4 days. Stability was determined by assaying three samples stored at -20 °C for 14 and 28 days post collection. RESULTS: Median (IQR) HbA1c was 60 (44.0-71.2) mmol/mol (7.6 (6.17-8.66) %) and 62 (45.0-69.0) mmol/mol (7.8 (6.27-8.46) %) for D10 and Quo-Test, respectively, with very good agreement (R2=0.969, P<0.0001). Mean (range) intra- and inter-assay variation was 1.2% (0.0-2.7%) and 1.6% (0.0-2.7%) for the D10 and 3.5% (0.0-6.7%) and 2.7% (0.7-5.1%) for the Quo-Test. Mean change in HbA1c after 28 days storage at -20 °C was -0.7% and +0.3% for D10 and Quo-Test respectively. Compared to the D10, Quo-Test showed 98% agreement for diagnosis of glucose intolerance (IGT and T2DM) and 100% for diagnosis of T2DM. CONCLUSION: Good agreement between the D10 and Quo-Test was seen across a wide HbA1c range. The Quo-Test POCT device provided similar performance to a laboratory based HPLC method.

Gold and Hydroxyapatite Nano-Composite Scaffolds for Anterior Cruciate Ligament Reconstruction: In Vitro Characterization.

Current anterior cruciate ligament (ACL) graft replacement materials often fail due to the lack of biological integration. While many newly developed extracellular matrix based scaffolds show good biocompatibility they often do not entice cellular remodeling and the rebuilding of a functional ligament. We have proposed the conjugation of gold nanoparticles (AuNP) and hydroxyapatite nanoparticles (nano-HAp) to acellular tissue to enhance cell attachment and proliferation while maintaining an improved degradation resistance and open microstructure. We are the first to investigate the double conjugation of AuNP and nano-HAp onto decellularized tissue to improve the tissue remodeling response. Decellularized porcine diaphragm was crosslinked with two types of nano-HAp and amine-functionalized AuNP with 1-ethyl-3-(3-dimethlaminopropyl) carbodiimide (EDC) crosslinker. Scaffolds were characterized using electron microscopy, differential scanning calorimetry, and fibroblast assays. Results demonstrated that scaffolds with nano-HAp have increased thermal stability at low levels of crosslinking. The open microstructure of the scaffold was not compromised allowing for cell migration while still providing increased degradation resistance. The addition of < 200 nm nano-HAp decreased cell viability compared to scaffolds without nanoparticles, but the addition of AuNP to scaffolds showed enhanced cell viability in the presence of < 200 nm nano-HAp. The addition of < 40 nm nano-HAp showed an increase in cell viability compared to scaffolds crosslinked without nanoparticles. It is concluded that attaching AuNP and < 40nm nano-HAp to extracellular matrices may improve overall properties.

An in vivo study of a gold nanocomposite biomaterial for vascular repair.

Currently vascular repairs are treated using synthetic or biologic patches, however these patches have an array of complications, including calcification, rupture, re-stenosis, and intimal hyperplasia. An active patch material composed of decellularized tissue conjugated to gold nanoparticles (AuNPs) was developed and the long term biocompatibility and cellular integration was investigated. Porcine abdominal aortic tissue was decellularized and conjugated with 100 nm gold nanoparticles (AuNP). These patches were placed over a longitudinal arteriotomy of the thoracic aorta in six pigs. The animals were monitored for six months. Gross, histological, and immunohistochemical analyses of the patches were performed after euthanasia. Grossly there was minimal scar tissue with the patches still visible on the outer surface of the vessel. The inner lumen was smooth with a seamless transition from patch to native tissue. Histology demonstrated infiltration of host cells into the patch material. The immunohistochemical results demonstrated an endothelial cell layer forming over the patch within the vessel. Smooth muscle cells were repopulating the biomaterial in all animals. These results demonstrated that the AuNP biomaterial patch integrated well with the host tissue and did not failed over the six month implantation time.

Materials characterization and histological analysis of explanted polypropylene, PTFE, and PET hernia meshes from an individual patient.

During its tenure in vivo, synthetic mesh materials are exposed to foreign body responses, which can alter physicochemical properties of the material. Three different synthetic meshes comprised of polypropylene, expanded polytetrafluoroethylene (ePTFE), and polyethylene terephthalate (PET) materials were explanted from a single patient providing an opportunity to compare physicochemical changes between three different mesh materials in the same host. Results from infrared spectroscopy demonstrated significant oxidation in polypropylene mesh while ePTFE and PET showed slight chemical changes that may be caused by adherent scar tissue. Differential scanning calorimetry results showed a significant decrease in the heat of enthalpy and melt temperature in the polypropylene mesh while the ePTFE and PET showed little change. The presence of giant cells and plasma cells surrounding the ePTFE and PET were indicative of an active foreign body response. Scanning electron micrographs and photo micrographs displayed tissue entrapment and distortion of all three mesh materials.

A comparative study of the remodeling and integration of a novel AuNP-tissue scaffold and commercial tissue scaffolds in a porcine model.

The extracellular matrices of a variety of human and animal tissues have been utilized as scaffold materials for soft tissue applications including hernia repair, dermal grafts, and tendon, ligament, and cartilage reconstruction. While these biological scaffolds are expected to demonstrate superior tissue integration, there is very little evidence documenting the properties and behavior of these materials in vivo. This in vivo study investigated four biological scaffolds: two commercially available (a moderately crosslinked scaffold and a noncrosslinked scaffold) and two novel porcine diaphragm biological scaffolds (one with and one without the incorporation of gold nanoparticles). The scaffolds were implanted in a porcine model and evaluated over 1, 3, and 6 months. The moderately crosslinked scaffolds demonstrated the least cellular infiltration and evidence of fibrosis. The noncrosslinked scaffolds demonstrated the greatest cellular infiltration, but these scaffolds were delaminated and exhibited a rapid loss of integrity. The porcine diaphragm scaffolds with and without nanoparticles showed evidence of tissue remodeling and cellular infiltration, with no evidence of encapsulation. While there were no significant differences in the performance of the two novel scaffolds, the gold nanoparticle scaffold typically exhibited higher cellular infiltration. This study demonstrated the potential biocompatibility of a gold nanoparticle-tissue scaffold.

Conjugation of gold nanoparticles to polypropylene mesh for enhanced biocompatibility.

Polypropylene mesh materials have been utilized in hernia surgery for over 40 years. However, they are prone to degradation due to the body's aggressive foreign body reaction, which may cause pain or complications, forcing mesh removal from the patient. To mitigate these complications, gold nanomaterials were attached to polypropylene mesh in order to improve cellular response. Pristine samples of polypropylene mesh were exposed to hydrogen peroxide/cobalt chloride solutions to induce formation of surface carboxyl functional groups. Gold nanoparticles were covalently linked to the mesh. Scanning electron microscopy confirmed the presence of gold nanoparticles. Differential scanning calorimetry and mechanical testing confirmed that the polypropylene did not undergo any significantly detrimental changes in physicochemical properties. A WST-1 cell culture study showed an increase in cellularity on the gold nanoparticle-polypropylene mesh as compared to pristine mesh. This study showed that biocompatibility of polypropylene mesh may be improved via the conjugation of gold nanoparticles.

Left ventricular stroke volume in the fetal sheep is limited by extracardiac constraint and arterial pressure.

1. Extracardiac constraint and sensitivity to arterial pressure may be critical factors that limit the functional reserves of the developing fetal heart in utero. We hypothesise that extracardiac constraint is the predominant factor that limits fetal stroke volume (SV). To test this hypothesis we studied six chronically instrumented fetal sheep to determine the relative roles that extracardiac constraint and arterial pressure play in determining left ventricular (LV) function. 2. Pregnant ewes (128-131 days gestation, term = 147 days) were anaesthetised (5 mg kg(-1) Propofol I.V., then 1.5 % halothane, 50 % O(2), balance N(2)O by inhalation) and instrumented using sterile surgical techniques to record LV end-diastolic pressure (P(lved)), aortic pressure (P(ao)), pericardial pressure (P(per)), and LV SV. 3. After a minimum of 72 h recovery, LV function was assessed by altering fetal blood volume to vary P(lved). Ventricular function curves were generated using two measures of ventricular function, SV and stroke work index (SWI = SV x P(ao)), and two measures of ventricular filling, P(lved) and LV end-diastolic transmural pressure (P(lved,tm) = P(lved) - P(per)). 4. Although decreasing P(lved) from the resting level decreased SV, increasing P(lved) from the resting level did not increase SV because the ventricular function curve plateaued. This plateau was not explained solely by an increase in aortic pressure, as the plateau remained present in the SWI versus P(lved) curve. When extracardiac constraint was accounted for (SV against P(lved,tm)), the plateau was largely eliminated (approximately 80 %). The remaining portion of the plateau (approximately 20 %) was eliminated when both extracardiac constraint and arterial pressure were accounted for (SWI versus P(lved,tm)). 5. Thus, the major limitation upon LV function in the near-term fetus results from extracardiac constraint limiting ventricular filling while, at the same time, a much smaller limitation arises from increasing arterial pressure.

Nitric oxide inhibition abolishes sleep-wake differences in cerebral circulation.

Nitric oxide (NO), being produced by active neurones and also being a cerebral vasodilator, may couple brain activity and blood flow in sleep, particularly during active sleep (AS), which is characterized by widespread neural activation and markedly elevated cerebral blood flow (CBF) compared with quiet wakefulness (QW) and quiet sleep (QS). This study examined CBF and cerebral vascular resistance (CVR) in lambs (n = 6) during spontaneous sleep-wake cycles before and after infusion of N(omega)-nitro-L-arginine (L-NNA), an inhibitor of NO synthase. L-NNA infusion produced increases in CVR and decreases in CBF during all sleep-wake stages, with the greatest changes occurring in AS (DeltaCVR, 88 +/- 19%; DeltaCBF -24 +/- 8%). The characteristic CVR and CBF differences among AS, QS, and QW disappeared within 1-3 h of L-NNA infusion, but had reappeared by 24 h despite persisting cerebral vasoconstriction. These experiments show that NO promotes cerebral vasodilatation during sleep as well as wakefulness, particularly during AS. Additionally, NO is the major, although not sole, determinant of the CBF differences that exist between sleep-wake states.

Right atrial pressure as measure of ventricular constraint in newborn lambs.

Although the lungs and pericardium constrain the heart and limit cardiac output, no method exists to assess this constraint in sick newborns. We hypothesize that a useful estimate of ventricular constraint may be obtained by measuring right atrial pressure (P(RA)) in the newborn. To test this hypothesis, we measured P(RA), thoracic inferior vena caval pressure (P(IVC); saline-filled catheters), and ventricular constraint (pericardial pressure, P(PER); liquid-containing balloon) in 4-wk-old (neonatal, n = 12) and 3-day-old (newborn, n = 6) anesthetized lambs. The measurements were made while LV filling pressure was altered (0-20 mmHg) and while positive end-expiratory pressure (PEEP) was maintained at 2.5 or 15 cmH2O. In all of the lambs, a strong linear relationship (r) existed between P(RA) and P(PER) (P(RA) = 1.19 P(PER) + 0.0, r = 0.99) and between P(IVC) and P(PER) (P(IVC) = 1.24 P(PER) + 0.1, r = 0.99; PEEP of 2.5 cmH2O). Similar relationships were also observed with increased PEEP (P(RA) = 1.29 P(PER)-1.2, r = 0.98 and P(IVC) = 1.32 P(PER)-1.2, r = 0.97). Because P(RA) provides an accurate measure of ventricular constraint in the normal lamb, it may be a useful measure of ventricular constraint in the sick newborn.

Cost segregation of assets offers tax benefits.

A cost-segregation study is an asset-reclassification strategy that accelerates tax-depreciation deductions. By using this strategy, healthcare facility owners can lower their current income-tax liability and increase current cash flow. Simply put, certain real estate is reclassified from long-lived real property to shorter-lived personal property for depreciation purposes. Depreciation deductions for the personal property then can be greatly accelerated, thereby producing greater present-value tax savings. An analysis of costs can be conducted from either detailed construction records, when such records are available, or by using qualified appraisers, architects, or engineers to perform the allocation analysis.

Age-related differences in the distortion of the sheep lung in response to localised pleural stress.

In order for diastolic filling to occur, the heart must displace the lung. Given the changes in lung structure and compliance that follow birth, we sought to determine whether the neonatal lung resists neighbouring structures encroaching into its space more than the adult lung and whether the lung surface making up the cardiac fossa resists distortion more than the lateral surface does. Pleural distortions, induced by applied pressures (Pappl) of 20-120 g cm(-2) at airway pressures (Paw) of 2.5-15 cm H2O, were recorded in isolated lungs of adult, neonatal (4-week-old) and newborn (1-week-old) sheep. The depth of pleural distortion increased (P < 0.05, ANOVA) with increasing Pappl in all lungs. Adult lungs were significantly more distortable than newborn and neonatal lungs (P < 0.05). As Paw increased, the distortability of the adult lung decreased progressively (P < 0.05) while the distortability of the newborn and neonatal lung remained constant at Paw of 2.5 and 5 cm H2O. Adult lungs also differed from newborn and neonatal lungs in that the cardiac fossal surface was significantly less distortable than the lateral surface. As newborn and neonatal lungs are less easily distorted than adult lungs, the potential for the lungs to limit cardiac filling is greater in the newborn and neonate than in the adult.

Effects of positive intrathoracic pressure on pulmonary and systemic hemodynamics.

The Frank-Starling Law accounts for many changes in cardiac performance previously attributed to changes in contractility in that changes in contractility might have been incorrectly inferred from changing ventricular function curves (i.e. systolic performance plotted against filling pressure) if diastolic compliance also changed. To apply the Frank-Starling Law in the presence of changing diastolic compliance, it is necessary to measure end-diastolic volume directly or to calculate end-diastolic transmural pressure, which requires that pericardial pressure be known. Under most normal circumstances, increased intrathoracic pressure (and other interventions, such as vasodilators or lower-body negative pressure, that decrease central blood volume) decreases the transmural end-diastolic pressures of both ventricles, their end-diastolic volumes and stroke work. However, when ventricular interaction is significant, the effects of these interventions might be quite different; this may be important in patients with heart-failure. Although these interventions decrease RV transmural pressure, they may increase LV transmural pressure, end-diastolic volume, and thus stroke work by the Frank-Starling mechanism.

Interactions between the right ventricle and pulmonary vasculature in the fetus.

A midsystolic plateau differentiates the pattern of fetal pulmonary trunk blood flow from aortic flow. To determine whether this plateau arises from interactions between the left (LV) and right ventricle (RV) via the ductus arteriosus or from interactions between the RV and the lung vasculature, we measured blood flows and pressures in the pulmonary trunk and aorta of eight anesthetized (ketamine and alpha-chloralose) fetal lambs. Wave-intensity analysis revealed waves of energy traveling forward, away from the LV and the RV early in systole. During midsystole, a wave of energy traveling back toward the RV decreased blood flow velocity from the RV and produced the plateau in blood flow. Calculations revealed that this backward-traveling wave originated as a forward-traveling wave generated by the RV that was reflected from the lung vasculature back toward the heart and not as a forward-traveling wave generated by the LV that crossed the ductus arteriosus. Elimination of this backward-traveling wave and its associated effect on RV flow may be an important component of the increase in RV output that accompanies birth.

Repetitive hypoxia rapidly depresses cardio-respiratory responses during active sleep but not quiet sleep in the newborn lamb.

1. Arousal from sleep is an important protective response to hypoxia that becomes rapidly depressed in active sleep (AS) when hypoxia is repeated. This study questioned whether there might also be selective depression of cardio-respiratory responses to hypoxia during AS. 2. Nine newborn lambs (7-22 days of age) were studied over three successive nights. The first and third nights were baseline studies (inspired oxygen fraction, Fi,O2 = 0.21). During the second night, during every epoch of sleep, lambs were exposed to 60 s episodes of isocapnic hypoxia (Fi,O2 = 0.10). 3. During quiet sleep (QS), the probability of arousal in hypoxia exceeded the probability of spontaneous arousal (P < 0.001) throughout repeated exposures to hypoxia. Similarly, there were persisting increases in ventilation (135 +/- 25 %), blood pressure (3 +/- 1 %) and heart rate (3 +/- 1 %). 4. By contrast, rapid depression of all responses occurred during repetitive hypoxia in AS. Thus, the probability of arousal in hypoxia exceeded the probability of spontaneous arousal during the first 10 hypoxia exposures (P < 0.001) but not thereafter. Similarly, during the first 10 exposures to hypoxia, the changes in ventilation (88 +/- 15 %) and blood pressure (5 +/- 1 %) were greater than subsequent responses (P < 0.05). 5. We conclude that, when repeated, hypoxia rapidly becomes ineffective in stimulating protective arousal, ventilatory and blood pressure responses in AS, but not in QS. Selective depression of responses during AS may render the newborn particularly vulnerable to hypoxia in this state.

Ventricular constraint in the fetus and newborn.

Birth is accompanied by a series of rapid adaptations of the cardiovascular system, one of the most notable being a doubling of left ventricular (LV) stroke volume. What makes this increase in LV stroke volume remarkable is that before birth the heart functions at a maximal level that cannot easily be increased with acute interventions such as volume infusion. Although changes in heart rate, contractility and afterload contribute to the adaptations of birth they do not adequately explain the doubling of LV stroke volume. Early studies obscured the role that ventricular preload plays in controlling fetal and newborn cardiac function by focusing on these other mechanisms and by failing to appreciate fully the significance of ventricular constraint in limiting heart function. Recent evidence suggests that ventricular constraint, arising from the tissues that surround the heart (chest wall, lungs and pericardium), limits fetal ventricular preload and thus determines the limits of fetal cardiac function. Relief of this constraint at birth, with aeration of the lungs and clearance of the lung liquid associated with the fetal lungs, may be the key mechanism that increases LV preload and thus increases LV stroke volume in the newborn.

Repetitive hypoxia rapidly depresses arousal from active sleep in newborn lambs.

1. Arousal from sleep is an important protective mechanism that is depressed by repeated episodes of hypoxia. We aimed to determine how rapidly arousal depression occurs during repeated hypoxia and to determine if the depression is sleep state specific. 2. Three successive 12 h overnight sleep recordings were performed in six newborn lambs instrumented to record sleep state, blood pressure, heart rate and blood gases. The first (control) and third (recovery) nights were baseline studies (inspired oxygen fraction, FI,O2 = 0.21) to determine the spontaneous arousal probability. During the second (test) study night, lambs were exposed to a 60 s episode of isocapnic hypoxia (FI,O2 = 0.10; inspired carbon dioxide fraction, FI,CO2 = 0.03) during every epoch of sleep. 3. During quiet sleep (QS), the probability of arousing to hypoxia (56%) remained significantly higher than the probability of arousing spontaneously (18%) throughout the repeated hypoxic exposures (chi(2) = 81.5, P < 0.001). By contrast, during active sleep (AS) arousal rapidly became depressed with repetition of the hypoxic stimulus; the probability of arousal in hypoxia (52%) was significantly higher than the probability of spontaneous arousal (12%) during the first ten hypoxic exposures (chi(2) = 18.2, P < 0.001), but there was no difference thereafter. 4. We conclude that, when repeated, moderate hypoxia very rapidly becomes ineffective as an arousing stimulus in AS, but not in QS. These results suggest that the arousal mechanism is particularly vulnerable to failure during AS.