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Introduction: Optimizing naloxone dosing in the context of increasing fentanyl and ultra-potent opioid (UPO) prevalence is an important consideration for emergency health care providers. The goal of this systematic review was to evaluate the association between initial and cumulative naloxone doses on effective reversal and adverse events in undifferentiated and fentanyl/UPO overdoses. Methods: We searched Embase, MEDLINE, Cochrane Central Register of Controlled Trials, DARE, CINAHL, Science Citation Index, reference lists, toxicology websites, and conference proceedings from July to October 2018 and back to 1972. Our search included pertinent indexing terms for UPOs. We included interventional and observational studies reporting on naloxone administration for opioid toxicity reversal in people ≥12 years old. Additionally, we accessed non-traditional evidence sources (case reports and series) given this rapidly changing field. We conducted inclusion screens, data extraction and quality assessments in duplicate. We summarized study characteristics and where reported, analyzed number of patients with clinical response. Response was defined as not receiving further naloxone doses and remaining alive. Results: We included 174 studies (108 case reports and series, 55 observational, 9 interventional) with 26,660 subjects (median age 35.1; 74.2% male). We observed lower response among patients exposed to fentanyl/UPO versus heroin for initial naloxone doses ≤0.4mg (56.8% versus 80.2%) and > 0.4mg (27.0% versus 82.1%). Mean cumulative doses were higher for fentanyl/UPO (2.10 mg, SD 1.80 mg) versus heroin (1.48 mg, SD 1.68 mg) overdoses. In North American studies the median cumulative dose used was higher for fentanyl/UPO versus heroin overdoses. A dose-response curve for fentanyl/UPO studies showed marked variability in doses among responders, indicating heterogeneity. Adverse events reporting was inconsistent; 10% of subjects experienced withdrawal based on studies in which they were reported. Conclusion: This is the first systematic review to summarize proportion of patients with clinical response by naloxone dose provided. While variable reporting, study quality, heterogeneity, and our outcome definitions limit the conclusions we can draw, it appears that higher initial doses and in some cases, higher cumulative naloxone doses were used and may be necessary to reverse toxicity due to fentanyl/UPO compared to other opioids. High-quality prospective studies assessing effectiveness and safety are needed.
Recent infection testing algorithms (RITA) for HIV combine serological assays with epidemiological data to determine likely recent infections, indicators of ongoing transmission. In 2016, we integrated RITA into national HIV surveillance in Ireland to better inform HIV prevention interventions. We determined the avidity index (AI) of new HIV diagnoses and linked the results with data captured in the national infectious disease reporting system. RITA classified a diagnosis as recent based on an AI < 1.5, unless epidemiological criteria (CD4 count <200 cells/mm3; viral load <400 copies/ml; the presence of AIDS-defining illness; prior antiretroviral therapy use) indicated a potential false-recent result. Of 508 diagnoses in 2016, we linked 448 (88.1%) to an avidity test result. RITA classified 12.5% of diagnoses as recent, with the highest proportion (26.3%) amongst people who inject drugs. On multivariable logistic regression recent infection was more likely with a concurrent sexually transmitted infection (aOR 2.59; 95% CI 1.04–6.45). Data were incomplete for at least one RITA criterion in 48% of cases. The study demonstrated the feasibility of integrating RITA into routine surveillance and showed some ongoing HIV transmission. To improve the interpretation of RITA, further efforts are required to improve completeness of the required epidemiological data.
Supportive social relationships can reduce both psychological and physiological responses to stressful experiences. Recently, studies have also assessed the potential for social relationships to buffer the intergenerational transmission of stress. The majority of these studies, however, have focussed on social learning as a mechanism responsible for the intergenerational transmission of stress. Evidence of biological mechanisms is lacking. The objective of the current study was, therefore, to determine whether the association between maternal adverse childhood experiences (ACEs) and infant hypothalamic–pituitary–adrenal (HPA) axis function is mediated by maternal HPA axis function during pregnancy and moderated by social support. Data were from 243 mother–infant dyads enrolled in a prospective longitudinal cohort (the Alberta Pregnancy Outcomes and Nutrition Study). Maternal history of ACEs was retrospectively assessed while maternal perceived social support and salivary cortisol were assessed prospectively at 6–22 weeks gestation (Time 1) and 27–37 weeks gestation (Time 2), and infant cortisol reactivity to a laboratory stressor and maternal perceived social support were assessed at 5–10 months postnatal (Time 3). Results revealed that maternal HPA axis function during pregnancy mediated the effects of maternal ACEs on infant HPA axis reactivity, suggesting that the maternal HPA axis is a mechanism by which maternal early life stress is transmitted to offspring. Furthermore, social support in the prenatal and postnatal periods moderated the cascade from maternal ACEs to infant HPA axis reactivity. Specifically, prenatal social support moderated the association between ACEs and maternal HPA axis function during pregnancy, and postnatal social support moderated the association between maternal HPA axis function and infant cortisol reactivity. These findings highlight the social sensitivity of the HPA axis and suggest the utility of social relationships as an intervention target to reduce the effects of maternal early life stress on infant outcomes.
Prenatal exposure to maternal mood disturbances shapes children's cognitive development reflected in the critical construct of executive functions (EFs). Little is known, however, about underlying mechanisms. By examining cortisol responses in both everyday and lab challenge settings, we tested whether the child/offspring hypothalamic–pituitary–adrenal axis mediates effects of prenatal maternal mood on child EFs at age 6. In 107 Canadian children born to women with a wide range of anxious and depressive symptoms during pregnancy, we found that in boys but not girls, depressed and/or anxious prenatal maternal mood is associated with heightened diurnal cortisol levels in everyday settings, as well as heightened cortisol reactivity to a lab challenge and that this heightened reactivity was associated with poorer EFs. Among boys we also observed that cortisol reactivity but not diurnal cortisol mediated the association between depressed and/or anxious prenatal maternal mood and EFs. Depressed and/or anxious prenatal maternal mood was related to child EFs for both girls and boys. To our knowledge, this is the first study to demonstrate a mediating role for child stress regulation in the association between prenatal maternal stress-related mood disturbances and child EFs, providing evidence of a mechanism contributing to fetal programming of cognition.
Currently policies enabling cattle herds to regain Official Tuberculosis Free (OTF) status after a bovine tuberculosis (bTB) herd incident vary between individual parts of the British Isles from requiring only one negative single comparative intradermal tuberculin test (SCITT) herd test when bTB infection is not confirmed to needing two consecutively negative SCITT herd tests after disclosure of two or more reactors, irrespective of bTB confirmation. This study used Kaplan–Meier curves and univariable and multivariable Cox Proportional Hazard models to evaluate the effect of the number of SCITT reactors and bTB confirmation on the risk of future bTB herd incident utilising data extracted from the national animal health database in Northern Ireland. Based on multivariable analyses the risk of a future bTB herd incident was positively associated with the number of SCITT reactors identified during the incident period (hazard ratio = 1.861 in incidents >5 SCITT reactors compared to incidents with only one SCITT reactor; P < 0.001), but not with bTB confirmation. These findings suggest that the probability of residual bTB infection in a herd increases with an increasing number of SCITT reactors disclosed during a bTB herd incident. It was concluded that bTB herd incidents with multiple SCITT reactors should be subjected to stricter control measures irrespective of bTB infection confirmation status.
Background: Acromegaly is associated with significant morbidity. The purpose of this study was to establish characteristics and outcomes of patients treated for acromegaly at The Ottawa Hospital, to compare our results with published reports from other centers and to identify opportunities to improve patient care. Methods: A retrospective chart review of patients surgically and medically treated for acromegaly between January 1, 2007 and December 31, 2016 was completed. Demographic information, biochemical data, presenting features, disease comorbidities, treatment interventions, and were collected. Results: Fifty-one patients were identified using CCI/ICD-10 codes and IGF-1 levels. Similar to other centers, the majority of patients had a macroadenoma (78.4% vs 11.8%) with a high percentage invading the cavernous sinus (57.5%). While surgical intervention was performed in 90% of patients, only 23.3% of patient achieved surgical cure (IGF-1 normalization within reference range). Approximately 30% of patients were controlled with adjuvant medical therapy while more than 40 % had elevated IGF-1 levels at last follow-up. Radiotherapy was less commonly used. Conclusions: Despite a multi-modal treatment approach for acromegaly, outcomes are variable. This study highlights the need for further research to better understand factors associated with surgical cure, response to medical therapy and the role of radiotherapy.
OBJECTIVES/SPECIFIC AIMS: Discrimination within the healthcare system and physician distrust have been associated with adverse clinical outcomes for people living with HIV; however, many studies do not link these variables to biological data. We hypothesize that perceived healthcare discrimination and physician distrust associates with higher longitudinal viremia among HIV-positive women. METHODS/STUDY POPULATION: A 2006 cross-sectional survey assessed healthcare-based discrimination and physician trust in 92 HIV-positive and 46 high-risk HIV-negative women from the Washington DC Women’s Interagency HIV Study (DC-WIHS). In addition, we identified HIV viral load trajectories and demographics from the HIV-positive women who contributed≥4 semi-annual visits from 1994 to 2015. Viral suppression was defined by assay detection limits (<80 to <20 copies/mL). Group-based probability trajectory analyses grouped women based on longitudinal viral load patterns, and identified 3 groups: sustained viremia (n=32) with low-viral suppression over time, intermittent viremia (n=27) with varying suppression over time, and non-viremia (n=33) with high-longitudinal viral suppression. Ordinal logistic regression models assessed trajectory group and discrimination variables, controlling for demographics, using stepwise selection with significance level of α=0.05. RESULTS/ANTICIPATED RESULTS: Most women were African American (60%), insured at the time of visit (89%) and nonsmokers (56%). While physician trust did not differ by HIV viral trajectory group, trust was lower among HIV-negative women compared with HIV-positive women (p=0.03). Over 1 in 5 HIV-positive women reported discrimination in the healthcare system based on HIV status (21.3%). Report of discrimination based on drug/alcohol use was higher among HIV-negative participants (19.2% vs. 6.5%, p=0.01). Among women with longitudinal sustained viremia, report of discrimination based on race ethnicity (29%, p=0.004) and sexual orientation (15.6%, p=0.008) were higher than within the nonviremic and intermittent trajectory groups. DISCUSSION/SIGNIFICANCE OF IMPACT: Physician trust did not associate with increased longitudinal viral suppression among HIV-positive women in Washington, DC. Lack of physician trust among high-risk HIV-negative women could have implications for uptake of prevention methods. Reports of discrimination vary between HIV-positive and HIV-negative women in the Washington, DC area. The findings of healthcare system distrust among HIV-negative women has implications outside the realm of HIV, as this lack of trust may impact risk for other disease states among similar populations of women.
Determination of the proportion of bovine tuberculosis (bTB) breakdowns attributed to a herd purchasing infected animals has not been previously quantified using data from the Animal and Public Health Information System (APHIS) database in Northern Ireland. We used a case–control study design to account for the infection process occurring in the disclosing bTB breakdown herds. Cases (N = 6926) were cattle moving to a future confirmed bTB breakdown where they would disclose as a confirmed bTB reactor or a Lesion at Routine Slaughter (LRS). Controls (N = 303 499) were cattle moving to a future confirmed bTB breakdown where they did not become a bTB reactor or LRS. Our study showed that the cattle leaving herds which disclosed bTB within 450 days had an increased odds of becoming a confirmed bTB reactor or LRS compared with the cattle which left herds that remained free for 450 days (odds ratio (OR) = 2·09: 95% CI 1·96–2·22). Of the 12 060 confirmed bTB breakdowns included in our study (2007–2015 inclusive), 31% (95% CI 29·8–31·5) contained a confirmed bTB reactor(s) or LRS(s) at the disclosing test which entered the herd within the previous 450 days. After controlling for the infection process occurring in the disclosing bTB breakdown herd, our study showed that 6·4% (95% CI 5·9–6·8) of bTB breakdowns in Northern Ireland were directly attributable to the movement of infected animals.
The aim of this study was to ascertain farmers’ knowledge of the risk of spread of infection from animals to humans, and their transmission prevention practices. This was a survey of farmers who submitted material to Ireland's Regional Veterinary Laboratories in 2015. There was an 84% response rate (1044 farmers). Ninety per cent of farmers were not aware that infection can be acquired from apparently healthy animals. Over half were not aware that disease could be contracted from sick poultry or pets. Conversely, the knowledge of the risk to pregnant women of infection from birthing animals was high (88%). Four-fifths of farmers sourced drinking water from a private well, and of these, 62% tested their water less frequently than once a year. Of dairy farmers, 39% drank unpasteurised milk once a week or more frequently. Veterinarians were the most commonly cited information source for diseases on farms. The survey findings indicate that the level of farmers’ knowledge and awareness of the spread of infection from animals to humans is a concern. Further education of the farming community is needed to increase awareness of both the potential biohazards present on farms and the practical measures that can be taken to mitigate the risk of zoonoses.
We present Chandra X-ray grating spectroscopy of the B0.2V star, θ Carina. θ Car is in a critical transition region between the latest O-type and earliest B-type stars, where some stars are observed to have UV-determined wind densities much lower than theoretically expected (e.g., Marcolino et al. 2009). In general, X-ray emission in this low-density wind regime should be less prominent than for O-stars (e.g., Martins et al. 2005), but observations suggest a higher than expected X-ray emission filling factor (Lucy 2012; Huenemoerder et al. 2012); if a larger fraction of the wind is shock-heated, it could explain the weak UV wind signature seen in weak wind stars, but this might severely challenge predictions of radiatively-driven wind theory.
We measured the line widths of several He-, H-like and Fe ions and the f/i ratio of He-like ions in the X-ray spectrum, which improves upon the results from Nazé et al. (2008) (XMM-Newton RGS) with additional measurements (Chandra HETG) of Mgxi and Sixiii by further constraining the X-ray emission location. The f/i ratio is modified by the proximity to the UV-emitting stellar photosphere, and is therefore a diagnostic of the radial location of the X-ray emitting plasma. The measured widths of X-ray lines are narrow, <300 km s−1 and the f/i ratios place the X-rays relatively close to the surface, both implying θ Car is a weak wind star. The measured widths are also consistent with other later-type stars in the weak wind regime, β Cru (Cohen et al. 2008), for example, and are smaller on average than earlier weak wind stars such as μ Col (Huenemoerder et al. 2012). This could point to a spectral type divide, where one hypothesis, low density, works for early-B type stars and the other hypothesis, a larger fraction of shock-heated gas, explains weak winds in late-O type stars. Archival IUE data still needs to be analyzed to determine the mass loss rate and hydrodynamical simulations will be compared with observations to determine which hypothesis works for θ Car.
As presented in terms of Newton's laws of motion, our notion of (dynamic) equilibrium is that “the sum of the forces is equal to mass times acceleration” applied to a free-body diagram. This does not generalize well to large, complex systems (with many DoFs), particularly if they are nonlinear. The concepts of virtual work and virtual energy allow us to present a formulation for the equilibrium of discrete systems that does not entail the use of summing forces on free-body diagrams. This formulation, usually referred to as analytical mechanics, generalizes very nicely for the many-body systems we wish to explore. It is quite versatile because it is applicable to nonlinear, nonconservative, and dynamic problems alike and is very suitable for numerical implementation. Furthermore, our complex systems, by necessity, involve approximations in the structural modeling, and our formulation is quite compatible with this necessity.
We first develop the principle of virtual work and then, through D'Alembert's principle, apply it to dynamic systems. The resulting governing equations are general enough to handle nonlinear systems. The different types of nonlinear contributions are then clarified. The work and energy ideas of this chapter are covered extensively in references 52, 54 and 90, and the style of presentation follows reference 30.
Principle of Virtual Work
Our idea of a structure is an object with multiple parts. We use the multimember structure of Figure 2.1 to illustrate some of the basic concepts in structural mechanics.
A plate is an extended body where one of the dimensions is substantially smaller than the other two. The plates in three-dimensional (3D) thin-walled structures (called shells and folded-plate structures) can support both in-plane and out-of-plane loading. Furthermore, because the plates are thin, they lend themselves to approximation – while the structure may be three-dimensional, the local behavior is two-dimensional under plane stress. Plates in flexure are the two-dimensional equivalent of beams, and classical plate theory is the equivalent of the Bernoulli-Euler beam theory, whereas the in-plane or membrane behavior of plates is analogous to that of rods. We consider both of these separately.
We first develop the strong formulation for plates and present their spectral forms. It turns out, however, that very few strong-form solutions are available for arbitrary BCs, but there is one class with periodic BCs where very useful results can be obtained. We concentrate on these.
Flexural Behavior of Flat Plates
We develop a thin-plate model (called classical plate theory) that does not take the transverse shear deformation into account – this is therefore the plate counterpart of the Bernoulli-Euler beam. We could develop a model (called the Mindlin plate theory) that takes the shear deformation into account; however, it is worth keeping in mind that if shear effects in the plate might be important, then the plate should be modeled using the 3D solid Hex20 element.
We investigated the dynamic equilibrium of various structural systems in the previous chapters. Now we consider a very important property of systems in equilibrium, namely, their stability. Our intuitive notion of stability is that small perturbations of a system (which are always present in real situations) only cause the system to have small motions about its (dynamic) equilibrium configuration. If the small perturbations cause motions that are excessive, we talk of an instability of the motion. Some situations where the stability of the motion arises are aeroelastic flutter, whirling of shafts, rotating saw blades and computer disks, belt drives, galloping of power lines, and control of structures.
Underlying this is the idea of a dynamic equilibrium position; although the system is in motion, it is stable in the sense that any disturbance eventually dies down, and the system returns to that dynamic state. This is a concept we make clear at the beginning.
In truth, instability is a nonlinear dynamic phenomenon because we are talking of structural behavior changing – the system is in one state and then moves to another. This new state could be near or far (in the phase-plane sense), and that informs the nature of the instability. Thus we also need to make clear the difference between the initiator of the instability and where the system goes.
Some Preliminary Stability Ideas
Central to the idea of instability is the concept of an unfolding parameter.
Our solution method of choice is to discretize all problems and solve the resulting simultaneous equations numerically. Sometimes deeper insights into a problem can be obtained by solving the continuous problem directly. This is not always feasible, does not generalize very well, and typically is restricted to linearized systems, but when it can be accomplished, the results can be very rewarding. This chapter therefore develops this aspect of dynamic analysis.
The first task is to derive adequate dynamic models to describe continuous systems; we use Hamilton's principle in conjunction with the Ritz method to derive these models in a consistent rational way. Section 3.1 developed the energies for a number of structural components. Hamilton's principal is used to convert these energy representations into a set of governing differential equations plus the associated boundary conditions. This is called the strong formulation of problems.
The derived models are in the form of a system of partial differential equations. Partial differential equations are notoriously difficult to solve in general; we introduce spectral analysis as a powerful tool for simplifying and solving problems arising in the analysis of continuous systems. In essence, dynamic problems are reduced to a series of pseudostatic problems, and thus they are amenable to the solution procedures that are standard for static problems.
Strong Formulation of Problems
The strong formulation of a problem comprises the set of governing equations plus the appropriate geometric and natural boundary conditions.
Real structures, of course, are not just a collection of springs and concentrated masses as modeled in the two preceding chapters; they are assembled systems comprising members such as panels and beams that have continuously distributed properties of mass and elasticity. Our analytical mechanics formulation is now extended to include these systems by replacing them with a discretized representation. The process of replacing a continuous body with a discrete representation is inherently approximate, but the principle of virtual work in conjunction with the Ritz method allows us to do this in a rational way. Furthermore, the approach adopted has the built-in capability to achieve any desirable level of accuracy. The ultimate computer implementation of the approach is in the form of the finite-element (FE) method.
The finite-element method is covered extensively in references such as 5, 18, 22, 30, 96, and 99 so only the aspects most relevant to the dynamics of structures are covered here. The principal structural types covered are frames and solids; structures such as plates and shells are rendered as special cases of three dimensional (3D) solids. The frame is modeled as having the separate actions of axial extension, bending, and torsion, and a FE model is developed for each of these. The dynamics of a general solid is modeled with the very versatile Hex20 element.
Our method of choice for solving general problems is the finite-element (FE) method. The drawback of the method is that it does not directly give insights into the phenomena being studied. To help overcome this, Part II introduces additional analysis methods. The choice of analysis depends on the type of problem being considered; therefore, this chapter is an attempt to classify the problem types encountered in structural dynamics so as to set the context for the types of analyses introduced. We find it most useful to use the loading (both its variation in time and its variation in space over time) as the main discriminator between the different problem types and introduce appropriate analysis methods accordingly. In broad terms, we distinguish between low-frequency loads that cause large deformations and higher-frequency loads that cause nonlinear responses but no significant change of geometry. This facilitate using the linearized versions of problems as a scheme to classify them.
We begin by surveying an array of problems based on the types of loading. What they have in common is that there are interactions between one or more bodies. How these interactions are modeled, to a large extent, dictates the type of problem that results. This is followed by an analysis of conservative loads, and it is shown how these can be treated as part of the system.