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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.
Introduction: Increasing opioid prescribing has been linked to an epidemic of opioid misuse. Our objective was to synthesize available evidence about patient-, prescriber-, medication-, and system-level risk factors for developing opioid misuse from prescribed opioids among patients presenting with pain unrelated to cancer. Our hypothesis was that we would identify risk factors predisposing patients to developing opioid misuse. Methods: We developed a systematic search strategy and applied it to nine electronic reference databases and six clinical trial registries. We hand searched related journals and conference proceedings, the reference lists of included studies, and the top 100 hits on Google. We included studies where a medical professional exposed adults or children to an opioid through a prescription. We excluded studies with over 50% cancer patients, palliative patients, and those with illicit opioid initiation. Two reviewers independently reviewed titles, abstracts, and full texts, and extracted data using standardized forms. We assessed study quality using risk of bias. We synthesized effect sizes of dichotomous risk factors on opioid misuse using inverse variance random-effects meta-analysis, and the inverse variance-weighted mean difference between opioid misusers and non-misusers for continuously measured factors. We conducted an a priori defined subgroup analysis among opioid-naïve patients. Results: Among 9,629 studies, 67 met our inclusion criteria. Among those who had been prescribed outpatient opioids, the following factors were associated with the development of misuse: a prior history of illicit drug use (OR: 4.21, 95% CI: 2.31-7.65), recent benzodiazepine use (OR: 2.57, 95% CI: 1.23-5.38), any mental health diagnosis (OR: 2.45, 95% CI: 1.91-3.15), any short acting (IR) opioid prescription (OR: 2.40, 95% CI: 1.15-5.02), younger age (OR: 2.19, 95%CI: 1.81-2.64), and male sex (OR: 1.23, 95% CI: 1.10-1.36). Among studies limiting their population to opioid-naïve patients, younger age was the most significant risk factor for opioid misuse (OR: 5.42, 95% CI:1.51-19.43). Conclusion: Of the risk factors examined, non-cancer pain patients with a prior history of substance use or mental health diagnoses were at highest risk for prescription opioid misuse. Younger opioid-naïve patients were at highest risk of misuse. Clinicians should consider these risk factors when managing acute pain in the emergency department.
Tissue engineering aims to grow artificial tissues in vitro to replace those in the body that have been damaged through age, trauma or disease. A recent approach to engineer artificial cartilage involves seeding cells within a scaffold consisting of an interconnected 3D-printed lattice of polymer fibres combined with a cast or printed hydrogel, and subjecting the construct (cell-seeded scaffold) to an applied load in a bioreactor. A key question is to understand how the applied load is distributed throughout the construct. To address this, we employ homogenisation theory to derive equations governing the effective macroscale material properties of a periodic, elastic–poroelastic composite. We treat the fibres as a linear elastic material and the hydrogel as a poroelastic material, and exploit the disparate length scales (small inter-fibre spacing compared with construct dimensions) to derive macroscale equations governing the response of the composite to an applied load. This homogenised description reflects the orthotropic nature of the composite. To validate the model, solutions from finite element simulations of the macroscale, homogenised equations are compared to experimental data describing the unconfined compression of the fibre-reinforced hydrogels. The model is used to derive the bulk mechanical properties of a cylindrical construct of the composite material for a range of fibre spacings and to determine the local mechanical environment experienced by cells embedded within the construct.
Karen A Waters, The Children's Hospital at Westmead and The University of Sydney, Camperdown, NSW, Australia,
Nicholas J Hunt, The University of Sydney, Camperdown, NSW, Australia,
Rita MacHaalani, The University of Sydney, Camperdown, NSW, Australia
Since deaths attributed to sudden infant death syndrome (SIDS) occur during sleep, failure to arouse in a stressful situation comprises one component in the proposed mechanism of death. While the infant was previously apparently healthy, the hypothesis underpinning neuropathological studies is that an underlying defect in the infant's brain has contributed to death. The defect in infants who do not arouse may be developmental, inherited, or secondary to previous non-fatal insults. The brainstem and hypothalamus are two regions housing nuclei with important roles in stress responses and arousal mechanisms. This chapter focuses on studies of the hypothalamus and how deficits in this region may contribute to SIDS.
The hypothalamus is a small but complex part of the brain with important roles in the homeostasis of energy balance, circadian rhythms, and stress responses, as well as growth and reproductive behaviors (1). As a regulatory center for so many functions, it receives input from, and transmits output to, a large number of other brain regions. Thus, as the hypothalamus controls many physiological functions, and is highly interconnected with other brain regions, it is an excellent candidate for abnormalities contributing to the pathogenesis of SIDS.
The hypothalamus was evaluated early in the 1990s in SIDS infants (2, 3). At that time, fewer neurotransmitters had been identified compared to today. But even without our current understanding (e.g. of the orexins which were discovered in 1998), the hypothalamus was of interest in SIDS because of its known role in the regulation of sleep. Findings at that time included increased tryptophan content and decreased serotonin, increased serotonin receptor binding, and increased monoamine oxidase-A (MOA) activity, with decreased choline acetyltransferase (ChAT) activity (2) (see Table 28.1).
Updating our knowledge of the hypothalamus and its potential role in SIDS is important, because our understanding of the hypothalamus is now more sophisticated with regards to its structure, functions, and development (1). In addition, a series of recent studies have made important advances in our understanding of abnormalities in the hypothalamus of SIDS infants.
Crib–biting is a stereotypic behaviour performed by approximately 5% of captive domestic horses. Dietary factors have been strongly associated with the development of oral stereotypies and risk factors for crib–biting, identified in recent epidemiological studies, include feeding high concentrate and/or low forage diets (Waters et al., 2002). Experimental work has shown that such diets are likely to result in increased gastric acidity (Murray and Eichorn, 1996; Nadeau et al., 2000). We therefore propose that young horses initiate crib–biting in an attempt to produce alkaline saliva to buffer their stomachs when alternative opportunities for mastication are limited. The aim of this study was to determine whether there was an association between crib–biting behaviour and stomach condition in foals.
Foals that had recently started to perform crib–biting were recruited into the study and compared with non–stereotypic foals. The stomachs of 15 crib-biting foals and 9 normal foals were examined using a video endoscope.
Auditory hallucinations (AH) are often considered a sign of a psychotic disorder. This is promoted by the DSM-5 category of Other Specified Schizophrenia Spectrum And Other Psychotic Disorder (OSSSOPD), the diagnostic criteria for which are fulfilled with the sole presence of persistent AH, in the absence of any other psychotic symptoms. And yet, persistent AH are not synonymous with having a psychotic disorder, and should therefore not be uncritically treated as such. Many people who seek treatment for persistent AH have no other psychotic symptoms, have preserved reality-testing capacities, and will never develop a schizophrenia spectrum disorder. Instead, hallucinations may be the result of many different causes, including borderline personality disorder, post-traumatic stress disorder (PTSD), hearing loss, sleep disorders or brain lesions, and they may even occur outside the context of any demonstrable pathology. In such cases, the usage of the DSM-5 diagnosis of OSSSOPD would be incorrect, and it may prompt unwarranted treatment with antipsychotic medication. We therefore argue that a DSM-5 diagnosis of Schizophrenia Spectrum Disorder (or any other type of psychotic disorder) characterized by AH should require at least one more symptom listed under the A-criterion (i.e. delusions, disorganized speech, disorganized or catatonic behavior or negative symptoms). Adhering to these more stringent criteria may help to distinguish between individuals with persistent AH which are part of a psychotic disorder, for whom antipsychotic medication may be helpful, and individuals with AH in the absence of such a disorder who may benefit from other approaches (e.g. different pharmacological interventions, improving coping style, trauma-related therapy).
Preliminary results of an extended multi-wavelength study of bright B- and Be-type stars are presented. This project aims at finding evidence for the existence of white-dwarf companions to Be stars which are predicted as the result of close binary evolution. Comparison of ROSAT all-sky survey data with simultaneous measurements of Hα profiles and infrared photometry suggests that there is no difference in the X-ray behaviour of Be stars with respect to that of normal B stars. The ROSAT X-ray luminosities of B and Be stars range from 10−8 to 10−5 times the bolometric luminosity.
The energy distribution of HR 2142 is studied in order to test the hypothesis that this star is an interacting binary with a cool Roche–lobe filling companion. We find that, for any reasonable choice of Teff, the companion should have been detected in the red part of the spectrum. We propose instead that the Be star is the outcome of a case B mass-transfer, which has pun it up. It is now surrounded by a mass-loss disc, rather than an accretion disc and is accompanied by either a helium star (resembling the Φ Per system) or by a white dwarf. If the binary was born spinning rapidly, alternatively the companion may be a solar-type, unevolved main sequence star. In case of a Helium star companion, there may be Helium lines visible (like in Φ Per), or the helium star may be detectable in the XUV, e.g. by the ROSAT XUV instrument. A white dwarf companion may be accreting material from the disc around the Be star and may show low luminosity X-ray emission. This emission may have been seen in the ROSAT PSPC X-Ray Survey.
Adolescents’ appearance-related concerns can provoke increasing emotional, social, and eating-related problems. The aims of this five-wave (2.5-year), multiple-informant longitudinal study were to (a) examine growth trajectories of appearance anxiety symptoms and appearance esteem, (b) identify whether trajectories differed by gender, and (c) examine several launching factors including parent-reported physical maturation, peer-rated physical appearance, body mass index, and appearance teasing by parents and peers. Participants were 387 adolescents (44% boys) aged 10 to 13 years at the first assessment. Steep growth in appearance anxiety symptoms was found for both girls and boys, but there was no average change in appearance esteem. Girls had more elevated appearance anxiety symptoms and lower appearance esteem than boys, girls’ body mass index was associated with symptoms, and earlier physical maturation and teasing about appearance, alone and in combination, were associated with growth in appearance anxiety symptoms for girls and boys. Earlier maturing boys who were highly teased by parents, but even more so when teased by peers, were at utmost risk for elevated appearance anxiety symptoms and increasing symptoms over time. In contrast, all girls exhibited elevated or increasing appearance anxiety symptoms across time, with the exception of girls with the latest maturation who also reported little teasing about their appearance.
The development of an economic capital model requires a decision to be made regarding how to aggregate capital requirements for the individual risk factors while taking into account the effects of diversification. Under the Individual Capital Adequacy Standards framework, UK life insurers have commonly adopted a correlation matrix approach due to its simplicity and ease in communication to the stakeholders involved, adjusting the result, where appropriate, to allow for non-linear interactions. The regulatory requirements of Solvency II have been one of the principal drivers leading to an increased use of more sophisticated aggregation techniques in economic capital models. This paper focusses on a simulation-based approach to the aggregation of capital requirements using copulas and proxy models. It describes the practical challenges in parameterising a copula including how allowance may be made for tail dependence. It also covers the challenges associated with fitting and validating a proxy model. In particular, the paper outlines how insurers could test, communicate and justify the choices made through the use of some examples.
Lower and middle income countries (LMICs) are home to >80% of the global population, but mental health researchers and LMIC investigator led publications are concentrated in 10% of LMICs. Increasing research and research outputs, such as in the form of peer reviewed publications, require increased capacity building (CB) opportunities in LMICs. The National Institute of Mental Health (NIMH) initiative, Collaborative Hubs for International Research on Mental Health reaches across five regional ‘hubs’ established in LMICs, to provide training and support for emerging researchers through hub-specific CB activities. This paper describes the range of CB activities, the process of monitoring, and the early outcomes of CB activities conducted by the five research hubs.
The indicators used to describe the nature, the monitoring, and the early outcomes of CB activities were developed collectively by the members of an inter-hub CB workgroup representing all five hubs. These indicators included but were not limited to courses, publications, and grants.
Results for all indicators demonstrate a wide range of feasible CB activities. The five hubs were successful in providing at least one and the majority several courses; 13 CB recipient-led articles were accepted for publication; and nine grant applications were successful.
The hubs were successful in providing CB recipients with a wide range of CB activities. The challenge remains to ensure ongoing CB of mental health researchers in LMICs, and in particular, to sustain the CB efforts of the five hubs after the termination of NIMH funding.
Ancient granite columns have been a pervasive element in the architecture of Rome since the Imperial era. However, in the fifteenth century, just as the effort to revive Antiquity intensified, these ubiquitous and durable ancient columns fell out of use. It was instead the stone travertine that became the columnar material of choice. Yet, just as quickly as this change occurred, within an exceptionally short period of thirty years, beginning with the construction of the Palazzo della Cancelleria courtyard, Rome saw a renascence in their application. While little has been made of this material shift, this article argues that the sudden extensive employment of spoliated granite columns was a crucial component in the recovery of a distinctly local Roman Antiquity. It was through the use and transformation of spolia that builders and patrons attempted to create an architecture that not only recalled Antiquity, but resubstantiated it, literally making it whole again.
The provision of prescribed vitamin D to all aged-care residents has been implemented in New Zealand as part of a government-led falls prevention programme. To our knowledge, there has been no evaluation of this universal programme on vitamin D status and functional and health outcomes. Thus, we aimed to determine 25-hydroxyvitamin D (25(OH)D) concentrations and their predictors in aged-care residents across the country and to investigate whether the government-funded programme was associated with adequate vitamin D status.
Cross-sectional survey of sociodemographic, biochemical, anthropometric, dietary and health characteristics. Blood samples were analysed for serum 25(OH)D and other biochemical measures. Multiple regression was used to examine predictors of vitamin D status.
Sixteen residential aged-care facilities throughout New Zealand.
Residents aged ≥60 years with residency duration >12 weeks (n 309).
Mean serum 25(OH)D was 89·9 (95 % CI 85·2, 94·5) nmol/l and monthly supplements (1250 µg (50 000 IU)) were taken by 75 % of all residents. Of those not taking a funded supplement, 65·3 % had serum 25(OH)D <50 nmol/l compared with only 1·5 % of supplement users. Being female, residing at lower latitude, increasing duration of aged-care residency and raised serum α1-acid glycoprotein were positively associated with higher 25(OH)D concentrations. Supplemental vitamin D from all sources was the strongest predictor, increasing serum 25(OH)D levels by more than 70 nmol/l. Furthermore, 25 % of participants had serum 25(OH)D levels >125 nmol/l.
Residents taking supplemental vitamin D had adequate vitamin D status; however monitoring of long-term supplementation should be considered, due to the high proportion of participants with high serum 25(OH)D levels.
We present a photomicrographic investigation of a sample of the Shroud of Turin, split from one used in the radiocarbon dating study of 1988 at Arizona. In contrast to other reports on less-documented material, we find no evidence to contradict the idea that the sample studied was taken from the main part of the shroud, as reported by Damon et al. (1989). We also find no evidence for either coatings or dyes, and only minor contaminants.
We report the discovery of carbonates in the Planetary Nebulae NGC 6302 and NGC 6537 (Kemper et al. 2002). In the ISO LWS spectra far-infrared features have been identified with calcite and dolomite by comparison with laboratory spectra of these minerals. This is the first time that carbonates have been identified outside the solar system. In a follow-up study (Kemper et al., in prep.) a detailed analysis of the mineral composition of the dust in NGC 6302 is presented.