Performance evaluation of a PET insert for preclinical MRI in stand-alone PET and simultaneous PET-MRI modes.

BACKGROUND: This study aimed to evaluate the performance of a preclinical PET insert in three configurations: as a stand-alone unit outside the MRI bore, inside the bore of a cryogen-free 3T MRI and, finally, while performing simultaneous PET/MRI studies. METHODS: The PET insert consists of two rings of six detectors, each detector comprising 8 × 12 SiPMs reading out dual offset layers of pixelated LYSO crystals with a 1.4-mm pitch. The inner diameter is 60 mm, transaxial field of view (FoV) 40 mm and axial FoV 98 mm. Evaluation was based on NEMA NU 4-2008 guidelines with appropriate modifications. Spatial resolution and sensitivity were measured inside and outside the MR bore. Image quality, count rate and quantitative performance were measured in all three configurations. The effect of temperature stability on PET sensitivity during fast spin echo sequences was also evaluated. B0 field homogeneity and T1 and T2 relaxation times were measured using a water-filled phantom, with and without simultaneous PET operation. Finally, PET and MRI scans of a mouse injected with 10 MBq [18F]NaF and a mouse injected with 16 MBq [18F]FDG were performed in sequential and simultaneous modes. RESULTS: Peak absolute sensitivity was 10.15% with an energy window of 250-750 keV. Absolute sensitivity values outside and inside the MR bore with MR idle agreed to within 0.1%. Outside the MR bore, spatial resolution was 1.21/1.59 mm FWHM (radial/tangential) 5 mm from the centre of the FoV which compared well with 1.19/1.26 mm FWHM inside the MR bore. There were no substantial differences between all three scan configurations in terms of peak NEC rate (175 kcps at 17 MBq), scatter or random fractions. Uniformity and recovery coefficients were also consistent between scanning modes. B0 field homogeneity and T1 and T2 relaxation times were unaltered by the presence of the PET insert. No significant differences were observed between sequential and simultaneous scans of the animals. CONCLUSIONS: We conclude that the performance of the PET insert and MRI system is not significantly affected by the scanning mode.

Optimising the process for conducting scoping reviews.

Knowledge synthesis constitutes a key part of evidence-based medicine and a scoping review is a type of knowledge synthesis that maps the breadth of literature on a topic. Conducting a scoping review is resource intensive and, as a result, it can be challenging to maintain best practices throughout the process. Much of the current guidance describes a scoping review framework or broad ways to conduct a scoping review. However, little detailed guidance exists on how to complete each stage to optimise the process. We present five recommendations based on our experience when conducting a particularly challenging scoping review: (1) engage the expertise of a librarian throughout the process, (2) conduct a truly systematic search, (3) facilitate communication and collaboration, (4) explore new tools or repurpose old ones, and (5) test every stage of the process. These recommendations add to the literature by providing specific and detailed advice on each stage of a scoping review. Our intent is for these recommendations to aid other teams that are undertaking knowledge synthesis projects.

Astrocytic TSPO Upregulation Appears Before Microglial TSPO in Alzheimer's Disease.

BACKGROUND: In vivo PET/SPECT imaging of neuroinflammation is primarily based on the estimation of the 18 kDa-translocator-protein (TSPO). However, TSPO is expressed by different cell types which complicates the interpretation. OBJECTIVE: The present study evaluates the cellular origin of TSPO alterations in Alzheimer's disease (AD). METHODS: The TSPO cell origin was evaluated by combining radioactive imaging approaches using the TSPO radiotracer [125I]CLINDE and fluorescence-activated cell sorting, in a rat model of AD (TgF344-AD) and in AD subjects. RESULTS: In the hippocampus of TgF344-AD rats, TSPO overexpression not only concerns glial cells but the increase is visible at 12 and 24 months in astrocytes and only at 24 months in microglia. In the temporal cortex of AD subjects, TSPO upregulation involved only glial cells. However, the mechanism of this upregulation appears different with an increase in the number of TSPO binding sites per cell without cell proliferation in the rat, and a microglial cell population expansion with a constant number of binding sites per cell in human AD. CONCLUSION: These data indicate an earlier astrocyte intervention than microglia and that TSPO in AD probably is an exclusive marker of glial activity without interference from other TSPO-expressing cells. This observation indicates that the interpretation of TSPO imaging depends on the stage of the pathology, and highlights the particular role of astrocytes.

Fluorescence-activated cell sorting to reveal the cell origin of radioligand binding.

Many studies have explored the role of TSPO (18 kDa translocator protein) as a marker of neuroinflammation using single-photon emission computed tomography (SPECT) or positron emission tomography (PET). In vivo imaging does not allow to determine the cells in which TSPO is altered. We propose a methodology based on fluorescence-activated cell sorting to sort different cell types of radioligand-treated tissues. We compared left/right hippocampus of rats in response to a unilateral injection of lipopolysaccharide (LPS), ciliary neurotrophic factor (CNTF) or saline. We finally applied this methodology in human samples (Alzheimer's disease patients and controls). Our data show that the pattern of TSPO overexpression differs across animal models of acute neuroinflammation. LPS induces a microglial expansion and an increase in microglial TSPO binding. CNTF is associated with an increase in TSPO binding in microglia and astrocytes in association with an increase in the number of microglial binding sites per cell. In humans, we show that the increase in CLINDE binding in Alzheimer's disease concerns microglia and astrocytes in the presence of a microglial expansion. Thus, the cellular basis of TSPO overexpression is condition dependent, and alterations in TSPO binding found in PET/SPECT imaging studies cannot be attributed to particular cell types indiscriminately.

Retrospective Review of the Use of Transdermal Buprenorphine Patches (Butrans) in a Pediatric Population.

Background: Buprenorphine is an opioid medication used for the treatment of moderate to severe pain. In Canada, buprenorphine is not indicated for use in the pediatric population and literature surrounding its use in pediatrics is limited. Our aim was to evaluate the safety of transdermal buprenorphine in a pediatric palliative care setting. Methods: Our study was performed at the IWK Health Centre. Medical records of 11 patients were examined for specific clinical characteristics. The study focused primarily on descriptive results; standard data analyses were not performed. Results: Buprenorphine was found to be well tolerated in our patient population. There were no adverse effects reported in 8 of 11 patients during their treatment with buprenorphine. The remaining 3 patients described mild adverse effects in the form of skin irritation which resolved with topical steroid treatment. Efficacy was reported as anecdotal quotes from patient records. Conclusion: In this study, the use of buprenorphine in this setting was safe in a small group of patients, with the only mild adverse effect noted being a contact dermatitis in 3 patients which resolved quickly. Other studies have also demonstrated buprenorphine to be a safe and an effective opioid for the treatment of severe pain at the end of life in a pediatric population. Given these results, the implementation of buprenorphine in pediatrics may be safe for use in patients who are unable to tolerate traditional opioid analgesic therapies.

Scoping review of symptoms in children with rare, progressive, life-threatening disorders.

BACKGROUND: Q3 conditions are progressive, metabolic, neurological or chromosomal childhood conditions without a cure. Children with these conditions face an unknown lifespan as well as unstable and uncomfortable symptoms. Clinicians and other healthcare professionals are challenged by a lack of evidence for symptom management for these conditions. AIMS: In this scoping review, we systematically identified and mapped the existing literature on symptom management for children with Q3 conditions. We focused on the most common and distressing symptoms, namely alertness, behavioural problems, bowel incontinence, breathing difficulties, constipation, feeding difficulties, sleep disturbance, temperature regulation, tone and motor problems and urinary incontinence. For children with complex health conditions, good symptom management is pertinent to ensure the highest possible quality of life. METHODS: Scoping review. Electronic database searches in Ovid MEDLINE, Embase and CINAHL and a comprehensive grey literature search. RESULTS: We included 292 studies in our final synthesis. The most commonly reported conditions in the studies were Rett syndrome (n=69), followed by Cornelia de Lange syndrome (n=25) and tuberous sclerosis (n=16). Tone and motor problems were the most commonly investigated symptom (n=141), followed by behavioural problems (n=82) and sleep disturbance (n=62). CONCLUSION: The evidence for symptom management in Q3 conditions is concentrated around a few conditions, and these studies may not be applicable to other conditions. The evidence is dispersed in the literature and difficult to access, which further challenges healthcare providers. More research needs to be done in these conditions to provide high-quality evidence for the care of these children.

Breaking Down Silos: Consensus-Based Recommendations for Improved Content, Structure, and Accessibility of Advance Directives in Emergency and Out-of-Hospital Settings.

Background: Patients receiving palliative care often interact with a variety of health care providers across various settings. While patients may experience good care from these services, the connection between these can be disjointed as care providers may work siloed from each other. This is particularly true in out-of-hospital and hospital emergency settings, where providers have no prior knowledge of the patient, particularly their advanced directives (ADs) and goals of care. In the Emergency Department or when paramedics respond to the home, ADs are further challenged by issues of clarity of content, contextual relevance, and accessibility. Objectives: (1) What content should be in AD for medical emergencies, and (2) what would ensure the AD is accessible in times of crisis? Design: Phase 1 involved a review of existing AD and published literature to generate a list of candidate elements. Phase 2 presented these in an online survey using modified Delphi method to paramedics, emergency nurses, and physicians. During phase 3, a focus group with palliative and emergency care providers and information technology experts was held regarding current accessibility of AD and a vision for improvement. The detailed focus group notes were coded using inductive analysis. Results: Fifty-five candidate elements were provided for the Delphi. After three rounds, 36 panelists achieved consensus on 46 elements. Participation was greater than 80% in all rounds. From the focus group on access, six themes emerged; (1) imprecise language, (2) mismatch of protocols, (3) lack of understanding by patients/families, (4) lack of AD, (5) difficulty accessing AD, and (6) opportunities: database, education. Conclusion: This project makes recommendations to improve palliative care in emergency or crisis situations and facilitate care consistent with patient's goals: (1) a consensus-based template for AD content; and (2) development of a centralized database. These findings served as the foundation for the "Paramedics Providing Palliative Care at Home" program.

A Scoping Review of Transdermal Buprenorphine Use for Non-surgical Pain in the Pediatric Population.

 A preliminary evaluation to review the scope and quality of evidence surrounding transdermal buprenorphine use in the pediatric setting for non-surgical pain was conducted. Our review revealed limited data available on the use of transdermal buprenorphine in pediatric patients. Most studies surrounding this subject involve accidental ingestion of buprenorphine and its use in the treatment of neonatal abstinence syndrome. While indicated for use only in adult populations, small studies have shown encouraging results in reducing pain in children with few, if any, adverse effects. This is reassuring from a clinical perspective, as we hope to highlight the available evidence and invite researchers to expand future studies. Through this review, we have identified significant gaps in the literature surrounding the safety and use of buprenorphine in the pediatric population. To our knowledge, there are no major studies investigating this subject, and it is our hope that future studies will explore the use of transdermal buprenorphine as an alternative pain management technique in pediatrics. The intent of our scoping review is to highlight the lack of research in this area; therefore, future studies may be conducted to support its use in North America.

Pharmacological interventions for chronic pain in children: an overview of systematic reviews.

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.

Monte Carlo investigation of the characteristics of radioactive beams for heavy ion therapy.

This work presents a simulation study evaluating relative biological effectiveness at 10% survival fraction (RBE10) of several different positron-emitting radionuclides in heavy ion treatment systems, and comparing these to the RBE10s of their non-radioactive counterparts. RBE10 is evaluated as a function of depth for three positron-emitting radioactive ion beams (10C, 11C and 15O) and two stable ion beams (12C and 16O) using the modified microdosimetric kinetic model (MKM) in a heterogeneous skull phantom subject to a rectangular 50 mm × 50 mm × 60 mm spread out Bragg peak. We demonstrate that the RBE10 of the positron-emitting radioactive beams is almost identical to the corresponding stable isotopes. The potential improvement in PET quality assurance image quality which is obtained when using radioactive beams is evaluated by comparing the signal to background ratios of positron annihilations at different intra- and post-irradiation time points. Finally, the incidental dose to the patient resulting from the use of radioactive beams is also quantified and shown to be negligible.

Development and Implementation of a Survey to Assess Health-Care Provider's Competency, Attitudes, and Knowledge About Perinatal Palliative Care.

Perinatal palliative care is an emerging area of health care. To date, no published tools assess health-care provider's knowledge and level of comfort in providing such care. A 2-phase study was undertaken to develop and implement a survey to evaluate the self-assessed competency, attitudes, and knowledge of health-care providers working in perinatal palliative care. Phase 1 included a review of the literature and appraisal of palliative and death-related instruments to inform the initial draft of the Perinatal Palliative Care Survey (PPCS). Twenty-four Canadian pediatric palliative care specialists critiqued the PPCS, establishing its face and content validity. Phase 2 involved administering the PPCS at 4 sites across Canada, resulting in 167 responses from nurses, physicians, and midwives. The majority of participants responded that they possessed a degree of comfort in providing perinatal palliative care, particularly with assessing pain (76%), managing pain (69%), assessing other symptoms (85%), and managing other symptoms (78%). Two areas where participants level of confidence or extreme confidence was diminished included having conversations with families about the possibility of their infant dying (55%) and knowing and accessing community palliative care resources (32%). Responses in the knowledge section identified gaps related to opioid use, pharmacological interventions for breathlessness, pain behaviors, and tolerance developed to opioids and sedatives. Eighty-six percent of respondents stated that if education about palliative care was made available, they would participate with priority topics identified as communication with families (75%), managing symptoms (69%), pain management (69%), and ethical issues (66%). The PPCS provides a useful assessment to determine the educational needs of health-care providers delivering perinatal palliative care.

TSPO and amyloid deposits in sub-regions of the hippocampus in the 3xTgAD mouse model of Alzheimer's disease.

The involvement of the 18kDa translocator protein (TSPO), a marker of neuroinflammation, in Alzheimer's disease (AD) remains controversial. In the present report, we used [125I]-CLINDE, a SPECT TSPO radiotracer never before used in AD, and we investigated the relationship between TSPO and amyloid plaque density (using [125I]-DRM106) in a triple transgenic mouse model of AD (3xTgAD, APPSWE, PS1M146V and TauP301L). Our results show that TSPO increases appear before those of amyloid deposits. Moreover, the different parts of the hippocampus are differentially affected. Indeed, for both TSPO and amyloid, the subiculum is affected earlier and the ventral hippocampus later than the dorsal hippocampus. In the subiculum and the dorsal hippocampus of 3xTgAD mice, a positive correlation between TSPO and of amyloid deposit levels is observed. This data supports the hypothesis that TSPO could be used as a predictive marker of amyloid pathology. In addition, our immunohistochemical data shows a segregation of TSPO in the hippocampus and immunofluorescence imaging revealed a mainly microglial origin of the TSPO expression. Thus, imaging TSPO with CLINDE may be a good alternative to PET radiotracers.

Opportunistic dose amplification for proton and carbon ion therapy via capture of internally generated thermal neutrons.

This paper presents Neutron Capture Enhanced Particle Therapy (NCEPT), a method for enhancing the radiation dose delivered to a tumour relative to surrounding healthy tissues during proton and carbon ion therapy by capturing thermal neutrons produced inside the treatment volume during irradiation. NCEPT utilises extant and in-development boron-10 and gadolinium-157-based drugs from the related field of neutron capture therapy. Using Monte Carlo simulations, we demonstrate that a typical proton or carbon ion therapy treatment plan generates an approximately uniform thermal neutron field within the target volume, centred around the beam path. The tissue concentrations of neutron capture agents required to obtain an arbitrary 10% increase in biological effective dose are estimated for realistic treatment plans, and compared to concentrations previously reported in the literature. We conclude that the proposed method is theoretically feasible, and can provide a worthwhile improvement in the dose delivered to the tumour relative to healthy tissue with readily achievable concentrations of neutron capture enhancement drugs.

Yoga for Young Adults With Noncurative Cancer: A Brief Report.

BACKGROUND: The practice of yoga has been shown to improve disease- and treatment-related side effects in the noncurative cancer patient. OBJECTIVE: This user experience study aimed to examine the feasibility and usefulness of a DVD-based yoga program for young adult cancer patients with a noncurative diagnosis. METHODS: Participants were asked to partake in a 7-week DVD-based yoga program and complete measures of program use and usefulness. RESULTS: Nine patients expressed study interest and 5 consented to participate. Four completed the full study protocol. Participants reported being satisfied with the program and described that it provided an opportunity for self-care. Improvements in functional, physical, and spiritual well-being and overall quality of life were found. Barriers included competing time demands and feeling unwell. No adverse events were reported. CONCLUSION: The program was viewed as an accessible and useful activity option; however, a desire for greater social support from relatable others was highlighted.

Opioids for cancer-related pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Opioids are used worldwide for the treatment of pain. Currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is to start with a low dose gradually titrated to effect or unacceptable adverse effect in the child. OBJECTIVES: To assess the analgesic efficacy, and adverse events, of opioids used to treat cancer-related pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid and Embase via Ovid from inception to 22 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials (RCTs), with or without blinding, of any dose, and any route, treating cancer-related pain in children and adolescents, comparing opioids with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. MAIN RESULTS: No studies were identified that were eligible for inclusion in this review (very low quality evidence). Several studies tested opioids on adults with cancer-related pain, but none in participants aged from birth to 17 years.We rated the quality of evidence as very low, downgraded due to a lack of available data; no analyses could be undertaken. AUTHORS' CONCLUSIONS: No conclusions can be drawn about efficacy or harm in the use of opioids to treat cancer-related pain in children and adolescents. As a result, there is no RCT evidence to support or refute the use of opioids to treat cancer-related pain in children and adolescents.