Long-term exposure to fine particulate matter, lung function and cognitive performance:A prospective Dutch cohort study on the underlying routes

Background Exposure to fine particulate matter and black carbon is related to cognitive impairment and poor lung function, but less is known about the routes taken by different types of air pollutants to affect cognition. Objectives We tested two possible routes of fine particulate matter (PM2.5) and black carbon (BC) in impairing cognition, and evaluated their importance: a direct route over the olfactory nerve or the blood stream, and an indirect route over the lung. Methods We used longitudinal observational data for 31232 people aged 18+ from 2006 to 2015 from the Dutch Lifelines cohort study. By linking current and past home addresses to air pollution exposure data from ELAPSE, long-term average exposure (≥ ten years) to PM2.5 and BC was calculated. Lung function was assessed by spirometry and Global Initiative (GLI) z-scores of forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) were calculated. Cognitive performance was measured by cognitive processing time (CPT) assessed by the Cogstate Brief Battery. Linear structural equation modeling was performed to test the direct/indirect associations. Results Higher exposure to PM2.5 but not BC was directly related to higher CPT and thus slower cognitive processing speed [18.33 (×10−3) SD above the mean (95% CI: 6.84, 29.81)]. The direct association of PM2.5 constituted more than 97% of the total effect. Mediation by lung function was low for PM2.5 with a mediated proportion of 1.78% (FEV1) and 2.62% (FVC), but higher for BC (28.49% and 46.22% respectively). Discussion Our results emphasize the importance of the lung acting as a mediator in the relationship between both exposure to PM2.5 and BC, and cognitive performance. However, higher exposure to PM2.5 was mainly directly associated with worse cognitive performance, which emphasizes the health-relevance of fine particles due to their ability to reach vital organs directly

A phase III wait-listed randomised controlled trial of novel targeted inter-professional clinical education intervention to improve cancer patients' reported pain outcomes (The Cancer Pain Assessment (CPAS) Trial): Study protocol

© 2019 The Author(s). Background: Variations in care models contribute to cancer pain being under-recognised and under-treated in half of all patients with cancer. International and national cancer pain management guidelines are achievable with minimal investment but require practice changes. While much of the cancer pain research over the preceding decades has focused on management interventions, little attention has been given to achieving better adherence to recommended cancer pain guideline screening and assessment practices. This trial aims to reduce unrelieved cancer pain by improving cancer and palliative doctors' and nurses' ('clinicians') pain assessment capabilities through a targeted inter-professional clinical education intervention delivered to participants' mobile devices ('mHealth'). Methods: A wait-listed, randomised control trial design. Cancer and/or palliative care physicians and nurses employed at one of the six participating sites across Australia will be eligible to participate in this trial and, on enrolment, will be allocated to the active or wait-listed arm. Participants allocated to the active arm will be invited to complete the mHealth cancer pain assessment intervention. In this trial, mHealth is defined as medical or public health practice supported by mobile devices (i.e. phones, patient monitoring devices, personal digital assistants and other wireless devices). This mHealth intervention integrates three evidence-based elements, namely: the COM-B theoretical framework; spaced learning pedagogy; and audit and feedback. This intervention will be delivered via the QStream online platform to participants' mobile devices over four weeks. The trial will determine if a tailored mHealth intervention, targeting clinicians' cancer pain assessment capabilities, is effective in reducing self-reported cancer pain scores, as measured by a Numerical Rating Scale (NRS). Discussion: If this mHealth intervention is found to be effective, in addition to improving cancer pain assessment practices, it will provide a readily transferable evidence-based framework that could readily be applied to other evidence practice gaps and a scalable intervention that could be administered simultaneously to multiple clinicians across diverse geographical locations. Moreover, if found to be cost-effective, it will help transform clinical continuing professional development. In summary, this mHealth intervention will provide health services with an opportunity to offer an evidence-based, pedagogically robust, cost-effective, scalable training alternative. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12618001103257. Registered on 3 July 2018

Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice.

Background: Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer’s disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood. Methods: To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine -hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine -hydroxylase (/) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation, and synaptic protein levels were assessed. Results: The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (/) single mutant mice were augmented in DBH (/)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptor 2A and increased N-methyl-D-aspartate receptor 2B levels and were independent of amyloid accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-dihydroxyphenylserine. Conclusions: These results indicate that early LC degeneration and subsequentNAdeficiency inADmay contribute to cognitive deficits via altered levels of calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptors and suggest that NA supplementation could be beneficial in early AD

Effect of pioglitazone treatment in a patient with secondary multiple sclerosis

BACKGROUND: Ligands of the peroxisome proliferator-activated receptor-gamma (PPARγ) induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. Preclinical studies have shown that the thiazolidinedione pioglitazone, an FDA-approved PPARγ agonist used to treat type 2 diabetes, delays the onset and reduces the severity of clinical symptoms in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). We therefore tested the safety and therapeutic potential of oral pioglitazone in a patient with secondary MS. CASE PRESENTATION: The rationale and risks of taking pioglitazone were carefully explained to the patient, consent was obtained, and treatment was initiated at 15 mg per day p.o. and then increased by 15 mg biweekly to 45 mg per day p.o. for the duration of the treatment. Safety was assessed by measurements of metabolic profiles, blood pressure, and edema; effects on clinical symptoms were assessed by measurement of cognition, motor function and strength, and MRI. Within 4 weeks the patient exhibited increased appetite, cognition and attention span. After 12 months treatment, body weight increased from 27.3 to 35.9 kg (32%) and maintained throughout the duration of the study. Upper extremity strength and coordination improved, and increased fine coordination was noted unilaterally after 8 months and bilaterally after 15 months. After 8 months therapy, the patient demonstrated improvement in orientation, short-term memory, and attention span. MRIs carried out after 10 and 18 months of treatment showed no perceptible change in overall brain atrophy, extent of demyelination, or in Gd-enhancement. After 3.0 years on pioglitazone, the patient continues to be clinically stable, with no adverse events. CONCLUSIONS: In a patient with secondary progressive MS, daily treatment with 45 mg p.o. pioglitazone for 3 years induced apparent clinical improvement without adverse events. Pioglitazone should therefore be considered for further testing of therapeutic potential in MS patients