Association between PM2.5 from a coal mine fire and FeNO concentration 7.5 years later.

BACKGROUND AND AIM: There are few long-term studies of respiratory health effects of landscape fires, despite increasing frequency and intensity due to climate change. We investigated the association between exposure to coal mine fire PM2.5 and fractional exhaled nitric oxide (FeNO) concentration 7.5 years later. METHODS: Adult residents of Morwell, who were exposed to the 2014 Hazelwood mine fire over 6 weeks, and unexposed residents of Sale, participated in the Hazelwood Health Study Respiratory Stream in 2021, including measurements of FeNO concentration, a marker of eosinophilic airway inflammation. Individual exposure to coal mine fire PM2.5 was modelled and mapped to time-location diaries. The effect of exposure to PM2.5 on log-transformed FeNO in exhaled breath was investigated using multivariate linear regression models in the entire sample and stratified by potentially vulnerable subgroups. RESULTS: A total of 326 adults (mean age: 57 years) had FeNO measured. The median FeNO level (interquartile range [IQR]) was 17.5 [15.0] ppb, and individual daily exposure to coal mine fire PM2.5 was 7.2 [13.8] µg/m3. We did not identify evidence of association between coal mine fire PM2.5 exposure and FeNO in the general adult sample, nor in various potentially vulnerable subgroups. The point estimates were consistently close to zero in the total sample and subgroups. CONCLUSION: Despite previous short-term impacts on FeNO and respiratory health outcomes in the medium term, we found no evidence that PM2.5 from the Hazelwood coal mine fire was associated with any long-term impact on eosinophilic airway inflammation measured by FeNO levels.

Assessing Rat Diaphragm Motor Unit Connectivity Outcome Measures as Quantitative Biomarkers of Phrenic Motor Neuron Degeneration and Compensation.

Loss of ventilatory muscle function is a consequence of motor neuron injury and neurodegeneration (e.g., cervical spinal cord injury and amyotrophic lateral sclerosis, respectively). Phrenic motor neurons are the final link between the central nervous system and muscle, and their respective motor units (groups of muscle fibers innervated by a single motor neuron) represent the smallest functional unit of the neuromuscular ventilatory system. Compound muscle action potential (CMAP), single motor unit potential (SMUP), and motor unit number estimation (MUNE) are established electrophysiological approaches that enable the longitudinal assessment of motor unit integrity in animal models over time but have mostly been applied to limb muscles. Therefore, the objectives of this study are to describe an approach in preclinical rodent studies that can be used longitudinally to quantify the phrenic MUNE, motor unit size (represented as SMUP), and CMAP, and then to demonstrate the utility of these approaches in a motor neuron loss model. Sensitive, objective, and translationally relevant biomarkers for neuronal injury, degeneration, and regeneration in motor neuron injury and diseases can significantly aid and accelerate experimental research discoveries to clinical testing.

Does diet quality moderate the long-term effects of discrete but extreme PM2.5 exposure on respiratory symptoms? A study of the Hazelwood coalmine fire.

In 2014, a fire at an open cut coalmine in regional Victoria, Australia burned for 6 weeks. Residents of the nearby town of Morwell were exposed to smoke, which included high levels of fine particulate matter (PM2.5). We investigated whether the long-term effects of PM2.5 on respiratory health were moderated by diet quality. A cross-sectional analysis was conducted of data collected 8.5 years after the mine fire from 282 residents of Morwell and 166 residents from the nearby unexposed town of Sale. Primary outcomes were respiratory symptoms. Exposure was coalmine fire-related PM2.5 and diet quality was assessed as Australian Recommended Food Score (ARFS) derived using the Australian Eating Survey (AES). The moderating effect of diet quality on respiratory outcomes associated with PM2.5 was assessed using logistic regression models, adjusting for potential confounders. Diet quality was poor in this sample, with 60% in the lowest category of overall diet quality. Overall diet quality and fruit and vegetable quality significantly attenuated the association between PM2.5 and prevalence of chronic cough and phlegm. Sauce/condiment intake was associated with a greater effect of PM2.5 on COPD prevalence. No other moderating effects were significant. The moderating effects of overall diet quality and vegetable and fruit intake aligned with a priori hypotheses, suggesting potential protective benefits. While more evidence is needed to confirm these findings, improving diets, especially fruit and vegetable intake, may provide some protection against the effects of smoke exposure from fire events.

Long-term effects of extreme smoke exposure on COVID-19: A cohort study.

BACKGROUND: In 2014, the Hazelwood coalmine fire shrouded the regional Australian town of Morwell in smoke and ash for 6 weeks. One of the fire's by-products, PM2.5 , is associated with an increased risk of COVID-19 and severe disease. However, it is unclear whether the effect persisted for years after exposure. In this study, we surveyed a cohort established prior to the pandemic to determine whether PM2.5 from the coalmine fire increased long-term vulnerability to COVID-19 and severe disease. METHODS: From August to December 2022, 612 members of the Hazelwood Health Study's adult cohort, established in 2016/17, participated in a follow-up survey that included standardized items to capture COVID-19 cases, as well as questions about hospitalization and vaccinations. Associations were evaluated in crude and adjusted logistic regression models. RESULTS: A total of 268 (44%) participants self-reported or met symptom criteria for having had COVID-19 at least once. All models found a positive association, with odds of COVID-19 increasing by between 4% and 30% for a 10 µg/m3 increase in coalmine fire-related PM2.5 exposure. However, the association was significant in only 2 of the 18 models. There were insufficient hospitalizations to examine severity (n = 7; 1%). CONCLUSION: The findings are inconclusive on the effect of coalmine fire-related PM2.5 exposure on long-term vulnerability to COVID-19. Given the positive association that was robust to modelling variations as well as evidence for a causal mechanism, it would be prudent to treat PM2.5 from fire events as a long-term risk factor until more evidence accumulates.

Somatic symptoms, psychological distress and trauma after disasters: lessons from the 2014 Hazelwood mine fire and 2019-20 Black Summer bushfires.

BACKGROUND: Wildfires cause significant physical and mental ill-health. How physical and mental symptoms interact following wildfire smoke exposure is unclear, particularly in the context of repeated exposures. In this cross-sectional study we investigated how posttraumatic stress and general psychological distress associated with somatic symptoms in a community exposed to multiple smoke events. METHODS: A random weighted sample of 709 adults exposed to smoke during the 2014 Hazelwood coal mine fire in south-eastern Australia completed a survey in 2020. The survey coincided with the Black Summer wildfires that caused a similar period of smoke haze in the region. Participants self-reported somatic symptoms (PHQ-15) and mine fire-related posttraumatic stress (IES-R) experienced over the previous week, general psychological distress (K10) experienced over the previous four weeks, lifetime health diagnoses and demographic information. Associations between posttraumatic stress, general psychological distress, and each PHQ-15 somatic symptom were analysed using ordinal logistic regression models. RESULTS: Overall, 36.2% of participants reported moderate- or high-level somatic symptomology. The most frequent somatic symptoms were fatigue, limb pain, trouble sleeping, back pain, headaches, and shortness of breath. After controlling for confounding factors, general psychological distress and posttraumatic stress were independently associated with all somatic symptoms (except menstrual problems in females for posttraumatic stress). CONCLUSIONS: Results highlight the high prevalence of somatic symptoms and their association with general psychological distress and posttraumatic stress within a community in the midst of a second large-scale smoke event. It is essential that healthcare providers and public health authorities consider the interconnections of these conditions when supporting communities affected by climate-related disasters.

An overview of clustering methods with guidelines for application in mental health research.

Cluster analyzes have been widely used in mental health research to decompose inter-individual heterogeneity by identifying more homogeneous subgroups of individuals. However, despite advances in new algorithms and increasing popularity, there is little guidance on model choice, analytical framework and reporting requirements. In this paper, we aimed to address this gap by introducing the philosophy, design, advantages/disadvantages and implementation of major algorithms that are particularly relevant in mental health research. Extensions of basic models, such as kernel methods, deep learning, semi-supervised clustering, and clustering ensembles are subsequently introduced. How to choose algorithms to address common issues as well as methods for pre-clustering data processing, clustering evaluation and validation are then discussed. Importantly, we also provide general guidance on clustering workflow and reporting requirements. To facilitate the implementation of different algorithms, we provide information on R functions and libraries.

Sociodemographic circumstances, health, and life experience shape posttraumatic distress trajectories among individuals exposed to smoke during a large-scale coal mine fire.

The 2014 Hazelwood coal mine fire in the Latrobe Valley, Australia, distributed toxic smoke into surrounding communities over 45 days. This study investigated risk and protective factors associated with four trajectories of posttraumatic distress (resilient, recovery, delayed-onset, chronic) among exposed adults. Participants (N = 709) completed surveys in 2016-2017 and 2019-2020 assessing mine fire-related particulate matter (PM2.5 ) exposure; sociodemographic, physical, and mental health variables; and exposure to other traumatic and recent stressful events. Mine fire-related posttraumatic distress was measured using the IES-R; trajectories were determined according to established clinical significance thresholds. Relative risk ratios (RRRs) were generated from multivariate multinomial regressions. The resilient trajectory was most common (77.0%). The chronic trajectory (8.5%) was associated with loneliness, RRR = 2.59, 95% CI [1.30, 5.16], and physical health diagnoses, RRR = 2.31, 95% CI [1.32, 4.02]. The delayed-onset trajectory (9.1%) was associated with multiple recent stressful events, RRR = 2.51, 95% CI [1.37, 4.59]; mental health diagnoses, RRR = 2.30, 95% CI [1.25, 4.24]; loneliness, RRR = 2.05, 95% CI [1.09, 3.88]; and male gender, RRR = 2.01, 95% CI [1.18, 3.44]. Socioeconomic advantage protected against chronic, RRR = 0.68, 95% CI [0.53, 0.86], and delayed-onset trajectory membership, RRR = 0.68, 95% CI [0.50, 0.94]; social support protected against chronic trajectory membership, RRR = 0.67, 95% CI [0.49, 0.92]. PM2.5 exposure did not determine trajectory. These findings enhance understanding of longer-term posttraumatic responses to large-scale smoke events and can inform mental health initiatives within at-risk communities.

Evaluating the impact of Hazelwood mine fire event on students' educational development with Bayesian interrupted time-series hierarchical meta-regression.

BACKGROUND: Environmental disasters such as wildfires, floods and droughts can introduce significant interruptions and trauma to impacted communities. Children and young people can be disproportionately affected with additional educational disruptions. However, evaluating the impact of disasters is challenging due to difficulties in establishing studies and recruitment post-disasters. OBJECTIVES: We aimed to (1) develop a Bayesian model using aggregated school-level data to evaluate the impact of environmental disasters on academic achievement and (2) evaluate the impact of the 2014 Hazelwood mine fire (a six-week fire event in Australia). METHODS: Bayesian hierarchical meta-regression was developed to evaluate the impact of the mine fire using easily accessible aggregated school-level data from the standardised National Assessment Program-Literacy and Numeracy (NAPLAN) test. NAPLAN results and school characteristics (2008-2018) from 69 primary/secondary schools with different levels of mine fire-related smoke exposure were used to estimate the impact of the event. Using an interrupted time series design, the model estimated immediate effects and post-interruption trend differences with full Bayesian statistical inference. RESULTS: Major academic interruptions across NAPLAN domains were evident in high exposure schools in the year post-mine fire (greatest interruption in Writing: 11.09 [95%CI: 3.16-18.93], lowest interruption in Reading: 8.34 [95%CI: 1.07-15.51]). The interruption was comparable to a four to a five-month delay in educational attainment and had not fully recovered after several years. CONCLUSION: Considerable academic delays were found as a result of a mine fire, highlighting the need to provide educational and community-based supports in response to future events. Importantly, this work provides a statistical method using readily available aggregated data to assess the educational impacts in response to other environmental disasters.

Long-term impact of the 2014 Hazelwood coal mine fire on emergency department presentations in Australia.

BACKGROUND: In 2014, wildfires ignited a coal mine in Australia, burning for 6 weeks, releasing large amounts of fine particulate matter ≤2.5 µm in diameter (PM2.5). We investigated the association between individual PM2.5 exposure and emergency department presentations (EDPs) within 5 years post-fire. METHODS: Survey and exposure data for 2725 residents from an exposed and unexposed town were linked with ED administrative data from 2009 to 2019. The association between individual PM2.5 and EDPs was assessed using recurrent survival analysis. RESULTS: A 10 µg/m3 increase in PM2.5 was associated with a 10% increase in respiratory EDPs (HR = 1.10; 95%CI:1.00-1.22) over 5 years post-fire. Increased risks of EDPs for ischaemic heart disease (HR = 1.39; 95%CI:1.12-1.73), atherothrombotic disease (HR = 1.27; 95%CI:1.08-1.50), and cardiovascular disease (HR = 1.10, 95%CI:0.99-1.22) were evident within 2.5 years. CONCLUSION: PM2.5 exposure from a 6-week mine fire increased the 5-year risk of respiratory conditions. An increased risk of CVD within 2.5 years post-fire subsided after this time.

A Strength Endurance Exercise Paradigm Mitigates Deficits in Hypoglossal-Tongue Axis Function, Strength, and Structure in a Rodent Model of Hypoglossal Motor Neuron Degeneration.

The tongue plays a crucial role in the swallowing process, and impairment can lead to dysphagia, particularly in motor neuron diseases (MNDs) resulting in hypoglossal-tongue axis degeneration (e.g., amyotrophic lateral sclerosis and progressive bulbar palsy). This study utilized our previously established inducible rodent model of dysphagia due to targeted degeneration of the hypoglossal-tongue axis. This model was created by injecting cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue base for retrograde transport to the hypoglossal (XII) nucleus via the hypoglossal nerve, which provides the sole motor control of the tongue. Our goal was to investigate the effect of high-repetition/low-resistance tongue exercise on tongue function, strength, and structure in four groups of male rats: (1) control + sham exercise (n = 13); (2) control + exercise (n = 10); (3) CTB-SAP + sham exercise (n = 13); and (4) CTB-SAP + exercise (n = 12). For each group, a custom spout with adjustable lick force requirement for fluid access was placed in the home cage overnight on days 4 and 6 post-tongue injection. For the two sham exercise groups, the lick force requirement was negligible. For the two exercise groups, the lick force requirement was set to ∼40% greater than the maximum voluntary lick force for individual rats. Following exercise exposure, we evaluated the effect on hypoglossal-tongue axis function (via videofluoroscopy), strength (via force-lickometer), and structure [via Magnetic Resonance Imaging (MRI) of the brainstem and tongue in a subset of rats]. Results showed that sham-exercised CTB-SAP rats had significant deficits in lick rate, swallow timing, and lick force. In exercised CTB-SAP rats, lick rate and lick force were preserved; however, swallow timing deficits persisted. MRI revealed corresponding degenerative changes in the hypoglossal-tongue axis that were mitigated by tongue exercise. These collective findings suggest that high-repetition/low-resistance tongue exercise in our model is a safe and effective treatment to prevent/diminish signs of hypoglossal-tongue axis degeneration. The next step is to leverage our rat model to optimize exercise dosing parameters and investigate corresponding treatment mechanisms of action for future translation to MND clinical trials.

An exploration of the trajectory of psychological distress associated with exposure to smoke during the 2014 Hazelwood coal mine fire.

Due to climate change, catastrophic events such as landscape fires are increasing in frequency and severity. However, relatively little is known about the longer-term mental health outcomes of such events. Follow-up was conducted of 709 adults exposed to smoke from the 2014 Hazelwood mine fire in Morwell, Victoria, Australia. Participants completed two surveys evaluating posttraumatic distress, measured using the Impact of Events Scale-Revised (IES-R), three and six years after the mine fire. Mixed-effects regression models were used to evaluate longitudinal changes in distress. IES-R total scores increased on average by 2.6 points (95%CI: 1.2 to 3.9 points) between the two survey rounds, with increases across all three posttraumatic distress symptom clusters, particularly intrusive symptoms. This increase in distress was evident across all levels of fine particulate matter (PM2.5) exposure to the mine fire smoke. Age was an effect modifier between mine fire PM2.5 exposure and posttraumatic distress, with younger adults impacted more by exposure to the mine fire. Greater exposure to PM2.5 from the mine fire was still associated with increased psychological distress some six years later, with the overall level of distress increasing between the two survey rounds. The follow-up survey coincided with the Black Summer bushfire season in south-eastern Australia and exposure to this new smoke event may have triggered distress sensitivities stemming from exposure to the earlier mine fire. Public health responses to disaster events should take into consideration prior exposures and vulnerable groups, particularly younger adults.

Nonsteroidal anti-inflammatory drug (ketoprofen) delivery differentially impacts phrenic long-term facilitation in rats with motor neuron death induced by intrapleural CTB-SAP injections.

Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) selectively eliminates respiratory (e.g., phrenic) motor neurons, and mimics motor neuron death and respiratory deficits observed in rat models of neuromuscular diseases. Additionally, microglial density increases in the phrenic motor nucleus following CTB-SAP. This CTB-SAP rodent model allows us to study the impact of motor neuron death on the output of surviving phrenic motor neurons, and the underlying mechanisms that contribute to enhancing or constraining their output at 7 days (d) or 28d post-CTB-SAP injection. 7d CTB-SAP rats elicit enhanced phrenic long-term facilitation (pLTF) through the Gs-pathway (inflammation-resistant in naïve rats), while pLTF is elicited though the Gq-pathway (inflammation-sensitive in naïve rats) in control and 28d CTB-SAP rats. In 7d and 28d male CTB-SAP rats and controls, we evaluated the effect of cyclooxygenase-1/2 enzymes on pLTF by delivery of the nonsteroidal anti-inflammatory drug, ketoprofen (IP), and we hypothesized that pLTF would be unaffected by ketoprofen in 7d CTB-SAP rats, but pLTF would be enhanced in 28d CTB-SAP rats. In anesthetized, paralyzed and ventilated rats, pLTF was surprisingly attenuated in 7d CTB-SAP rats and enhanced in 28d CTB-SAP rats (both p < 0.05) following ketoprofen delivery. Additionally in CTB-SAP rats: 1) microglia were more amoeboid in the phrenic motor nucleus; and 2) cervical spinal inflammatory-associated factor expression (TNF-α, BDNF, and IL-10) was increased vs. controls in the absence of ketoprofen (p < 0.05). Following ketoprofen delivery, TNF-α and IL-10 expression was decreased back to control levels, while BDNF expression was differentially affected over the course of motor neuron death in CTB-SAP rats. This study furthers our understanding of factors (e.g., cyclooxygenase-1/2-induced inflammation) that contribute to enhancing or constraining pLTF and its implications for breathing following respiratory motor neuron death.

Axon and Myelin Sheath Segmentation in Electron Microscopy Images using Meta Learning.

Various neurological diseases affect the morphology of myelinated axons. Quantitative analysis of these structures and changes occurring due to neurodegeneration or neuroregeneration is of great importance for characterization of disease state and treatment response. This paper proposes a robust, meta-learning based pipeline for segmentation of axons and surrounding myelin sheaths in electron microscopy images. This is the first step towards computation of electron microscopy related bio-markers of hypoglossal nerve degeneration/regeneration. This segmentation task is challenging due to large variations in morphology and texture of myelinated axons at different levels of degeneration and very limited availability of annotated data. To overcome these difficulties, the proposed pipeline uses a meta learning-based training strategy and a U-net like encoder decoder deep neural network. Experiments on unseen test data collected at different magnification levels (i.e, trained on 500X and 1200X images, and tested on 250X and 2500X images) showed improved segmentation performance by 5% to 7% compared to a regularly trained, comparable deep learning network.

The Ighmbp2D564N mouse model is the first SMARD1 model to demonstrate respiratory defects.

Spinal muscular atrophy with respiratory distress type I (SMARD1) is a neurodegenerative disease defined by respiratory distress, muscle atrophy and sensory and autonomic nervous system defects. SMARD1 is a result of mutations within the IGHMBP2 gene. We have generated six Ighmbp2 mouse models based on patient-derived mutations that result in SMARD1 and/or Charcot-Marie Tooth Type 2 (CMT2S). Here we describe the characterization of one of these models, Ighmbp2D564N (human D565N). The Ighmbp2D564N/D564N mouse model mimics important aspects of the SMARD1 disease phenotype, including motor neuron degeneration and muscle atrophy. Ighmbp2D564N/D564N is the first SMARD1 mouse model to demonstrate respiratory defects based on quantified plethysmography analyses. SMARD1 disease phenotypes, including the respiratory defects, are significantly diminished by intracerebroventricular (ICV) injection of ssAAV9-IGHMBP2 and the extent of phenotypic restoration is dose-dependent. Collectively, this model provides important biological insight into SMARD1 disease development.

Long-term impacts of coal mine fire-emitted PM2.5 on hospitalisation: a longitudinal analysis of the Hazelwood Health Study.

BACKGROUND: Little is known about the long-term health impacts of exposures to landscape fire smoke. We aimed to evaluate the association between exposure to coal mine fire-related particulate matter 2.5 µm or less in diameter (PM2.5) and hospitalisation in the 5 years following the 6-week Hazelwood coal mine fire in Australia in 2014. METHODS: We surveyed 2725 residents (mean age: 58.3 years; 54.3% female) from an exposed and a comparison town. Individual PM2.5 exposures during the event were estimated using modelled PM2.5 concentrations related to the coal mine fire and self-reported location data. The individual exposure and survey data were linked with hospitalisation records between January 2009 and February 2019. Recurrent event survival analysis was used to evaluate relationships between PM2.5 exposure and hospitalisation following mine fire, adjusting for important covariates. RESULTS: Each 10-µg/m3 increase in mine fire-related PM2.5 was associated with a 9% increased hazard [hazard ratio (HR) = 1.09; 95% confidence interval (CI): 1.01, 1.17] of respiratory hospitalisation over the next 5 years, with stronger associations observed for females (HR = 1.16; 95% CI: 1.06, 1.27) than males (HR = 0.99; 95% CI: 0.89, 1.11). In particular, increased hazards were observed for hospitalisations for asthma (HR = 1.43; 95% CI: 1.19, 1.73) and chronic obstructive pulmonary disease (HR = 1.14; 95% CI: 1.02, 1.28). No such association was found for hospitalisations for cardiovascular diseases, mental illness, injuries, type 2 diabetes, renal diseases or neoplasms. CONCLUSIONS: A 6-week exposure to coal mine fire-related PM2.5 was associated with increased hazard of respiratory hospitalisations over the following 5 years, particularly for females.

Are e-cigarette use and vaping associated with increased respiratory symptoms and poorer lung function in a population exposed to smoke from a coal mine fire?

BACKGROUND AND OBJECTIVE: E-cigarette use has become increasingly prevalent, but there is some evidence demonstrating potential harms with frequent use. We aimed to identify the profiles of e-cigarette users from a regional community in Australia and investigate the associations of e-cigarettes with respiratory symptoms and lung function. METHODS: A total of 519 participants completed a cross-sectional study. Exposure to e-cigarettes was collected via a validated questionnaire. Respiratory symptoms were evaluated via a self-reported questionnaire and lung function measured with spirometry and forced oscillation technique (FOT). Linear and logistic regression models were fitted to investigate the associations between e-cigarettes and outcomes, while controlling for confounders such as tobacco smoking. RESULTS: Of the 519 participants, 46 (9%) reported e-cigarette use. Users tended to be younger (mean ± SD 45.2 ± 14.5 vs. 55.3 ± 16.0 years in non-users), concurrently using tobacco products (63% vs. 12% in non-users), have a mental health diagnosis (67% vs. 37% in non-users) and have self-reported asthma (63% vs. 42% in non-users). After controlling for known confounders, chest tightness (OR = 2.4, 95% CI 1.2-4.9, p = 0.02) was associated with e-cigarette use. Spirometry was not different after adjustment for confounding. However, FOT showed more negative reactance and a greater area under the reactance curve in e-cigarette users than non-users. CONCLUSION: E-cigarette use was associated with increased asthma symptoms and abnormal lung mechanics in our sample, supporting a potential health risk posed by these products. Vulnerable populations such as young adults and those with mental health conditions have higher usage, while there is high concurrent tobacco smoking.

Divergent receptor utilization is necessary for phrenic long-term facilitation over the course of motor neuron loss following CTB-SAP intrapleural injections.

Intrapleural injection of cholera toxin B conjugated to saporin (CTB-SAP) mimics respiratory motor neuron death and respiratory deficits observed in rat models of neuromuscular diseases. Seven-day CTB-SAP rats elicit enhanced phrenic long-term facilitation (pLTF) primarily through TrkB and PI3K/Akt-dependent mechanisms [i.e., Gs-pathway, which can be initiated by adenosine 2A (A2A) receptors in naïve rats], whereas 28-day CTB-SAP rats elicit moderate pLTF though BDNF- and MEK-/ERK-dependent mechanisms [i.e., Gq-pathway, which is typically initiated by serotonin (5-HT) receptors in naïve rats]. Here, we tested the hypothesis that pLTF following CTB-SAP is 1) A2A receptor-dependent at 7 days and 2) 5-HT receptor-dependent at 28 days. Adult Sprague-Dawley male rats were anesthetized, paralyzed, ventilated, and exposed to acute intermittent hypoxia (AIH; 3-, 5-min bouts of 10.5% O2) following bilateral, intrapleural injections at 7 days and 28 days of 1) CTB-SAP (25 µg) or 2) unconjugated CTB and SAP (control). Intrathecal C4 delivery included either the 1) A2A receptor antagonist (MSX-3; 10 µM; 12 µL) or 2) 5-HT receptor antagonist (methysergide; 20 mM; 15 µL). pLTF was abolished with A2A receptor inhibition in 7-day, not 28-day, CTB-SAP rats versus controls (P < 0.05), whereas pLTF was abolished following 5-HT receptor inhibition in 28-day, not 7-day, CTB-SAP rats versus controls (P < 0.05). In addition, 5-HT2A receptor expression was unchanged in CTB-SAP rats versus controls, whereas 5-HT2B receptor expression was decreased in CTB-SAP rats versus controls (P < 0.05). This study furthers our understanding of the contribution of differential receptor activation to pLTF and its implications for breathing following respiratory motor neuron death.NEW & NOTEWORTHY The current study investigates underlying receptor-dependent mechanisms contributing to phrenic long-term facilitation (pLTF) following CTB-SAP-induced respiratory motor neuron death at 7 days and 28 days. We found that A2A receptors are required for enhanced pLTF in 7-day CTB-SAP rats, whereas 5-HT receptors are required for moderate pLTF in 28-day CTB-SAP rats. Targeting these time-dependent mechanisms have implications for breathing maintenance over the course of many neuromuscular diseases.

Improving medication adherence in adult kidney transplantation (IMAKT): A pilot randomised controlled trial.

Resources to support long-term medication adherence in kidney transplantation are limited. This study aimed to determine the efficacy of an intervention designed for kidney transplant recipients to enhance medication adherence. A single-blind, multi-site, 12-month pilot randomised controlled trial was conducted at all five public hospitals providing adult kidney transplantation in Victoria, Australia. Participants were recruited at 4 to 6 weeks post-transplantation. Thirty-five participants were randomly assigned to a 3-month intervention, involving a face-to-face meeting (a medication review and a consumer-centred video) and health coaching every two weeks. Thirty-six were randomised to receive usual care. All participants were followed for nine months post-intervention. There were no differences in adherence between groups measured by Medication Event Monitoring System (MEMS), however, it was underutilised by 42% of participants. Based on the self-reported Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS©) score, the percentage of adherent participants decreased significantly between baseline and 3 to 12 months in the control group (p-values < 0.001) whilst the percentage of adherent participants in the intervention group remained constant over time. No group differences were detected in other outcomes. Due to the complex medication regimen, developing and testing a medication adherence intervention is difficult in kidney transplantation.

Amblyomma maculatum-associated rickettsiae in vector tissues and vertebrate hosts during tick feeding.

Rickettsia parkeri, a causative agent of spotted fever rickettsiosis, is transmitted by Amblyomma maculatum (Gulf Coast tick), a tick that may also carry a non-pathogenic spotted fever group Rickettsia, "Candidatus Rickettsia andeanae". Here, we evaluated R. parkeri and "Candidatus R. andeanae" in tissues from A. maculatum prior to, during, and after blood feeding on rabbits. Using colony-reared A. maculatum that were capillary-fed uninfected cells, R. parkeri, "Candidatus R. andeanae", or both rickettsiae, we detected higher levels of Rickettsia spp. in the respective treatment groups. Rickettsial levels increased during blood feeding for both R. parkeri and "Candidatus R. andeanae", with a greater increase in R. parkeri in co-infected ticks compared to singly-infected ticks. We detected transovarial transmission of "Candidatus R. andeanae" in egg and larval cohorts and confirmed vertical transmission of R. parkeri in one group of larvae. Rabbits from all Rickettsia-exposed groups seroconverted on immunofluorescent antibody testing using R. parkeri antigen. Visualization of "Candidatus R. andeanae" in tick salivary glands suggested potential transmission via tick feeding. Here, rickettsial levels in artificially infected ticks demonstrate changes during feeding and transovarial transmission that may be relevant for interpreting rickettsial levels detected in wild A. maculatum.