Prediction of motor and non-motor Parkinson's disease symptoms using serum lipidomics and machine learning: a 2-year study.

Identifying biological factors which contribute to the clinical progression of heterogeneous motor and non-motor phenotypes in Parkinson's disease may help to better understand the disease process. Several lipid-related genetic risk factors for Parkinson's disease have been identified, and the serum lipid signature of Parkinson's disease patients is significantly distinguishable from controls. However, the extent to which lipid profiles are associated with clinical outcomes remains unclear. Untargeted high-performance liquid chromatography-tandem mass spectrometry identified >900 serum lipids in Parkinson's disease subjects at baseline (n = 122), and the potential for machine learning models using these lipids to predict motor and non-motor clinical scores after 2 years (n = 67) was assessed. Machine learning models performed best when baseline serum lipids were used to predict the 2-year future Unified Parkinson's disease rating scale part three (UPDRS III) and Geriatric Depression Scale scores (both normalised root mean square error = 0.7). Feature analysis of machine learning models indicated that species of lysophosphatidylethanolamine, phosphatidylcholine, platelet-activating factor, sphingomyelin, diacylglycerol and triacylglycerol were top predictors of both motor and non-motor scores. Serum lipids were overall more important predictors of clinical outcomes than subject sex, age and mutation status of the Parkinson's disease risk gene LRRK2. Furthermore, lipids were found to better predict clinical scales than a panel of 27 serum cytokines previously measured in this cohort (The Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium). These results suggest that lipid changes may be associated with clinical phenotypes in Parkinson's disease.

Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and loss of various muscular functions. Dyslipidaemia is prevalent in amyotrophic lateral sclerosis with aberrant changes mainly in cholesterol ester and triglyceride. Despite this, little is known about global lipid changes in amyotrophic lateral sclerosis or in relation to disease progression. The present study incorporated a longitudinal lipidomic analysis of amyotrophic lateral sclerosis serum with a comparison with healthy controls using advanced liquid chromatography-mass spectrometry. The results established that diglyceride, the precursor of triglyceride, was enriched the most, while ceramide was depleted the most in amyotrophic lateral sclerosis compared with controls, with the diglyceride species (18:1/18:1) correlating significantly to neurofilament light levels. The prenol lipid CoQ8 was also decreased in amyotrophic lateral sclerosis and correlated to neurofilament light levels. Most interestingly, the phospholipid phosphatidylethanolamine and its three derivatives decreased with disease progression, in contrast to changes with normal ageing. Unsaturated lipids that are prone to lipid peroxidation were elevated with disease progression with increases in the formation of toxic lipid products. Furthermore, in vitro studies revealed that phosphatidylethanolamine synthesis modulated TARDBP expression in SH-SY5Y neuronal cells. Finally, diglyceride, cholesterol ester and ceramide were identified as potential lipid biomarkers for amyotrophic lateral sclerosis diagnosis and monitoring disease progression. In summary, this study represents a longitudinal lipidomics analysis of amyotrophic lateral sclerosis serum and has provided new insights into multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

Stop motion: using high resolution spatiotemporal data to estimate and locate stationary and movement behaviour in an office workplace.

Prolonged periods of stationary behaviour, a common occurrence in many office workplaces, are linked with a range of physical disorders. Investigating the physical context of this behaviour may be a key to developing effective interventions. This study aimed to estimate and locate the stationary and movement behaviours of office workers (n = 10) by segmenting spatiotemporal data collected over 5 days in an office work-based setting. The segmentation method achieved a balanced accuracy ≥85.5% for observation classification and ≥90% for bout classification when compared to reference data. The results show the workers spent the majority of their time stationary (Mean = 86.4%) and had on average, 28.4 stationary and 25.9 moving bouts per hour. While these findings accord with other studies, the segmented data was also visualised, revealing that the workers were stationary for periods ≥5 min at multiple locations and these locations changed across time. Practitioner Summary: This study applied a data segmentation method to classify stationary and moving behaviours from spatiotemporal data collected in an office workplace. The segmented data revealed not only what behaviours occurred but also their location, duration, and time. Segmenting spatiotemporal data may add valuable physical context to aid workplace research.

Health promotion interventions to improve oral health of adolescents: A systematic review and meta-analysis.

OBJECTIVES: To evaluate the effectiveness of health promotion interventions on oral health knowledge, behaviour and status of healthy adolescents. METHODS: This review included randomized controlled trials (RCTs) of oral health promotion interventions targeting adolescents. Primary clinical outcomes (gingival health, plaque scores, caries) and secondary proxy outcomes were evaluated. Meta-analysis of primary outcomes was conducted where possible, with subgroup analysis based on intervention (comprehensive health promotion and education-only). RESULTS: Thirty-seven eligible publications reporting on 28 unique RCTs of oral health promotion interventions were included. Quality appraisal of studies ranged from 48% to 96%. Interventions reported ranged from single-session interventions to community-wide programmes, including clinical preventive procedures and take-home products. Half used a health behaviour change theory to inform their intervention. The meta-analysis pooling of results favoured the intervention over control for all clinical outcomes, except DMFS in the education-only subgroup. Stronger intervention effects were seen in the comprehensive intervention subgroup than the education-only subgroup for DMFS (P = .02). This effect was slight, but not as clear in all other clinical categories. The majority of studies reported improvements in oral health knowledge, attitudes and behaviours. More positive outcomes were found with longer programmes, especially for dental caries outcomes. CONCLUSIONS: Oral health promotion programmes targeting adolescents have the ability to improve clinical oral health outcomes in the short and long term. Programmes should use more behavioural theory-based interactive and strategic methods, including self-awareness and the use of the wider community and peers for oral health promotion activities over a longer intervention duration.

Discharge against medical advice in culturally and linguistically diverse Australian children.

OBJECTIVES: This study quantifies the prevalence and rates of discharge against medical advice (DAMA) in culturally and linguistically diverse (CALD) children and assesses the independent association between CALD status and DAMA accounting for key demographic confounders in a large tertiary Australian hospital network. METHODS: Prospectively collected data between 2010 and 2018 were extracted from the hospital network electronic medical records system for admitted patients (n=192 037), outpatients (n=268 904) and between 2015 and 2018 for emergency department (ED) patients (n=158 903). CALD status was defined as 'preferred language being not English' and DAMA was measured as 'discharge at own risk' in admissions, 'no show' in outpatients, 'left without being seen' and 'did not wait' in ED. Data were analysed using χ² test, bivariate analysis and multivariate logistic regression. RESULTS: The prevalence of DAMA was 1.34% in admitted patients, 19.31% in outpatients and 12.64% in ED patients. Rates of DAMA were higher among CALD children compared to non-CALD children (1.75% vs 1.29% in admitted patients, 26.53% vs 17.92% in outpatients and 18.74% vs 11.61% in ED patients). CALD status was independently associated with DAMA in admitted children (OR=1.30, 95% CI 1.15 to 1.44), outpatients (OR=1.55; 95% CI 1.51 to 1.58) and ED patients (OR=1.60; 95% CI 1.53 to 1.66). CONCLUSION: Being from a CALD background places children at increased risks to DAMA. Implementing appropriate health service responses may ensure equitable access and quality care for children from CALD backgrounds to reduce the rates of DAMA and its associated ramifications.

Fine-scale behavioural adjustments of prey on a continuum of risk.

In the wild, prey species often live in the vicinity of predators, rendering the ability to assess risk on a moment-to-moment basis crucial to survival. Visual cues are important as they allow prey to assess predator species, size, proximity and behaviour. However, few studies have explicitly examined prey's ability to assess risk based on predator behaviour and orientation. Using mosquitofish, Gambusia holbrooki, and their predator, jade perch, Scortum barcoo, under controlled conditions, we provide some of the first fine-scale characterization of how prey adapt their behaviour according to their continuous assessment of risk based on both predator behaviour and angular distance to the predator's mouth. When these predators were inactive and posed less of an immediate threat, prey within the attack cone of the predator showed reductions in speed and acceleration characteristic of predator-inspection behaviour. However, when predators became active, prey swam faster with greater acceleration and were closer together within the attack cone of predators. Most importantly, this study provides evidence that prey do not adopt a uniform response to the presence of a predator. Instead, we demonstrate that prey are capable of rapidly and dynamically updating their assessment of risk and showing fine-scale adjustments to their behaviour.

Predictors of Discharge Against Medical Advice in a Tertiary Paediatric Hospital.

BACKGROUND: Patients who discharge against medical advice (DAMA) from hospital carry a significant risk of readmission and have increased rates of morbidity and mortality. We sought to identify the demographic and clinical characteristics of DAMA patients from a tertiary paediatric hospital. METHODS: Data were extracted retrospectively from electronic medical records for all inpatient admissions over a 5-year period. Demographic characteristics (age, sex, Aboriginality, socioeconomic status and remoteness of residence) and clinical characteristics (admitting hospital site, level of urgency on admission, diagnosis and previous DAMA) were extracted and logistic regression models were used to identify predictors of DAMA with 95% confidence intervals. RESULTS: There were 246,359 admissions for 124,757 patients, of which 1871 (0.8%) admissions and 1730 patients (1.4%) DAMA. Predictors of DAMA in a given admission were hospital site (OR 4.8, CI 4.2-5.7, p < 0.01), a mental health/behavioural diagnosis (OR 3.3, CI 2.2-4.8, p < 0.01), Aboriginality (OR 1.6, CI 1.3-2.1, p < 0.01), emergency rather than elective admissions (OR 0.7ha, CI 0.6-0.8, p < 0.01), a gastrointestinal diagnosis (OR 1.5, CI 1.1-2.0, p = 0.04) and a history of previous DAMA (OR 2.0, CI 1.2-3.2, p = 0.05). CONCLUSIONS: There are clear predictors of DAMA in this tertiary hospital admission cohort and identification of these provides opportunities for intervention at a practice and policy level in order to prevent adverse outcomes.

Disparate binding kinetics by an intrinsically disordered domain enables temporal regulation of transcriptional complex formation.

Intrinsically disordered regions are highly represented among mammalian transcription factors, where they often contribute to the formation of multiprotein complexes that regulate gene expression. An example of this occurs with LIM-homeodomain (LIM-HD) proteins in the developing spinal cord. The LIM-HD protein LHX3 and the LIM-HD cofactor LDB1 form a binary complex that gives rise to interneurons, whereas in adjacent cell populations, LHX3 and LDB1 form a rearranged ternary complex with the LIM-HD protein ISL1, resulting in motor neurons. The protein-protein interactions within these complexes are mediated by ordered LIM domains in the LIM-HD proteins and intrinsically disordered LIM interaction domains (LIDs) in LDB1 and ISL1; however, little is known about how the strength or rates of binding contribute to complex assemblies. We have measured the interactions of LIM:LID complexes using FRET-based protein-protein interaction studies and EMSAs and used these data to model population distributions of complexes. The protein-protein interactions within the ternary complexes are much weaker than those in the binary complex, yet surprisingly slow LDB1:ISL1 dissociation kinetics and a substantial increase in DNA binding affinity promote formation of the ternary complex over the binary complex in motor neurons. We have used mutational and protein engineering approaches to show that allostery and modular binding by tandem LIM domains contribute to the LDB1LID binding kinetics. The data indicate that a single intrinsically disordered region can achieve highly disparate binding kinetics, which may provide a mechanism to regulate the timing of transcriptional complex assembly.

External cavity diode lasers with 5kHz linewidth and 200nm tuning range at 1.55µm and methods for linewidth measurement.

Two simple external cavity diode laser designs using fibre pigtailed gain chips are tested and their properties compared with a high end DBR fibre laser. These ECDLs demonstrate a FWHM linewidth as low as 5.2kHz with a fitted Lorentzian FWHM linewidth as low as 1.6kHz. Tuning ranges of 200nm covering 1420nm to 1620nm were demonstrated. To the best of our knowledge these are the narrowest linewidth and most broadly tunable external cavity diode lasers reported to date. The improvement in linewidth is attributed to greatly enhanced acoustic isolation allowed by using fiber coupled gain chips and by replacing kinematic mounts with a pair of rotatable wedges for cavity alignment which eliminates acoustic resonances. A detailed description and discussion of techniques used to characterize the frequency noise and linewidths of these lasers is provided.

Construction and characterization of external cavity diode lasers for atomic physics.

Since their development in the late 1980s, cheap, reliable external cavity diode lasers (ECDLs) have replaced complex and expensive traditional dye and Titanium Sapphire lasers as the workhorse laser of atomic physics labs. Their versatility and prolific use throughout atomic physics in applications such as absorption spectroscopy and laser cooling makes it imperative for incoming students to gain a firm practical understanding of these lasers. This publication builds upon the seminal work by Wieman, updating components, and providing a video tutorial. The setup, frequency locking and performance characterization of an ECDL will be described. Discussion of component selection and proper mounting of both diodes and gratings, the factors affecting mode selection within the cavity, proper alignment for optimal external feedback, optics setup for coarse and fine frequency sensitive measurements, a brief overview of laser locking techniques, and laser linewidth measurements are included.

Social interactions affect physiological consequences of sublethal copper exposure in rainbow trout, Oncorhynchus mykiss.

The interactions of sublethal waterborne copper exposure and social dominance behavior were examined in juvenile rainbow trout. Dominance hierarchies were determined between pairs of fish by behavioral observations and among groups of 10 fish by the use of passive integrated transponder (PIT) tagging equipment. The present study is one of the first to utilize this novel PIT tag method for behavioral assessment. Feeding behavior was quantified by placing a PIT tag recorder at the entrance to the feeding area. Linear dominance hierarchies were documented based on these observations of feeding behavior. Dominance hierarchies established in control water were not altered by exposure to 30 microg/L of copper; however, physiological responses of fish to sublethal concentrations of copper were related to social rank. Subordinate fish exhibited a higher accumulation of copper in both gill and liver tissue. Subordinates of paired fish were also shown to have a higher uptake of sodium than dominant fish, and the uptake of sodium was correlated with uptake of copper from the water. Therefore, within a population of fish, it cannot be assumed that individuals of different social status will exhibit the same physiological responses to the presence of copper.