Polymyalgia rheumatica shows metabolomic alterations that are further altered by glucocorticoid treatment: Identification of metabolic correlates of fatigue.

OBJECTIVE: In polymyalgia rheumatica (PMR), glucocorticoids (GCs) relieve pain and stiffness, but fatigue may persist. We aimed to explore the effect of disease, GCs and PMR symptoms in the metabolite signatures of peripheral blood from patients with PMR or the related disease, giant cell arteritis (GCA). METHODS: Nuclear magnetic resonance spectroscopy was performed on serum from 40 patients with untreated PMR, 84 with new-onset confirmed GCA, and 53 with suspected GCA who later were clinically confirmed non-GCA, and 39 age-matched controls. Further samples from PMR patients were taken one and six months into glucocorticoid therapy to explore relationship of metabolites to persistent fatigue. 100 metabolites were identified using Chenomx and statistical analysis performed in SIMCA-P to examine the relationship between metabolic profiles and, disease, GC treatment or symptoms. RESULTS: The metabolite signature of patients with PMR and GCA differed from that of age-matched non-inflammatory controls (R2 > 0.7). There was a smaller separation between patients with clinically confirmed GCA and those with suspected GCA who later were clinically confirmed non-GCA (R2 = 0.135). In PMR, metabolite signatures were further altered with glucocorticoid treatment (R2 = 0.42) but did not return to that seen in controls. Metabolites correlated with CRP, pain, stiffness, and fatigue (R2 ≥ 0.39). CRP, pain, and stiffness declined with treatment and were associated with 3-hydroxybutyrate and acetoacetate, but fatigue did not. Metabolites differentiated patients with high and low fatigue both before and after treatment (R2 > 0.9). Low serum glutamine was predictive of high fatigue at both time points (0.79-fold change). CONCLUSION: PMR and GCA alter the metabolite signature. In PMR, this is further altered by glucocorticoid therapy. Treatment-induced metabolite changes were linked to measures of inflammation (CRP, pain and stiffness), but not to fatigue. Furthermore, metabolite signatures distinguished patients with high or low fatigue.

Elevated fullness and bloating as correlates of eating pathology: Implications for screening.

A minority of individuals with eating disorders report being asked about their eating by health care professionals; delayed detection of eating disorders may contribute to poorer outcomes. The current study investigated common meal-related gastrointestinal symptoms (i.e., elevated fullness and bloating) as correlates of eating pathology that may be more readily disclosed to health professionals and indicate the need to assess for eating pathology. The current study also tested the hypothesis that elevated fullness and bloating are more strongly linked to eating pathology among those with higher body dissatisfaction. 281 university students (70.1% female, 84.3% white) completed gastrointestinal symptom and eating pathology assessments. Elevated fullness and bloating were each associated with increased purging, restrictive eating behaviors, and likelihood of having an eating disorder. Elevated fullness and bloating were more strongly linked to purging and probable eating disorder diagnosis with higher, relative to lower, body dissatisfaction. However, body dissatisfaction did not moderate the relationship between gastrointestinal symptoms and restrictive eating behaviors. Results indicate that elevated fullness and bloating are correlates of eating pathology. Healthcare professionals should consider and/or assess for eating pathology when elevated fullness and bloating are reported; further assessment of body dissatisfaction may be helpful in identifying purging behaviors.

Development and user-testing of a digital patient decision aid to facilitate shared decision-making for people with stable angina.

BACKGROUND: Research shows that people with stable angina need decision support when considering elective treatments. Initial treatment is with medicines but patients may gain further benefit with invasive percutaneous coronary intervention (PCI). Choosing between these treatments can be challenging for patients because both confer similar benefits but have different risks. Patient decision aids (PtDAs) are evidence-based interventions that support shared decision-making (SDM) when making healthcare decisions. This study aimed to develop and user-test a digital patient decision aid (CONNECT) to facilitate SDM for people with stable angina considering invasive treatment with elective PCI. METHODS: A multi-phase study was conducted to develop and test CONNECT (COroNary aNgioplasty dECision Tool) using approaches recommended by the International Patient Decision Aid Standards Collaboration: (i) Steering Group assembled, (ii) review of clinical guidance, (iii) co-design workshops with patients and cardiology health professionals, (iv) first prototype developed and 'alpha' tested (semi-structured cognitive interviews and 12-item acceptability questionnaire) with patients, cardiologists and cardiac nurses, recruited from two hospitals in Northern England, and (v) final PtDA refined following iterative user-feedback. Quantitative data were analysed descriptively and qualitative data from the interviews analysed using deductive content analysis. RESULTS: CONNECT was developed and user-tested with 34 patients and 29 cardiology health professionals. Findings showed that CONNECT was generally acceptable, usable, comprehensible, and desirable. Participants suggested that CONNECT had the potential to improve care quality by personalising consultations and facilitating SDM and informed consent. Patient safety may be improved as CONNECT includes questions about symptom burden which can identify asymptomatic patients unlikely to benefit from PCI, as well as those who may need to be fast tracked because of worsening symptoms. CONCLUSIONS: CONNECT is the first digital PtDA for people with stable angina considering elective PCI, developed in the UK using recommended processes and fulfilling international quality criteria. CONNECT shows promise as an approach to facilitate SDM and should be evaluated in a clinical trial. Further work is required to standardise the provision of probabilistic risk information for people considering elective PCI and to understand how CONNECT can be accessible to underserved communities.

Experiential modulation of social dominance in a SYNGAP1 rat model of Autism Spectrum Disorders.

Advances in the understanding of developmental brain disorders such as autism spectrum disorders (ASDs) are being achieved through human neurogenetics such as, for example, identifying de novo mutations in SYNGAP1 as one relatively common cause of ASD. A recently developed rat line lacking the calcium/lipid binding (C2) and GTPase activation protein (GAP) domain may further help uncover the neurobiological basis of deficits in children with ASD. This study focused on social dominance in the tube test using Syngap+/Δ-GAP (rats heterozygous for the C2/GAP domain deletion) as alterations in social behaviour are a key facet of the human phenotype. Male animals of this line living together formed a stable intra-cage hierarchy, but they were submissive when living with wild-type (WT) cage-mates, thereby modelling the social withdrawal seen in ASD. The study includes a detailed analysis of specific behaviours expressed in social interactions by WT and mutant animals, including the observation that when the Syngap+/Δ-GAP mutants that had been living together had separate dominance encounters with WT animals from other cages, the two higher ranking Syngap+/Δ-GAP rats remained dominant whereas the two lower ranking mutants were still submissive. Although only observed in a small subset of animals, these findings support earlier observations with a rat model of Fragile X, indicating that their experience of winning or losing dominance encounters has a lasting influence on subsequent encounters with others. Our results highlight and model that even with single-gene mutations, dominance phenotypes reflect an interaction between genotypic and environmental factors.

Quantitative prediction of the extent of pelvic tumour ablation by magnetic resonance-guided high intensity focused ultrasound.

BACKGROUND: Patient suitability for magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) therapy of pelvic tumors is currently assessed by visual estimation of the proportion of tumor that can be reached by the device's focus (coverage). Since it is important to assess whether enough energy reaches the tumor to achieve ablation, a methodology for estimating the proportion of the tumor that can be ablated (treatability) was developed. Predicted treatability was compared against clinically achieved thermal ablation. METHODS: MR Dixon sequence images of five patients with recurrent gynecological tumors were acquired during their treatment. Acousto-thermal simulations were performed using k-Wave for three exposure points (the deepest and shallowest reachable focal points within the tumor, identified from tumor coverage analysis, and a point halfway in-between) per patient. Interpolation between the resulting simulated ablated tissue volumes was used to estimate the maximum treatable depth and hence, tumor treatability. Predicted treatability was compared both to predicted tumor coverage and to the clinically treated tumor volume. The intended and simulated volumes and positions of ablated tissues were compared. RESULTS: Predicted treatability was less than coverage by 52% (range: 31-78%) of the tumor volume. Predicted and clinical treatability differed by 9% (range: 1-25%) of tumor volume. Ablated tissue volume and position varied with beam path length through tissue. CONCLUSION: Tumor coverage overestimated patient suitability for MRgHIFU therapy. Employing patient-specific simulations improved treatability assessment. Patient treatability assessment using simulations is feasible.

Prediction of pelvic tumour coverage by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) from referral imaging.

BACKGROUND: Patient suitability for magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) ablation of pelvic tumors is initially evaluated clinically for treatment feasibility using referral images, acquired using standard supine diagnostic imaging, followed by MR screening of potential patients lying on the MRgHIFU couch in a 'best-guess' treatment position. Existing evaluation methods result in ≥40% of referred patients being screened out because of tumor non-targetability. We hypothesize that this process could be improved by development of a novel algorithm for predicting tumor coverage from referral imaging. METHODS: The algorithm was developed from volunteer images and tested with patient data. MR images were acquired for five healthy volunteers and five patients with recurrent gynaecological cancer. Subjects were MR imaged supine and in oblique-supine-decubitus MRgHIFU treatment positions. Body outline and bones were segmented for all subjects, with organs-at-risk and tumors also segmented for patients. Supine images were aligned with treatment images to simulate a treatment dataset. Target coverage (of patient tumors and volunteer intra-pelvic soft tissue), i.e. the volume reachable by the MRgHIFU focus, was quantified. Target coverage predicted from supine imaging was compared to that from treatment imaging. RESULTS: Mean (±standard deviation) absolute difference between supine-predicted and treatment-predicted coverage for 5 volunteers was 9 ± 6% (range: 2-22%) and for 4 patients, was 12 ± 7% (range: 4-21%), excluding a patient with poor acoustic coupling (coverage difference was 53%). CONCLUSION: Prediction of MRgHIFU target coverage from referral imaging appears feasible, facilitating further development of automated evaluation of patient suitability for MRgHIFU.

Prospective Comparison of Preoperative Predictive Performance Between 3 Leading Frailty Instruments.

BACKGROUND: Guidelines recommend routine preoperative frailty assessment for older people. However, the degree to which frailty instruments improve predictive accuracy when added to traditional risk factors is poorly described. Our objective was to measure the accuracy gained in predicting outcomes important to older patients when adding the Clinical Frailty Scale (CFS), Fried Phenotype (FP), or Frailty Index (FI) to traditional risk factors. METHODS: This was an analysis of a multicenter prospective cohort of elective noncardiac surgery patients ≥65 years of age. Each frailty instrument was prospectively collected. The added predictive performance of each frailty instrument beyond the baseline model (age, sex, American Society of Anesthesiologists' score, procedural risk) was estimated using likelihood ratio test, discrimination, calibration, explained variance, and reclassification. Outcomes analyzed included death or new disability, prolonged length of stay (LoS, >75th percentile), and adverse discharge (death or non-home discharge). RESULTS: We included 645 participants (mean age, 74 [standard deviation, 6]); 72 (11.2%) participants died or experienced a new disability, 164 (25.4%) had prolonged LoS, and 60 (9.2%) had adverse discharge. Compared to the baseline model predicting death or new disability (area under the curve [AUC], 0.67; R, 0.08, good calibration), prolonged LoS (AUC, 0.73; R, 0.18, good calibration), and adverse discharge (AUC, 0.78; R, 0.16, poor calibration), the CFS improved fit per the likelihood ratio test (P < .02 for death or new disability, <.001 for LoS, <.001 for discharge), discrimination (AUC = 0.71 for death or new disability, 0.76 for LoS, 0.82 for discharge), calibration (good for death or new disability, LoS, and discharge), explained variance (R = 0.11 for death or new disability, 0.22 for LoS, 0.25 for discharge), and reclassification (appropriate directional reclassification) for all outcomes. The FP improved discrimination and R for all outcomes, but to a lesser degree than the CFS. The FI improved discrimination for death or new disability and R for all outcomes, but to a lesser degree than the CFS and the FP. These results were consistent in internal validation. CONCLUSIONS: Frailty instruments provide meaningful increases in accuracy when predicting postoperative outcomes for older people. Compared to the FP and FI, the CFS appears to improve all measures of predictive performance to the greatest extent and across outcomes. Combined with previous research demonstrating that the CFS is easy to use and requires less time than the FP, clinicians should consider its use in preoperative practice.

Developmental outcomes following prenatal exposure to methamphetamine: A Western Australian perspective.

AIM: To describe neurodevelopmental outcomes among a cohort of Western Australian infants exposed to maternal methamphetamine use during pregnancy and to determine whether the Ages and Stages Questionnaire is a reliable screening tool for this population. METHODS: Methamphetamine-using women were approached for participation when referred to the state-wide perinatal specialist drug and alcohol service for pregnancy care. Drug use during pregnancy was self-reported in each trimester using a standardised questionnaire. Ages and Stages Questionnaires were completed by infant care givers at 4 and 12 months, and development was formally assessed at 12 months using the Griffiths Mental Development Scales. Griffiths results for term-born infants in our cohort were compared to a Western Australian historical cohort of 443 healthy 1-2-year-olds. RESULTS: A total of 112 methamphetamine-using pregnant women participated in the study, who gave birth to 110 live-born infants. Ages and Stages Questionnaires were completed for 89 (81%) and 78 (71%) of the infants at 4 and 12 months, respectively. The Ages and Stages assessment identified 30 infants (33.7%) as having a potential developmental delay at 4 months and 29 infants (38.7%) as having a potential developmental delay at 12 months. Griffiths assessments were performed on 64 (58%) of the infants, with a mean general quotient of 92.7. This was significantly lower in term-born babies compared to the historical cohort (who had a median general quotient of 113.0). There was a weak correlation between 12-month Ages and Stages scores and Griffiths general quotients (r = 0.322) and no correlation between 4-month Ages and Stages Questionnaire scores and later Griffiths results. CONCLUSIONS: Infants born to women reporting methamphetamine use during pregnancy are at increased risk of developmental delay and may warrant enhanced developmental follow-up. However, they are a challenging group to follow due to complex psychosocial factors. Ages and Stages Questionnaires at 4 and 12 months were not helpful in screening for infants who had a developmental delay at 12 months.

Patients' Experiences of Cardiovascular Health Education and Risk Communication: A Qualitative Synthesis.

Coronary heart disease (CHD) has no cure, and patients with myocardial infarction are at high risk for further cardiac events. Health education is a key driver for patients' understanding and motivation for lifestyle change, but little is known about patients' experience of such education. In this review, we aimed to explore how patients with CHD experience health education and in particular risk communication. A total of 2,221 articles were identified through a systematic search in five databases. 40 articles were included and synthesized using thematic analysis. Findings show that both "what" was communicated, and "the way" it was communicated, had the potential to influence patients' engagement with lifestyle changes. Communication about the potential of lifestyle change to reduce future risk was largely missing causing uncertainty, anxiety, and, for some, disengagement with lifestyle change. Recommendations for ways to improve health education and risk communication are discussed to inform international practice.

Spotted Fever Group Rickettsia Infection and Transmission Dynamics in Amblyomma maculatum.

Tick vectors are capable of transmitting several rickettsial species to vertebrate hosts, resulting in various levels of disease. Studies have demonstrated the transmissibility of both rickettsial pathogens and novel Rickettsia species or strains with unknown pathogenicity to vertebrate hosts during tick blood meal acquisition; however, the quantitative nature of transmission remains unknown. We tested the hypothesis that if infection severity is a function of the rickettsial load delivered during tick transmission, then a more virulent spotted fever group (SFG) Rickettsia species is transmitted at higher levels during tick feeding. Using Amblyomma maculatum cohorts infected with Rickettsia parkeri or "Candidatus Rickettsia andeanae," a quantitative PCR (qPCR) assay was employed to quantify rickettsiae in tick salivary glands and saliva, as well as in the vertebrate hosts at the tick attachment site over the duration of tick feeding. Significantly greater numbers of R. parkeri than of "Ca Rickettsia andeanae" rickettsiae were present in tick saliva and salivary glands and in the vertebrate hosts at the feeding site during tick feeding. Microscopy demonstrated the presence of both rickettsial species in tick salivary glands, and immunohistochemical analysis of the attachment site identified localized R. parkeri, but not "Ca Rickettsia andeanae," in the vertebrate host. Lesions were also distinct and more severe in vertebrate hosts exposed to R. parkeri than in those exposed to "Ca Rickettsia andeanae." The specific factors that contribute to the generation of a sustained rickettsial infection and subsequent disease have yet to be elucidated, but the results of this study suggest that the rickettsial load in ticks and during transmission may be an important element.

Personalized perioperative medicine: a scoping review of personalized assessment and communication of risk before surgery.

BACKGROUND: Personalized medicine aims to improve outcomes through application of therapy directed by individualized risk profiles. Whether personalized risk assessment is routinely applied in practice is unclear; the impact of personalized preoperative risk prediction and communication on outcomes has not been synthesized. Our objective was to perform a scoping review to examine the extent, range, and nature of studies where personalized risk was evaluated preoperatively and communicated to the patient and/or healthcare professional. METHODS: A systematic search was developed, peer-reviewed, and applied to Embase, Medline, CINAHL, and Cochrane databases to identify studies of individuals having or considering surgery, where a process to assess personalized risk was applied and where these estimates were communicated to a patient and/or healthcare professional. All stages of the review were completed in duplicate. We narratively synthesized and described identified themes. RESULTS: We identified 796 studies; 24 underwent full-text review. Seven studies were included; one communicated personalized risk to patients, four to a healthcare professional, and two to both. Cardiac (n = 2) and orthopedic surgery (n = 2) were the most common surgical specialties. Four studies used electronic risk calculators, and three used paper-based tools. Personalized preoperative risk assessment and communication may improve accuracy of information provided to patients, improve consent processes, and influence length of stay. Methodologic weaknesses in study design were common. CONCLUSIONS: Personalized preoperative risk assessment and communication may improve patient and system outcomes. This evidence is limited, however, by weaknesses in study design. Appropriately powered, low risk of bias evaluation of personalized risk communication before surgery is needed.

Role of Sca2 and RickA in the Dissemination of Rickettsia parkeri in Amblyomma maculatum.

The Gram-negative obligate intracellular bacterium Rickettsia parkeri is an emerging tick-borne human pathogen. Recently, R. parkeri Sca2 and RickA have been implicated in adherence and actin-based motility in vertebrate host cell infection models; however, the rickettsia-derived factors essential to tick infection are unknown. Using R. parkeri mutants lacking functional Sca2 or RickA to compare actin polymerization, replication, and cell-to-cell spread in vitro, similar phenotypes in tick and mammalian cells were observed. Specifically, actin polymerization in cultured tick cells is controlled by the two separate proteins in a time-dependent manner. To assess the role of Sca2 and RickA in dissemination in the tick host, Rickettsia-free Amblyomma maculatum, the natural vector of R. parkeri, was exposed to wild-type, R. parkeri rickA::tn, or R. parkeri sca2::tn bacteria, and individual tick tissues, including salivary glands, midguts, ovaries, and hemolymph, were analyzed at 12 h and after continued bloodmeal acquisition for 3 or 7 days postexposure. Initially, ticks exposed to wild-type R. parkeri had the highest rickettsial load across all organs; however, rickettsial loads decreased and wild-type rickettsiae were cleared from the ovaries at 7 days postexposure. In contrast, ticks exposed to R. parkeririckA::tn or R. parkerisca2::tn had comparatively lower rickettsial loads, but bacteria persisted in all organs for 7 days. These data suggest that while RickA and Sca2 function in actin polymerization in tick cells, the absence of these proteins did not change dissemination patterns within the tick vector.

Nonselective Persistence of a Rickettsia conorii Extrachromosomal Plasmid during Mammalian Infection.

Scientific analysis of the genus Rickettsia is undergoing a rapid period of change with the emergence of viable genetic tools. The development of these tools for the mutagenesis of pathogenic bacteria will permit forward genetic analysis of Rickettsia pathogenesis. Despite these advances, uncertainty still remains regarding the use of plasmids to study these bacteria in in vivo mammalian models of infection, namely, the potential for virulence changes associated with the presence of extrachromosomal DNA and nonselective persistence of plasmids in mammalian models of infection. Here, we describe the transformation of Rickettsia conorii Malish 7 with the plasmid pRam18dRGA[AmTrCh]. Transformed R. conorii stably maintains this plasmid in infected cell cultures, expresses the encoded fluorescent proteins, and exhibits growth kinetics in cell culture similar to those of nontransformed R. conorii. Using a well-established murine model of fatal Mediterranean spotted fever, we demonstrate that R. conorii(pRam18dRGA[AmTrCh]) elicits the same fatal outcomes in animals as its untransformed counterpart and, importantly, maintains the plasmid throughout infection in the absence of selective antibiotic pressure. Interestingly, plasmid-transformed R. conorii was readily observed both in endothelial cells and within circulating leukocytes. Together, our data demonstrate that the presence of an extrachromosomal DNA element in a pathogenic rickettsial species does not affect either in vitro proliferation or in vivo infectivity in models of disease and that plasmids such as pRam18dRGA[AmTrCh] are valuable tools for the further genetic manipulation of pathogenic rickettsiae.

Classification of fibroglandular tissue distribution in the breast based on radiotherapy planning CT.

BACKGROUND: Accurate segmentation of breast tissues is required for a number of applications such as model based deformable registration in breast radiotherapy. The accuracy of breast tissue segmentation is affected by the spatial distribution (or pattern) of fibroglandular tissue (FT). The goal of this study was to develop and evaluate texture features, determined from planning computed tomography (CT) data, to classify the spatial distribution of FT in the breast. METHODS: Planning CT data of 23 patients were evaluated in this study. Texture features were derived from the radial glandular fraction (RGF), which described the distribution of FT within three breast regions (posterior, middle, and anterior). Using visual assessment, experts grouped patients according to FT spatial distribution: sparse or non-sparse. Differences in the features between the two groups were investigated using the Wilcoxon rank test. Classification performance of the features was evaluated for a range of support vector machine (SVM) classifiers. RESULTS: Experts found eight patients and 15 patients had sparse and non-sparse spatial distribution of FT, respectively. A large proportion of features (>9 of 13) from the individual breast regions had significant differences (p <0.05) between the sparse and non-sparse group. The features from middle region had most significant differences and gave the highest classification accuracy for all the SVM kernels investigated. Overall, the features from middle breast region achieved highest accuracy (91%) with the linear SVM kernel. CONCLUSION: This study found that features based on radial glandular fraction provide a means for discriminating between fibroglandular tissue distributions and could achieve a classification accuracy of 91%.

Whole-body MRI of patients with polymyalgia rheumatica identifies a distinct subset with complete patient-reported response to glucocorticoids.

OBJECTIVES: To determine whether whole-body MRI defines clinically relevant subgroups within polymyalgia rheumatica (PMR) including glucocorticoid responsiveness. METHODS: 22 patients with PMR and 16 with rheumatoid arthritis (RA), untreated and diagnosed by consultant rheumatologists, underwent whole-body, multiple-joint MRI, scored by two experts. Patients with PMR reported whether they felt 'back to normal' on glucocorticoid therapy and were followed for a median of 2 years. RESULTS: All patients with PMR were deemed to respond to glucocorticoids clinically. A characteristic pattern of symmetrical, extracapsular inflammation, adjacent to greater trochanter, acetabulum, ischial tuberosity and/or symphysis pubis, was observed in 14/22 of the PMR cases. In PMR, this pattern was associated with complete glucocorticoid response (p=0.01), higher pretreatment C-reactive protein (CRP) and serum interleukin-6 (IL-6), and better post-treatment fatigue and function. Only 1/14 in the extracapsular group could stop glucocorticoids within 1 year, compared with 4/7 of the others. A score derived from the five sites discriminating best between PMR and RA correlated with IL-6 (p<0.002). IL-6 levels ≥16.8 pg/mL had 86% sensitivity and 86% specificity for the extracapsular MRI pattern. CONCLUSIONS: A subset of patients with rheumatologist-diagnosed PMR had a characteristic, extracapsular pattern of MRI inflammation, associated with elevated IL-6/CRP and with complete patient-reported glucocorticoid responsiveness.

The prediction and monitoring of toxicity associated with long-term systemic glucocorticoid therapy.

Glucocorticoids are often required for adequate control of inflammation in many serious inflammatory diseases; common indications for long-term treatment include polymyalgia rheumatica, giant cell arteritis, asthma and chronic obstructive pulmonary disease. Long-term glucocorticoid therapy is, however, associated with many adverse effects involving skin, gastro-intestinal, eye, skeletal muscle, bone, adrenal, cardio-metabolic and neuropsychiatric systems. This balance between benefits and risks of glucocorticoids is important for clinical practice and glucocorticoid-related adverse effects can significantly impair health-related quality of life. Understanding the nature and mechanisms of glucocorticoid-related adverse effects may inform how patients are monitored for toxicity and identify those groups, such as older people, that may need closer monitoring. For clinical trials in diseases commonly treated with glucocorticoids, standardised measurement of glucocorticoid-related adverse effects would facilitate future evidence synthesis and meta-analysis.

Predicting cervical cancer target motion using a multivariate regression model to enable patient selection for adaptive external beam radiotherapy.

Background and purpose: Interfraction motion during cervical cancer radiotherapy is substantial in some patients, minimal in others. Non-adaptive plans may miss the target and/or unnecessarily irradiate normal tissue. Adaptive radiotherapy leads to superior dose-volume metrics but is resource-intensive. The aim of this study was to predict target motion, enabling patient selection and efficient resource allocation. Materials and methods: Forty cervical cancer patients had CT with full-bladder (CT-FB) and empty-bladder (CT-EB) at planning, and daily cone-beam CTs (CBCTs). The low-risk clinical target volume (CTVLR) was contoured. Mean coverage of the daily CTVLR by the CT-FB CTVLR was calculated for each patient. Eighty-three investigated variables included measures of organ geometry, patient, tumour and treatment characteristics. Models were trained on 29 patients (171 fractions). The Two-CT multivariate model could use all available data. The Single-CT multivariate model excluded data from the CT-EB. A univariate model was trained using the distance moved by the uterine fundus tip between CTs, the only method of patient selection found in published cervix plan-of-the-day studies. Models were tested on 11 patients (68 fractions). Accuracy in predicting mean coverage was reported as mean absolute error (MAE), mean squared error (MSE) and R2. Results: The Two-CT model was based upon rectal volume, dice similarity coefficient between CT-FB and CT-EB CTVLR, and uterine thickness. The Single-CT model was based upon rectal volume, uterine thickness and tumour size. Both performed better than the univariate model in predicting mean coverage (MAE 7 %, 7 % and 8 %; MSE 82 %2, 65 %2, 110 %2; R2 0.2, 0.4, -0.1). Conclusion: Uterocervix motion is complex and multifactorial. We present two multivariate models which predicted motion with reasonable accuracy using pre-treatment information, and outperformed the only published method.

Comparing the healthy development of youth Australian Rules Footballers across talent development and community settings.

Objectives: This study aimed to compare talent development athletes to community-level athletes in Australian Rules Football across various markers of healthy youth development. Methods: Survey data were collected from 363 youth athletes (126 women, 232 men, 5 not reported; Mage=18.69 years, SDage=2.62 years, age range 16-25 years) playing Australian Rules Football at a talent development (recruited from Australian Football League Talent Pathway, n=220) or community (n=143) level. Measures included markers of physical health (eg, general health, risk-taking behaviours), psychological and emotional well-being (eg, mental health symptoms, life satisfaction), family and social relationships (eg, social support, relationship status), educational and occupational attainment/engagement (eg, career satisfaction, education), ethical behaviour (eg, moral self-image), civic engagement, life skills (eg, self-mastery, coping), and demographics. Results: Based on regression models, relative to community-level athletes, talent development athletes reported better physical health (d=0.51), lower injury rates (OR=0.50) and less problematic drug use (d=-0.46). Talent development athletes also reported better psychological and emotional well-being, evidenced by lower stress (d=-0.30), higher life satisfaction (d=0.47) and less problematic gambling (d=-0.34). Additionally, talent development athletes reported higher family support (d=0.49), lower likelihood of poor educational outcomes (less than expected educational stage; OR=0.37), lower intention to complete less than year 12 education (OR=0.18), higher career satisfaction (d=0.42), higher self-mastery (d=0.37) and higher perfectionistic striving (d=0.59). Conclusion: Findings demonstrate markers of healthier development within talent development athletes relative to community athlete peers. Investment in community-level sports may be warranted to improve healthy development. However, further causal evidence is required.

Moderate and heavy metabolic stress interval training improve arterial stiffness and heart rate dynamics in humans.

Traditional continuous aerobic exercise training attenuates age-related increases of arterial stiffness, however, training studies have not determined whether metabolic stress impacts these favourable effects. Twenty untrained healthy participants (n = 11 heavy metabolic stress interval training, n = 9 moderate metabolic stress interval training) completed 6 weeks of moderate or heavy intensity interval training matched for total work and exercise duration. Carotid artery stiffness, blood pressure contour analysis, and linear and non-linear heart rate variability were assessed before and following training. Overall, carotid arterial stiffness was reduced (p < 0.01), but metabolic stress-specific alterations were not apparent. There was a trend for increased absolute high-frequency (HF) power (p = 0.10) whereas both absolute low-frequency (LF) power (p = 0.05) and overall power (p = 0.02) were increased to a similar degree following both training programmes. Non-linear heart rate dynamics such as detrended fluctuation analysis [Formula: see text] also improved (p > 0.05). This study demonstrates the effectiveness of interval training at improving arterial stiffness and autonomic function, however, the metabolic stress was not a mediator of this effect. In addition, these changes were also independent of improvements in aerobic capacity, which were only induced by training that involved a high metabolic stress.