Associations between fatigue impact and physical and neurobehavioural factors: An exploration in people with progressive multiple sclerosis.

BACKGROUND: Fatigue is common in people with multiple sclerosis (MS). Understanding the relationship between fatigue, physical and neurobehavioural factors is important to inform future research and practice. Few studies explore this explicitly in people with progressive MS (pwPMS). OBJECTIVE: To explore relationships between self-reported fatigue, physical and neurobehavioural measures in a large, international progressive MS sample of cognitively impaired people recruited to the CogEx trial. METHODS: Baseline assessments of fatigue (Modified Fatigue Impact Scale; MFIS), aerobic capacity (VO2peak), time in moderate-vigorous physical activity (MVPA; accelerometery over seven-days), walking performance (6-minute walk test; 6MWT), self-reported walking difficulty (MS Walking Scale; MSWS-12), anxiety and depression (Hospital Anxiety and Depression Scale; HADS and Beck Depression Inventory-II; BDI-II), and disease impact (MS Impact Scale-29, MSIS-29) were assessed. Participants were categorised as fatigued (MFISTotal >=38) or non-fatigued (MFISTotal ≤38). STATISTICAL ANALYSIS: Differences in individuals categorised as fatigued or non-fatigued were assessed (t-tests, chi square). Pearson's correlation and partial correlations (adjusted for EDSS score, country, sex, and depressive symptoms) determined associations with MFISTotal, MFISPhysical, MFISCognitive and MFISPsychosocial, and the other measures. Multivariable logistic regression evaluated the independent association of fatigue (categorised MFISTotal) with physical and neurobehavioural measures. RESULTS: The sample comprised 308 pwPMS (62 % female, 27 % primary progressive, 73 % secondary progressive), mean age 52.5 ± 7.2 yrs, median EDSS score 6.0 (4.5-6.5), mean MFISTotal 44.1 ± 17.1, with 67.2 % categorised as fatigued. Fatigued participants walked shorter distances (6MWT, p = 0.043), had worse MSWS-12 scores (p < 0.001), and lower average % in MVPA (p = 0.026). The magnitude of associations was mostly weak between MFISTotal and physical measures (r = 0.13 to 0.18), apart from the MSWS-12 where it was strong (r = 0.51). The magnitude of correlations were strong between the MFISTotal and neurobehavioural measures of anxiety (r = 0.56), depression (r = 0.59), and measures of disease impact (MSIS-physical r = 0.67; MSIS-mental r = 0.71). This pattern was broadly similar for the MSIF subscales. The multivariable model indicated a five-point increase in MSWS-12 was associated with a 14 % increase in the odds of being fatigued (OR [95 %CI]: 1.14 [1.07-1.22], p < 0.0001) CONCLUSION: Management of fatigue should consider both physical and neurobehavioural factors, in cognitively impaired persons with progressive MS.

Adaptation and content validation of measure yourself medical outcomes profile (MYMOP) for 7-11 year-old children.

BACKGROUND: The Measure Yourself Medical Outcome Profile (MYMOP) is an individualised tool designed for adults but used with children without any evidence of validation in this population. Individualised instruments are patient-specific rather than disease-specific and therefore can be applied across various health conditions. This study sought to adapt, and content validate the MYMOP for application in 7-11 year old children. METHODS: There were two main phases of the four iterations: expert consultation (three rounds) and interviews with child-parent pairs at the Outpatient clinics of a Children's Hospital. Thematic analysis was undertaken using an inductive, interpretative approach. RESULTS: Four paediatricians completed the first survey, five paediatricians participated in the focus group, and four paediatric health-related quality of life (HRQOL) research experts completed the second survey. Several changes were recommended to the MYMOP by the expert groups. Twenty-five children (17 general medicine, and 8 diabetes/endocrine clinic) aged 7-11 years completed the draft paediatric MYMOP (P-MYMOP) and were interviewed. Results demonstrated that the majority of participants were able to identify their own problems and activity limitations, and all participants understood the 7-point faces scale. Most parents and children perceived that the P-MYMOP would be useful to complete before clinic appointments. CONCLUSIONS: The P-MYMOP is the first content-validated generic individualised HRQOL measure for children 7-11 years old. Given that validation is an iterative process, further research to assess its feasibility, reliability, and construct validity is required.

Comparison of effect of CTG + STan with CTG alone on emergency Cesarean section rate: STan Australian Randomized controlled Trial (START).

OBJECTIVE: To investigate whether use of ST analysis of the fetal electrocardiogram (STan) as an adjunct to continuous cardiotocography (CTG) reduces the rate of emergency Cesarean section (EmCS) compared with CTG alone. METHODS: This was a randomized controlled trial of patients with a singleton fetus in cephalic presentation at ≥ 36 weeks' gestation, requiring continuous electronic fetal monitoring during labor at a tertiary maternity hospital in Adelaide, Australia, between January 2018 and July 2021. Participants were randomized to undergo CTG + STan or CTG alone. The calculated sample size was 1818 participants. The primary outcome was EmCS. Secondary outcomes included metabolic acidosis, a composite adverse perinatal outcome, and other maternal and neonatal morbidity and safety outcomes. RESULTS: The present study enrolled 970 women, of whom 967 were included in the primary analysis. EmCS occurred in 107/482 (22.2%) deliveries in the CTG + STan arm and in 107/485 (22.1%) in the CTG arm (adjusted relative risk, 1.02 (95% CI, 0.81-1.27); P = 0.89). There was no difference in the rate of adverse maternal or neonatal outcomes between arms. CONCLUSIONS: The addition of STan as an adjunct to continuous CTG did not reduce the EmCS rate. The smaller-than-anticipated sample size meant that this study was underpowered to detect absolute differences of ≤ 5% and, therefore, this negative finding could be due to a Type-2 error. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study.

BACKGROUND: Performing cognitive-motor dual tasks (DTs) may result in reduced walking speed and cognitive performance. The effect in persons with progressive multiple sclerosis (pwPMS) having cognitive dysfunction is unknown. OBJECTIVE: To profile DT-performance during walking in cognitively impaired pwPMS and examine DT-performance by disability level. METHODS: Secondary analyses were conducted on baseline data from the CogEx-study. Participants, enrolled with Symbol Digit Modalities Test 1.282 standard deviations below normative value, performed a cognitive single task ([ST], alternating alphabet), motor ST (walking) and DT (both). Outcomes were number of correct answers on the alternating alphabet task, walking speed, and DT-cost (DTC: decline in performance relative to the ST). Outcomes were compared between EDSS subgroups (≤ 4, 4.5-5.5, ≥ 6). Spearman correlations were conducted between the DTCmotor with clinical measures. Adjusted significance level was 0.01. RESULTS: Overall, participants (n = 307) walked slower and had fewer correct answers on the DT versus ST (both p < 0.001), with a DTCmotor of 15.8% and DTCcognitive of 2.7%. All three subgroups walked slower during the DT versus ST, with DTCmotor different from zero (p's < 0.001). Only the EDSS ≥ 6 group had fewer correct answers on the DT versus ST (p < 0.001), but the DTCcognitive did not differ from zero for any of the groups (p ≥ 0.039). CONCLUSION: Dual tasking substantially affects walking performance in cognitively impaired pwPMS, to a similar degree for EDSS subgroups.

Data harmonization for collaborative research among MS registries: A case study in employment.

OBJECTIVE: To assess the feasibility of collaboration and retrospective data harmonization among three multiple sclerosis (MS) registries by investigating employment status. METHODS: We used the Maelstrom guidelines to facilitate retrospective harmonization of data from three MS registries, including the NARCOMS (North American Research Committee on MS) Registry, German MS Register (GMSR), and United Kingdom MS (UK-MS) Register. A protocol was developed based on the guidelines, and summary-level data were used to combine results. Employment status and a limited set of factors associated with employment (age, sex, education, and disability level) were harmonized. A meta-analytic approach was used to pool estimates using a weighted average of logistic regression estimates and their variances in a random effects model. RESULTS: Employment status, age, sex, education, and disability were mapped. The overall employment rate was 57% (11,143 employed out of 19,562 persons with MS) with the GMSR having the highest proportion of participants employed (66.2%), followed by the UK-MS (55.2%) and NARCOMS (43.0%) registries. As disability level increased, the odds of not being employed increased. CONCLUSION: Harmonization across registries was feasible. The Maelstrom guidelines provide a valuable roadmap for conducting high-quality harmonization projects. The pooling of data sources has the potential to be an important mechanism for conducting research in MS.

Comparing the effect of STan (cardiotocographic electronic fetal monitoring (CTG) plus analysis of the ST segment of the fetal electrocardiogram) with CTG alone on emergency caesarean section rates: study protocol for the STan Australian Randomised controlled Trial (START).

BACKGROUND: Cardiotocography is almost ubiquitous in its use in intrapartum care. Although it has been demonstrated that there is some benefit from continuous intrapartum fetal monitoring using cardiotocography, there is also an increased risk of caesarean section which is accompanied by short-term and long-term risks to the mother and child. There is considerable potential to reduce unnecessary operative delivery with up to a 60% false positive diagnosis of fetal distress using cardiotocography alone. ST analysis of the fetal electrocardiogram is a promising adjunct to cardiotocography alone, and permits detection of metabolic acidosis of the fetus, potentially reducing false positive diagnosis of fetal distress. METHODS: This study will be a single-centre, parallel-group, randomised controlled trial, conducted over 3 years. The primary hypothesis will be that the proportion of women with an emergency caesarean section on ST analysis will not equal that for women on cardiotocography monitoring alone. Participants will be recruited at the Women's and Children's Hospital, a high-risk specialty facility with approximately 5000 deliveries per annum. A total of 1818 women will be randomised to the treatment or conventional arm with an allocation ratio of 1:1, stratified by parity. The primary outcome is emergency caesarean section (yes/no). Statistical analysis will follow standard methods for randomised trials and will be performed on an intention-to-treat basis. Secondary maternal and neonatal outcomes will also be analysed. Additional study outcomes include psychosocial outcomes, patient preferences and cost-effectiveness. DISCUSSION: Approximately 20% of Australian babies are delivered by emergency caesarean section. This will be the first Australian trial to examine ST analysis of the fetal electrocardiogram as an adjunct to cardiotocography as a potential method for reducing this proportion. The trial will be among the first to comprehensively examine ST analysis, taking into account the impact on psychosocial well-being as well as cost-effectiveness. This research will provide Australian evidence for clinical practice and guideline development as well as for policy-makers and consumers to make informed, evidence-based choices about care in labour. TRIAL REGISTRATION: ANZCTR, ACTRN1261800006268 . Registered on 19 January 2018.

Carbetocin reduces the need for additional uterotonics in elective caesarean delivery: a systematic review, meta-analysis and trial sequential analysis of randomised controlled trials.

BACKGROUND: Carbetocin has been found to be superior to oxytocin in terms of need for additional uterotonics and prevention of postpartum haemorrhage at caesarean delivery. However, this is based on combined data from labouring and non-labouring parturients and it remains unclear how effective carbetocin is in the purely elective setting. The aim of this review was to compare carbetocin to oxytocin in elective caesarean delivery. METHODS: Medline, Embase, CINAHL, Web of Science, and the Cochrane databases were searched for randomised controlled trials in any language. The primary outcome was need for additional uterotonics. Secondary outcomes were mean blood loss, need for blood transfusion and incidence of postpartum haemorrhage >1000 mL. RESULTS: Nine studies with a total of 1962 patients were included. Trial sequential analysis confirmed that the information size (n=1692) had surpassed that required (n=1166) in order to demonstrate a statistically significant reduction in the use of additional uterotonics. Need for additional uterotonics was reduced by 53% with carbetocin compared to oxytocin (OR 0.47, 95% CI 0.34 to 0.64; P <0.001, I2=63.5). The number needed-to-treat was 11. The risk of bias, data heterogeneity and inconsistency in reporting bleeding outcomes made it difficult to reach definite conclusions about prevention of PPH. CONCLUSIONS: Carbetocin is associated with a reduced need for additional uterotonics when compared with oxytocin at elective caesarean delivery. Standardisation of bleeding-related outcomes in studies is necessary to facilitate synthesis of data in future analyses.

Evaluating the Utility of a Postprocessing Algorithm for MRI Evaluation of Optic Neuritis.

BACKGROUND AND PURPOSE: MR imaging is useful for the detection and/or confirmation of optic neuritis. The objective of this study was to determine whether a postprocessing algorithm selectively increases the contrast-to-noise ratio of abnormal optic nerves in optic neuritis, facilitating this diagnosis on MR imaging. MATERIALS AND METHODS: In this retrospective case-control study, coronal FLAIR images and coronal contrast-enhanced T1WI from 44 patients (31 eyes with clinically confirmed optic neuritis and 28 control eyes) underwent processing using a proprietary postprocessing algorithm designed to detect and visually highlight regions of contiguous increases in signal intensity by increasing the signal intensities of regions that exceed a predetermined threshold. For quantitative evaluation of the effect on image processing, the contrast-to-noise ratio of equivalent ROIs and the contrast-to-noise ratio between optic nerves and normal-appearing white matter were measured on baseline and processed images. The effect of image-processing on diagnostic performance was evaluated by masked reviews of baseline and processed images by 6 readers with varying experience levels. RESULTS: In abnormal nerves, processing resulted in an increase in the median contrast-to-noise ratio from 17.8 to 85.0 (P < .001) on FLAIR and from 19.4 to 93.7 (P < .001) on contrast-enhanced images. The contrast-to-noise ratio for control optic nerves was not affected by processing (P = 0.13). Image processing had a beneficial effect on radiologists' diagnostic performance, with an improvement in sensitivities for 5/6 readers and relatively unchanged specificities. Interobserver agreement improved following processing. CONCLUSIONS: Processing resulted in a selective increase in the contrast-to-noise ratio for diseased nerves and corresponding improvement in the detection of optic neuritis on MR imaging by radiologists.

Image Processing to Improve Detection of Mesial Temporal Sclerosis in Adults.

In this retrospective case-control study, we investigated whether an image-processing algorithm designed to exaggerate the intensity of diseased hippocampi on FLAIR images can improve the diagnostic accuracy and interobserver reliability of radiologists in detecting mesial temporal sclerosis-related hippocampal signal alteration. Herein, we share the results of this study that showed that the image processing improved the confidence of radiologists in detecting mesial temporal sclerosis-related signal alteration, allowing an improved sensitivity, specificity, and interobserver reliability.

A systematic review of randomised controlled trials evaluating the use of patient-reported outcome measures (PROMs).

BACKGROUND: Patient-reported outcome measures (PROMs) could play an important role in identifying patients' needs and goals in clinical encounters, improving communication and decision-making with clinicians, while making care more patient-centred. Comprehensive evidence that PROMS are an effective intervention is lacking in single randomised controlled trials (RCTs). METHODS: A systematic search was performed using controlled vocabulary related to the terms: clinical care setting and patient-reported outcome. English language studies were included if they were a RCT with a PROM as an intervention in a patient population. Included studies were analysed and their methodologic quality was appraised using the Cochrane Risk of Bias tool. The protocol was registered with PROSPERO (CRD42016034182). RESULTS: Of 4302 articles initially identified, 115 underwent full-text review resulting in 22 studies reporting on 25 comparisons. The majority of included studies were conducted in USA (11), among cancer patients (11), with adult participants only (20). Statistically significant and robust improvements were reported in the pre-specified outcomes of the process of care (2) and health care (3). Additionally, five, eight and three statistically significant but possibly non-robust findings were reported in the process of care, health and patient satisfaction outcomes, respectively. CONCLUSIONS: Overall, studies that compared PROM to standard care either reported a positive effect or were not powered to find pre-specified differences. There is justification for the use of a PROM as part of standard care, but further adequately powered studies on their use in different contexts are necessary for a more comprehensive evidence base.

The effects of meat consumption on global health.

Meat represents an important source of high-quality dietary protein for a large proportion of the global population. In addition, red meat, in particular, significantly contributes to the intake of a wide range of micronutrients, including iron, zinc, selenium, vitamin D and vitamin B12. While these nutrients can be supplied in sufficient amounts by consumption of a range of fruit and vegetables, in many developing countries, where the availability of such foods may be limited, access to meat often protects against malnutrition and improves child cognitive development. Excessive consumption of meat and meat products is often associated with overconsumption of energy and fat, resulting in excess weight, obesity and an increased risk of chronic diseases, such as cardiovascular disease and type 2 diabetes. In addition, certain components of fresh and processed red meat may further increase the risk of these diseases and predispose the consumer to cancer, particularly colorectal cancer. In the face of population growth and global warming, there is increasing concern about the sustainability of farm animal production. Thus, while a modest intake of meat represents an important strategy to avoid essential nutrient deficiencies, limiting its intake can reduce the development of a range of chronic diseases and could have significant beneficial effects on global food security.

Pour une grande majorité de la population mondiale, la viande est une source importante de protéines de qualité. En particulier, la viande rouge contient divers micronutriments essentiels, dont le fer, le zinc, le sélénium, la vitamine D et la vitamine B12. Ces nutriments sont certes présents dans de nombreux fruits et légumes mais la disponibilité de ces aliments est souvent limitée dans les pays en développement, de sorte que c'est la consommation de viande qui permet de lutter contre la malnutrition et qui contribue au développement cognitif des enfants. D'un autre côté, une consommation excessive de viande et de produits carnés est fréquemment associée à une surconsommation de lipides et de protéines, avec pour effets une surcharge pondérale voire de l'obésité et un risque accru de maladies chroniques, dont les maladies cardiovasculaires et le diabète de type 2. En outre, certaines composantes de la viande rouge fraîche ou transformée majorent les risques associés à ces maladies ainsi que celui de développer un cancer, notamment colorectal. Compte tenu de la croissance de la population mondiale et du réchauffement climatique, la durabilité de la production animale est une question de plus en plus préoccupante. Par conséquent, si la consommation de viande en faibles quantités est une stratégie efficace pour lutter contre les carences en nutriments essentiels, le fait de limiter cette consommation permet de réduire l'exposition à plusieurs maladies chroniques et pourrait avoir un impact positif significatif sur la sécurité alimentaire à l'échelle mondiale.

La carne constituye una importante fuente de proteínas alimentarias de gran calidad para una enorme proporción de la población mundial. Además, la carne roja, en particular, contribuye en gran medida a la adquisición de muy diversos micronutrientes, sobre todo hierro, zinc, selenio, vitamina D y vitamina B12 y, si bien es posible obtener estos nutrientes ingiriendo cantidades suficientes de diversas frutas y hortalizas, en muchos países en desarrollo, donde este tipo de alimentos a veces escasea, la posibilidad de consumir carne suele proteger de la malnutrición y mejorar el desarrollo cognitivo del niño. Un consumo excesivo de carne y productos cárnicos suele acarrear una aportación excesiva de energía y grasas, lo que se traduce en sobrepeso, obesidad y un mayor riesgo de enfermedades crónicas como las cardiovasculares o la diabetes de tipo 2. Además, ciertos componentes de la carne roja fresca o procesada pueden elevar el riesgo de padecer estas dolencias y predisponer al consumidor al cáncer, en particular el colorrectal. Ante el crecimiento demográfico y el calentamiento planetario, cada vez preocupa más la cuestión de la sostenibilidad de la producción de animales de granja. Así pues, a la vez que un consumo modesto de carne constituye un importante expediente para evitar carencias en nutrientes esenciales, el hecho de limitar la ingesta puede reducir la aparición de toda una serie de enfermedades crónicas y podría tener efectos muy positivos en la seguridad alimentaria mundial.

National estimates of self-reported sitting time in adults with multiple sclerosis.

BACKGROUND: Limited data exist on the prevalence and distribution of sedentary behavior (SB) in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to describe sitting time as a metric of SB in a large national sample of people with MS. METHODS: A total of 8004 individuals from the North American Research Committee on MS (NARCOMS) Registry completed the sitting time question from the International Physical Activity Questionnaire in spring 2015. We present descriptive data on sitting time for the total sample and across sociodemographic, clinical, and behavioral characteristics. RESULTS: The final sample included 6483 individuals. Of these, 36.7% were classified with mild disability, 24.7% with moderate disability, and 38.6% with severe disability. Median sitting time for the total sample was 480 min/day (P25 = 310 min/day, P75 = 720 min/day). Sitting time was highest for individuals with MS who were male (540 min/day), not married (540 min/day), had a disease duration >30 years (540 min/day), were underweight (540.5 min/day), had an annual income of < $15,000 (585 min/day), presented with a progressive form of MS (600 min/day), were classified as insufficiently active (600 min/day), or presented with severe disability (661 min/day). CONCLUSION: Sitting time is twice as high in individuals with MS compared to the general population (240 min/day).

Temporal Evolution of Disc in Young Patients with Low Back Pain and Stress Reaction in Lumbar Vertebrae.

BACKGROUND AND PURPOSE: Although stress-induced bony changes often resolve with conservative treatment, the long-term effects of such mechanical stresses on intervertebral discs have not been studied. We aimed to assess the differences in the temporal evolution of disc in segments of the lumbar spine with and without signs of increased mechanical stresses. MATERIALS AND METHODS: Using MR imaging performed >6 months apart, 2 radiologists evaluated lumbar intervertebral discs for degenerative changes affecting the annulus fibrosus, the nucleus pulposus, and the endplates in 42 patients (22 male, 20 female; mean age, 16.0 ± 3.7 years [range, 7-25 years]) with low back pain and imaging evidence of stress reaction/fracture in the lumbar spine. Data were analyzed for differences in the presence and progression of disc degeneration in stressed versus nonstressed segments. RESULTS: At baseline, stressed discs had a higher burden of annular fissures, radial fissures, herniation, and nuclear degeneration. Endplate defect burden was comparable in stressed and control discs. At follow-up, the burden of new annular fissures and endplate defects was comparable for stressed and control discs. However, a higher proportion of stressed discs showed worsening nuclear signal intensity grade (14.3% versus 0% control discs; P = .008) and worsening nuclear degeneration grade (11.9% versus 0% control discs; P = .02). An increased risk of progressive nuclear degeneration of stressed discs was observed irrespective of the outcome of bony changes. CONCLUSIONS: Stressed discs exhibit a higher burden of nuclear and annular degeneration at baseline. These discs have a higher risk of progressive nuclear degeneration irrespective of improvement or worsening of stress-related bony changes.

Fully human CD19-specific chimeric antigen receptors for T-cell therapy.

Impressive results have been achieved by adoptively transferring T-cells expressing CD19-specific CARs with binding domains from murine mAbs to treat B-cell malignancies. T-cell mediated immune responses specific for peptides from the murine scFv antigen-binding domain of the CAR can develop in patients and result in premature elimination of CAR T-cells increasing the risk of tumor relapse. As fully human scFv might reduce immunogenicity, we generated CD19-specific human scFvs with similar binding characteristics as the murine FMC63-derived scFv using human Ab/DNA libraries. CARs were constructed in various formats from several scFvs and used to transduce primary human T-cells. The resulting CD19-CAR T-cells were specifically activated by CD19-positive tumor cell lines and primary chronic lymphocytic leukemia cells, and eliminated human lymphoma xenografts in immunodeficient mice. Certain fully human CAR constructs were superior to the FMC63-CAR, which is widely used in clinical trials. Imaging of cell surface distribution of the human CARs revealed no evidence of clustering without target cell engagement, and tonic signaling was not observed. To further reduce potential immunogenicity of the CARs, we also modified the fusion sites between different CAR components. The described fully human CARs for a validated clinical target may reduce immune rejection compared with murine-based CARs.

The effects of air pollution on asthma hospital admissions in Adelaide, South Australia, 2003-2013: time-series and case-crossover analyses.

BACKGROUND: Air pollution can have adverse health effects on asthma sufferers, but the effects vary with geographic, environmental and population characteristics. There has been no long time-series study in Australia to quantify the effects of environmental factors including pollen on asthma hospitalizations. OBJECTIVES: This study aimed to assess the seasonal impact of air pollutants and aeroallergens on the risk of asthma hospital admissions for adults and children in Adelaide, South Australia. METHODS: Data on hospital admissions, meteorological conditions, air quality and pollen counts for the period 2003-2013 were sourced. Time-series analysis and case-crossover analysis were used to assess the short-term effects of air pollution on asthma hospitalizations. For the time-series analysis, generalized log-linear quasi-Poisson and negative binomial regressions were used to assess the relationships, controlling for seasonality and long-term trends using flexible spline functions. For the case-crossover analysis, conditional logistic regression was used to compute the effect estimates with time-stratified referent selection strategies. RESULTS: A total of 36,024 asthma admissions were considered. Findings indicated that the largest effects on asthma admissions related to PM2.5 , NO2 , PM10 and pollen were found in the cool season for children (0-17 years), with the 5-day cumulative effects of 30.2% (95% CI: 13.4-49.6%), 12.5% (95% CI: 6.6-18.7%), 8.3% (95% CI: 2.5-14.4%) and 4.2% (95% CI: 2.2-6.1%) increases in risk of asthma hospital admissions per 10 unit increments, respectively. The largest effect for ozone was found in the warm season for children with the 5-day cumulative effect of an 11.7% (95% CI: 5.8-17.9%) increase in risk of asthma hospital admissions per 10 ppb increment in ozone level. CONCLUSION: Findings suggest that children are more vulnerable and the associations between exposure to air pollutants and asthma hospitalizations tended to be stronger in the cool season compared to the warm season, with the exception of ozone. This study has important public health implications and provides valuable evidence for the development of policies for asthma management.

Maternal high-fat feeding in pregnancy programs atherosclerotic lesion size in the ApoE*3 Leiden mouse.

Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high-fat diet in utero, programed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat, n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat, n=12). Dams were fed the chow diet during the suckling period. At 28 days postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (P<0.001). There was no direct effect of prenatal diet on plasma triglycerides or cholesterol; however, transgenic ApoE*3 Leiden offspring displayed raised cholesterol when on an atherogenic diet compared with wild-type controls (P=0.031). Lesion size was correlated with plasma lipid parameters after adjustment for genotype, maternal diet and postnatal diet (R 2=0.563, P<0.001). ApoE*3 Leiden mothers fed a MHF diet developed hypercholesterolemia (plasma cholesterol two-fold higher than in chow-fed mothers, P=0.011). The data strongly suggest that maternal hypercholesterolemia programs later susceptibility to atherosclerosis. This is consistent with previous observations in humans and animal models.

Synergism between cAMP and PPARγ Signalling in the Initiation of UCP1 Gene Expression in HIB1B Brown Adipocytes.

Expression of the brown adipocyte-specific gene, uncoupling protein 1 (UCP1), is increased by both PPARγ stimulation and cAMP activation through their ability to stimulate the expression of the PPAR coactivator PGC1α. In HIB1B brown preadipocytes, combination of the PPARγ agonist, rosiglitazone, and the cAMP stimulator forskolin synergistically increased UCP1 mRNA expression, but PGC1α expression was only increased additively by the two drugs. The PPARγ antagonist, GW9662, and the PKA inhibitor, H89, both inhibited UCP1 expression stimulated by rosiglitazone and forskolin but PGC1α expression was not altered to the same extent. Reporter studies demonstrated that combined rosiglitazone and forskolin synergistically activated transcription from a full length 3.1 kbp UCP1 luciferase promoter construct, but the response was only additive and much reduced when a minimal 260 bp proximal UCP1 promoter was examined. Rosiglitazone and forskolin in combination were able to synergistically stimulate promoters comprising of tandem repeats of either PPREs or CREs. We conclude that rosiglitazone and forskolin act together to synergistically activate the UCP1 promoter directly rather than by increasing PGC1α expression and by a mechanism involving cross-talk between the signalling systems regulating the CRE and PPRE on the promoters.

Operation and recovery of a seasonally-loaded UK waste stabilisation pond system.

An intermittent discharge waste stabilisation pond system was trialled for treatment of a seasonal wastewater load from a campsite. The system showed rapid acclimatisation to incoming load, with chlorophyll-a exceeding 700 mg l(-1) within 2 weeks and filtered and unfiltered effluent biochemical oxygen demand below 20 and 30 mg l(-1) respectively. Good performance continued for some weeks, after which photosynthetic oxygenation capacity in the first pond was seriously impaired by a shock loading believed to include fatty material. Inflow to the system was suspended and a surface film was broken up, after which the pond recovered within an 8-day period. Laboratory experiments indicated that interventions such as artificial aeration and dilution with effluent had no beneficial effect although mixing may have increased the rate of recovery.

The progression of end-stage osteoarthritis: analysis of data from the Australian and Norwegian joint replacement registries using a multi-state model.

OBJECTIVE: The incidence of joint replacements is considered an indicator of symptomatic end-stage osteoarthritis (OA). We analysed data from two national joint replacement registries in order to investigate whether evidence of a pattern of progression of end-stage hip and knee OA could be found in data from large unselected populations. DESIGN: We obtained data on 78,634 hip and 122,096 knee arthroplasties from the Australian Orthopaedic Association National Joint Replacement Registry and 19,786 hip and 12,082 knee arthroplasties from the Norwegian Arthroplasty Register. A multi-state model was developed where individuals were followed from their first recorded hip or knee arthroplasty for OA to receiving subsequent hip and/or knee arthroplasties. We used this model to estimate relative hazard rates and probabilities for each registry separately. RESULTS: The hazard rates of receiving subsequent arthroplasties in non-cognate joints were higher on the contralateral side than on the ipsilateral side to the index arthroplasty, especially if the index was a hip arthroplasty. After 5 years, the estimated probabilities of having received a knee contralateral to the index hip were more than 1.7 times the probabilities of having received a knee ipsilateral to the index hip. CONCLUSION: The results indicate that there is an association between the side of the first hip arthroplasty and side of subsequent knee arthroplasties. Further studies are needed to investigate whether increased risk of receiving an arthroplasty in the contralateral knee is related to having a hip arthroplasty and/or preoperative factors such as pain and altered gait associated with hip OA.