Effectiveness of an anti-inflammatory diet versus low-fat diet for knee osteoarthritis: the FEAST randomised controlled trial protocol.

INTRODUCTION: Chronic inflammation plays a key role in knee osteoarthritis pathophysiology and increases risk of comorbidities, yet most interventions do not typically target inflammation. Our study will investigate if an anti-inflammatory dietary programme is superior to a standard care low-fat dietary programme for improving knee pain, function and quality-of-life in people with knee osteoarthritis. METHODS AND ANALYSIS: The eFEct of an Anti-inflammatory diet for knee oSTeoarthritis study is a parallel-group, assessor-blinded, superiority randomised controlled trial. Following baseline assessment, 144 participants aged 45-85 years with symptomatic knee osteoarthritis will be randomly allocated to one of two treatment groups (1:1 ratio). Participants randomised to the anti-inflammatory dietary programme will receive six dietary consultations over 12 weeks (two in-person and four phone/videoconference) and additional educational and behaviour change resources. The consultations and resources emphasise nutrient-dense minimally processed anti-inflammatory foods and discourage proinflammatory processed foods. Participants randomised to the standard care low-fat dietary programme will receive three dietary consultations over 12 weeks (two in-person and one phone/videoconference) consisting of healthy eating advice and education based on the Australian Dietary Guidelines, reflecting usual care in Australia. Adherence will be assessed with 3-day food diaries. Outcomes are assessed at 12 weeks and 6 months. The primary outcome will be change from baseline to 12 weeks in the mean score on four Knee injury and Osteoarthritis Outcome Score (KOOS4) subscales: knee pain, symptoms, function in daily activities and knee-related quality of life. Secondary outcomes include change in individual KOOS subscale scores, patient-perceived improvement, health-related quality of life, body mass and composition using dual-energy X-ray absorptiometry, inflammatory (high-sensitivity C reactive protein, interleukins, tumour necrosis factor-α) and metabolic blood biomarkers (glucose, glycated haemoglobin (HbA1c), insulin, liver function, lipids), lower-limb function and physical activity. ETHICS AND DISSEMINATION: The study has received ethics approval from La Trobe University Human Ethics Committee. Results will be presented in peer-reviewed journals and at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12622000440729.

Two healthy lifestyle scores are associated with lower subsequent fatigue risk using inverse probability weighting in an international longitudinal cohort of people with multiple sclerosis.

BACKGROUND AND PURPOSE: Several modifiable lifestyle factors have been associated with the onset and health outcomes of multiple sclerosis (MS), including clinically significant fatigue. A combined lifestyle score approach represents one method of assessing their relationship with clinical outcomes. The aim was to examine the association of two lifestyle scores with clinically significant fatigue and change thereof over 2.5 years' follow-up using inverse probability treatment weighting (IPTW). METHODS: Data on sociodemographic, lifestyle, and clinical characteristics surveyed from an international cohort of people with MS at baseline and at 2.5-year follow-up were used. Fatigue was defined by the Fatigue Severity Scale (FSS >5) and healthy lifestyle by the Healthy Lifestyle Index Score (HLIS) and the Smoking, Nutrition, Alcohol Consumption and Physical Activity (SNAP) score. Analyses were by IPTW accounting for age, sex, MS type, disability, treated comorbidity number, immunomodulatory medication use, prescription antifatigue medication use, and ongoing relapse symptoms. RESULTS: In total, 1268 participants completed the FSS at both time points; approximately 62% had fatigue. Using doubly robust IPTW, high (>11/20) HLIS (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.81-0.98) and high (>3/5) SNAP (OR 0.82, 95% CI 0.73-0.90) were each associated with lower risk of fatigue at follow-up. Evaluating change in fatigue, a higher SNAP score was associated with a lower risk of fatigue (OR 0.89, 95% CI 0.80-0.97) but the score for HLIS did not reach statistical significance (OR 0.93, 95% CI 0.85-1.01). CONCLUSION: These results suggest a robust role for key lifestyle factors in preventing clinically significant fatigue and may represent a place for lifestyle modification in improving clinical outcomes in MS.

SF-6D health state utilities for lifestyle, sociodemographic and clinical characteristics of a large international cohort of people with multiple sclerosis.

BACKGROUND: While many studies have examined the impacts of multiple sclerosis (MS) on health-related quality of life (HRQoL), none have used the SF-6D multi-attribute utility instrument in a large international cohort (> 2000 subjects) of people with MS. OBJECTIVES: To derive SF-6D health state utilities (HSUs) for participants of the HOLISM (Health Outcomes and Lifestyle In a Sample of people with Multiple Sclerosis) international cohort and to describe the distribution and determinants thereof. METHODS: HSUs were generated using the SF-6D for participants with sufficient SF-36 data [n = 2185/2466 (88.6%)]. Mean HSUs for sociodemographic, clinical and modifiable lifestyle factors (including diet, physical activity, supplement use) were evaluated. Determinants of HSU were then evaluated by linear regression, adjusted for age, sex, MS type, disability, fatigue, and prescription antidepressant use. RESULTS: Mean HSU for the sample was 0.67 (SD = 0.13) and diminished with increasing MS-related disability, robust to adjustment, supporting the SF-6D's discriminatory power in people with MS. Severe disability and clinically significant fatigue were each associated with 11% lower HSU (95% CI = - 0.13, - 0.10 and - 0.12, - 0.10), and depression risk with 10%-lower HSU (95% CI = - 0.11, - 0.08). Employment, higher socioeconomic and married/partnered statuses, larger social-network size, greater physical activity, and vitamin D and omega-3 supplement use were associated with significantly higher HSU, and overweight/obese BMI and tobacco smoking with lower HSU. Age, sex, and education were not associated. CONCLUSION: Modifiable lifestyle factors including healthy diet, increased physical activity and supplement use were associated with higher HRQOL among people with MS. The SF-6D instrument revealed significant discriminatory power in this international cohort of people with MS.

Multiple imputation methods for handling missing values in a longitudinal categorical variable with restrictions on transitions over time: a simulation study.

BACKGROUND: Longitudinal categorical variables are sometimes restricted in terms of how individuals transition between categories over time. For example, with a time-dependent measure of smoking categorised as never-smoker, ex-smoker, and current-smoker, current-smokers or ex-smokers cannot transition to a never-smoker at a subsequent wave. These longitudinal variables often contain missing values, however, there is little guidance on whether these restrictions need to be accommodated when using multiple imputation methods. Multiply imputing such missing values, ignoring the restrictions, could lead to implausible transitions. METHODS: We designed a simulation study based on the Longitudinal Study of Australian Children, where the target analysis was the association between (incomplete) maternal smoking and childhood obesity. We set varying proportions of data on maternal smoking to missing completely at random or missing at random. We compared the performance of fully conditional specification with multinomial and ordinal logistic imputation, and predictive mean matching, two-fold fully conditional specification, indicator based imputation under multivariate normal imputation with projected distance-based rounding, and continuous imputation under multivariate normal imputation with calibration, where each of these multiple imputation methods were applied, accounting for the restrictions using a semi-deterministic imputation procedure. RESULTS: Overall, we observed reduced bias when applying multiple imputation methods with restrictions, and fully conditional specification with predictive mean matching performed the best. Applying fully conditional specification and two-fold fully conditional specification for imputing nominal variables based on multinomial logistic regression had severe convergence issues. Both imputation methods under multivariate normal imputation produced biased estimates when restrictions were not accommodated, however, we observed substantial reductions in bias when restrictions were applied with continuous imputation under multivariate normal imputation with calibration. CONCLUSION: In a similar longitudinal setting we recommend the use of fully conditional specification with predictive mean matching, with restrictions applied during the imputation stage.

Longitudinal Associations of Modifiable Lifestyle Factors With Positive Depression-Screen Over 2.5-Years in an International Cohort of People Living With Multiple Sclerosis.

Background: Depression is common and has a significant impact on quality of life for many people with multiple sclerosis (MS). A preventive management approach via modification of lifestyle risk factors holds potential benefits. We examined the relationship between modifiable lifestyle factors and depression risk and the change in depression over 2.5 years. Methods: Sample recruited using online platforms. 2,224 (88.9%) at baseline and 1,309 (93.4%) at 2.5 years follow up completed the necessary survey data. Depression risk was measured by the Patient Health Questionnaire-2 (PHQ-2) at baseline and Patient Health Questionniare-9 (PHQ-9) at 2.5-years follow-up. Multivariable regression models assessed the relationships between lifestyle factors and depression risk, adjusted for sex, age, fatigue, disability, antidepressant medication use, and baseline depression score, as appropriate. Results: The prevalence of depression risk at 2.5-years follow-up in this cohort was 14.5% using the PHQ-2 and 21.7% using the PHQ-9. Moderate alcohol intake, being a non-smoker, diet quality, no meat or dairy intake, vitamin D supplementation, omega 3 supplement use, regular exercise, and meditation at baseline were associated with lower frequencies of positive depression-screen 2.5 years later. Moderate alcohol intake was associated with greater likelihood of becoming depression-free and a lower likelihood of becoming depressed at 2.5-years follow-up. Meditating at least once a week was associated with a decreased frequency of losing depression risk, against our expectation. After adjusting for potential confounders, smoking, diet, physical activity, and vitamin D and omega-3 supplementation were not associated with a change in risk for depression. Conclusion: In a large prospective cohort study of people with MS and depression, in line with the emerging treatment paradigm of early intervention, these results suggest a role for some lifestyle factors in depression risk. Further studies should endeavor to explore the impact of positive lifestyle change and improving depression in people living with MS.

Longitudinal Associations of the Healthy Lifestyle Index Score With Quality of Life in People With Multiple Sclerosis: A Prospective Cohort Study.

Objective: To explore the association between combined lifestyle risk factors with quality of life in people with multiple sclerosis (MS) over 2.5 years. Methods: People with MS were recruited to participate in a comprehensive online survey regarding their demographic and clinical characteristics, health-related quality of life (HRQOL), and lifestyle behaviors including physical activity, alcohol consumption, cigarette smoking, body mass index, and dietary habits measured at baseline and 2.5-year follow-up. A combined healthy lifestyle index score (HLIS) was constructed by assigning scores of 0-4 to each of the lifestyle risk factors, for which higher values indicate healthier lifestyle behavior. Multivariable linear regression modeling was used to assess whether the HLIS at baseline was associated with the physical and mental HRQOL over the study period in this sample of people with MS. Results: Of 2,466 participants with confirmed MS, 1,401 (57%) completed the follow-up. Multivariable linear regression analyses demonstrated that every 5-point increase (of a possible total of 20) in the baseline HLIS was associated with 1.7 (95% CI: 0.2-3.2) and 2.5 (95% CI: 1.0-4.0) higher scores in the change in physical and mental HRQOL components from baseline to follow-up respectively. Conclusion: Findings suggest the importance of healthy lifestyle behavior in quality of life in MS. A healthy lifestyle program focusing on these behaviors has the potential to positively influence health-related quality of life for people with MS.

Health outcomes and adherence to a healthy lifestyle after a multimodal intervention in people with multiple sclerosis: Three year follow-up.

BACKGROUND: Modifiable risk factors such as smoking and sedentary lifestyle adversely affect multiple sclerosis (MS) progression. Few multimodal behavioural interventions have been conducted for people with MS, and follow-up beyond 1 year is rare for lifestyle interventions. This study assessed adoption and adherence to healthy lifestyle behaviours and health outcomes 3 years after a lifestyle modification intervention, using generalized estimating equation models to account for within-participant correlation over time. METHODS: 95 people with MS completed baseline surveys before participating in 5-day MS lifestyle risk-factor modification workshops. 76 and 78 participants completed the 1-year and 3-year follow-up surveys respectively. Mean age at 3-year follow-up was 47 years, 72% were female, most (62.8%) had MS for 5 years or less, and 73% had relapsing remitting MS (RRMS). RESULTS: Compared to baseline, participants reported clinically meaningful increases in physical (mean difference (MD): 8.0, 95% Confidence Interval (CI): 5.2-10.8) and mental health (MD: 9.2, CI: 5.8-12.6) quality of life (QOL) at 1-year, and physical (MD: 8.7, CI: 5.3-12.2) and mental health (MD: 8.0, CI: 4.2-11.8) QOL at 3-year follow-up. There was a small decrease in disability from baseline to 1-year follow-up (MD: 0.9, CI: 0.9,1.0) and to 3-year follow-up (MD: 1.0, CI: 0.9,1.0), which was not clinically meaningful. Of those with RRMS, compared to baseline, fewer had a relapse during the year before 1-year follow-up (OR: 0.1, CI 0.0-0.2) and 3-year follow-up (OR: 0.15, CI 0.06-0.33). Participants' healthy diet score, the proportion meditating ≥1 hours a week, supplementing with ≥ 5000IU vitamin D daily, and supplementing with omega-3 flaxseed oil increased at 1-year follow-up and was sustained, although slightly lower at 3-year follow-up. However, there was no evidence for a change in physical activity and not enough smokers to make meaningful comparisons. Medication use increased at 1-year follow-up and at 3-year follow-up. CONCLUSION: The results provide evidence that lifestyle risk factor modification is feasible and sustainable over time, in a small self-selected and motivated sample of people with MS. Furthermore, participation in a lifestyle intervention is not associated with a decrease in MS medication use.

Pain in People with Multiple Sclerosis: Associations with Modifiable Lifestyle Factors, Fatigue, Depression, Anxiety, and Mental Health Quality of Life.

BACKGROUND: People with multiple sclerosis (MS) often experience pain, which can interfere with mobility, employment, and quality of life (QOL). METHODS: This cross-sectional study explored associations between pain, demographic, disease, and modifiable lifestyle factors in an international sample of people with MS recruited online. RESULTS: Substantial pain, of moderate/severe intensity and interfering at least moderately with work/household or enjoyment of life in the past 4 weeks, was reported by 682/2,362 (28.9%). Substantial pain was associated with fatigue (odds ratio (OR): 6.7, 95% confidence interval (CI): 4.9,9.3), depression (OR:4.0, 95% CI:3.2,5.1), anxiety (OR:2.4, 95% CI:1.9,2.9), and lower mental health QOL (Mean Difference: -14.7, 95% CI:-16.6,-12.8). Regression analyses showed that smoking (OR: 2.0, 95% CI:1.35,2.87) and obesity (OR:2.1, 95% CI: 1.5,2.8), moderate alcohol use (OR: 0.7, 95% CI:0.5,0.9), moderate (OR 0.7, 95% CI: 0.55,0.98) or high (OR 0.6, 95% CI: 0.4,0.8) physical activity level, and healthy diet (OR 0.8, 95% CI: 0.75,0.95, per 10 points) were associated with substantial pain. CONCLUSION: Our results show clear associations with modifiable lifestyle factors and substantial pain in MS. These factors are already considered in the prevention and management of pain in other populations but have not previously been considered in MS. Conversely, pain and associated common MS comorbidities, such as depression, anxiety, and fatigue, may hamper efforts to start or maintain healthy behaviors. Strategies to overcome these barriers need to be considered. Further research should clarify the direction of these associations.

Lifestyle, medication and socio-demographic determinants of mental and physical health-related quality of life in people with multiple sclerosis.

BACKGROUND: Health-related quality of life (QOL) is a key outcome for people with multiple sclerosis (MS). While modifiable lifestyle factors, like smoking, physical activity and vitamin D, have strong associations with development and progression of MS, few studies have examined such associations with QOL. METHODS: Using patient-reported data from 2312 people with MS from 54 countries, regression models explored associations of socio-demographic, therapeutic and lifestyle factors with QOL, using the Multiple Sclerosis Quality of Life-54 (MSQOL-54). RESULTS: Participants were on average 45.6 years old, 82.4% women, mostly partnered (74.1%), with a university degree (59.5%). Controlling for socio-demographic factors and disability, factors associated with better physical health composite (PHC) (on a 100 point scale) were: moderate and high physical activity compared to low (5.9 [95% confidence interval: 4.2, 7.6] and 9.9 [CI: 8.1, 11.6] points higher score respectively); non-smoking compared to current smoking (4.6 points [CI: 2.4, 6.7]); better diet (per 10 points on the 100 point Diet Habits Questionnaire scale (DHQ) 1.6 points [CI: 1.0, 2.2] points); normal body mass index (BMI) versus overweight or obese (2.1 points [CI: 0.4, 3.7] and 2.4 points [CI: 0.5, 4.3]); fewer comorbidities (4.4 points [CI: 3.9, 4.9]); and not taking a disease-modifying drug (DMD) (2.1 points [CI: 0.7, 3.4]). Better mental health composite (MHC) determinants were: moderate and high physical activity compared to low (4.0 points [CI: 2.0, 6.0] and 5.7 points [CI: 3.5, 8.0]); non-smoking compared to current (6.7 points [CI: 4.1, 9.3]); better diet (2.8 points [CI: 1.9, 3.5]); normal BMI versus overweight or obese (3.1 points [CI: 1.1, 5.1] and 3.5 points [CI: 1.3, 5.7]); meditating regularly (2.2 points [CI: 0.2, 4.2]); and no DMD use (2.9 points [CI: 1.3, 4.6]). CONCLUSIONS: While causality cannot be concluded from cross-sectional data, the associations between modifiable lifestyle factors and QOL suggest significant potential for secondary prevention of the known deterioration of QOL for people with MS through lifestyle risk factor modification.

Genomic prediction of coronary heart disease.

AIMS: Genetics plays an important role in coronary heart disease (CHD) but the clinical utility of genomic risk scores (GRSs) relative to clinical risk scores, such as the Framingham Risk Score (FRS), is unclear. Our aim was to construct and externally validate a CHD GRS, in terms of lifetime CHD risk and relative to traditional clinical risk scores. METHODS AND RESULTS: We generated a GRS of 49 310 SNPs based on a CARDIoGRAMplusC4D Consortium meta-analysis of CHD, then independently tested it using five prospective population cohorts (three FINRISK cohorts, combined n = 12 676, 757 incident CHD events; two Framingham Heart Study cohorts (FHS), combined n = 3406, 587 incident CHD events). The GRS was associated with incident CHD (FINRISK HR = 1.74, 95% confidence interval (CI) 1.61-1.86 per S.D. of GRS; Framingham HR = 1.28, 95% CI 1.18-1.38), and was largely unchanged by adjustment for known risk factors, including family history. Integration of the GRS with the FRS or ACC/AHA13 scores improved the 10 years risk prediction (meta-analysis C-index: +1.5-1.6%, P < 0.001), particularly for individuals ≥60 years old (meta-analysis C-index: +4.6-5.1%, P < 0.001). Importantly, the GRS captured substantially different trajectories of absolute risk, with men in the top 20% of attaining 10% cumulative CHD risk 12-18 y earlier than those in the bottom 20%. High genomic risk was partially compensated for by low systolic blood pressure, low cholesterol level, and non-smoking. CONCLUSIONS: A GRS based on a large number of SNPs improves CHD risk prediction and encodes different trajectories of lifetime risk not captured by traditional clinical risk scores.

Associations of Lifestyle, Medication, and Socio-Demographic Factors with Disability in People with Multiple Sclerosis: An International Cross-Sectional Study.

OBJECTIVE: Emerging evidence links modifiable lifestyle risk factors to disease progression in multiple sclerosis (MS). We sought further evidence around this hypothesis through detailed analysis of the association with disability of lifestyle behaviours of a large international sample of people with MS. MATERIALS AND METHODS: A total of 2469 people with MS from 57 countries provided self-reported data via cross-sectional online survey on lifestyle (mostly with validated tools) and the primary outcome measure, disability (Patient Determined Disease Steps), categorised from 8 steps into 3 categories, mild, moderate and major disability. Multinomial logistic regression modelling derived relative risk ratios (RRRs) for disability categories. RESULTS: RRRs of having moderate vs mild disability were: diet (per 30 points on 100 point scale) 0.72 (95%CI 0.52-0.98), ever smoking 1.32 (1.06-1.65), exercise (moderate/high vs low) 0.35 (0.28-0.44), latitude (per degree from the equator) 1.02 (1.01-1.04), and number of comorbidities (2 vs none) 1.43 (1.04-1.95), (3 vs none) 1.56 (1.13-2.16). RRRs of having major vs mild disability were: exercise (moderate/high vs low) 0.07 (0.04-0.11), alcohol consumption (moderate vs low) 0.45 (0.30-0.68), plant-based omega 3 supplementation 0.39 (0.18-0.86), and disease-modifying medication use 0.45 (0.29-0.70). CONCLUSIONS: Healthier lifestyle has strong associations with disability in our large international sample of people with MS, supporting further investigation into the role of lifestyle risk factors in MS disease progression.

Quantifying low birth weight, preterm birth and small-for-gestational-age effects of malaria in pregnancy: a population cohort study.

BACKGROUND: The association between malaria during pregnancy and low birth weight (LBW) is well described. This manuscript aims to quantify the relative contribution of malaria to small-for-gestational-age (SGA) infants and preterm birth (PTB) in pregnancies accurately dated by ultrasound on the Thai-Myanmar border at the Shoklo Malaria Research Unit. METHODS AND FINDINGS: From 2001 to 2010 in a population cohort of prospectively followed pregnancies, we analyzed all singleton newborns who were live born, normal, weighed in the first hour of life and with a gestational age (GA) between 28+0 and 41+6 weeks. Fractional polynomial regression was used to determine the mean birthweight and standard deviation as functions of GA. Risk differences and factors of LBW and SGA were studied across the range of GA for malaria and non-malaria pregnancies. From 10,264 newborns records, population centiles were created. Women were screened for malaria by microscopy a median of 22 [range 1-38] times and it was detected and treated in 12.6% (1,292) of pregnancies. Malaria was associated with LBW, PTB, and SGA compared to those without malaria. Nearly two-thirds of PTB were classified as LBW (68% (539/789)), most of which 83% (447/539) were not SGA. After GA 39 weeks, 5% (298/5,966) of non-LBW births were identified as SGA. Low body mass index, primigravida, hypertension, smoking and female sex of the newborn were also significantly and independently associated with LBW and SGA consistent with previous publications. CONCLUSIONS: Treated malaria in pregnancy was associated with an increased risk for LBW, PTB, and SGA, of which the latter are most important for infant survival. Using LBW as an endpoint without adjusting for GA incorrectly estimated the effects of malaria in pregnancy. Ultrasound should be used for dating pregnancies and birth weights should be expressed as a function (or adjusted for GA) of GA in future malaria in pregnancy studies.

Elemental and metabolite profiling of nickel hyperaccumulators from New Caledonia.

Leaf material from nine Ni hyperaccumulating species was collected in New Caledonia: Homalium kanaliense (Vieill.) Briq., Casearia silvana Schltr, Geissois hirsuta Brongn. & Gris, Hybanthus austrocaledonicus Seem, Psychotria douarrei (G. Beauvis.) Däniker, Pycnandra acuminata (Pierre ex Baill.) Swenson & Munzinger (syn Sebertia acuminata Pierre ex Baill.), Geissois pruinosa Brongn. & Gris, Homalium deplanchei (Viell) Warb. and Geissois bradfordii (H.C. Hopkins). The elemental concentration was determined by inductively-coupled plasma optical emission spectrometry (ICP-OES) and from these results it was found that the species contained Ni concentrations from to 250-28,000 mg/kg dry mass. Gas chromatography mass spectrometry (GC-MS)-based metabolite profiling was then used to analyse leaves of each species. The aim of this study was to target Ni-binding ligands through correlation analysis of the metabolite levels and leaf Ni concentration. Approximately 258 compounds were detected in each sample. As has been observed before, a correlation was found between the citric acid and Ni concentrations in the leaves for all species collected. However, the strongest Ni accumulator, P. douarrei, has been found to contain particularly high concentrations of malonic acid, suggesting an additional storage mechanism for Ni. A size exclusion chromatography separation protocol for the separation of Ni-complexes in P. acuminata sap was also applied to aqueous leaf extracts of each species. A number of metabolites were identified in complexes with Ni including Ni-malonate from P. douarrei. Furthermore, the levels for some metabolites were found to correlate with the leaf Ni concentration. These data show that Ni ions can be bound by a range of small molecules in Ni hyperaccumulation in plants.