Feelings of depression, pain and walking difficulties have the largest impact on the quality of life of people with multiple sclerosis, irrespective of clinical phenotype.

BACKGROUND: The symptoms that have the largest impact on health-related quality of life (HRQoL) in people with multiple sclerosis (MS) may vary by MS phenotype (relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)). Knowing these symptoms assists in symptom management. OBJECTIVE: To examine the associations between 13 common MS symptoms and HRQoL in the total sample and stratified by MS phenotype. METHOD: The study included 1985 participants. HRQoL was measured with two multi-attribute utility instruments: assessment of quality of life with eight dimensions (AQoL-8D) and European quality of life with five dimensions and five levels for each dimension (EQ-5D-5L). Multivariable linear regression was used to identify the symptoms that had the largest impact on the HRQoLs. RESULTS: Feelings of depression, pain, fatigue, and feelings of anxiety were most strongly associated with AQoL-8D and EQ-5D-5L. Walking difficulties additionally contributed to reduced EQ-5D-5L. The strongest single predictors in the multivariable analyses were feelings of depression or pain for AQoL-8D and walking difficulties for EQ-5D-5L, irrespective of MS phenotype. CONCLUSION: The strongest single predictors for the AQoL-8D and EQ-5D-5L were feelings of depression, pain and walking difficulties, irrespective of MS phenotype. Reducing these symptoms may have the largest impact on improving HRQoL in all MS phenotypes of people with MS.

Comorbidities are prevalent and detrimental for employment outcomes in people of working age with multiple sclerosis.

BACKGROUND: More work is needed to understand the burden of comorbidities in people with multiple sclerosis (MS). OBJECTIVE: To assess prevalence of 30 comorbidities and impacts of comorbidities on employment outcomes in a working-aged MS cohort. METHODS: Participants were from the Australian MS Longitudinal Study (n = 929). Information on specific comorbidity was obtained (whether or not each was present, doctor-diagnosed, limited their activities and being treated). RESULTS: Comorbidities most frequently reported to limit activities were osteoarthritis (51%), migraines (40%), anxiety (33%), depression (29%) and allergies (18%). Mean MS-related work productivity loss in past 4 weeks was 1.3 days for those without comorbidities and 2.5 days for those with any comorbidity. The annual population costs of work productivity loss were highest for people with depression, allergies, anxiety, migraines and osteoarthritis. Higher number of comorbidities was associated with more work productivity loss and a higher likelihood of not working. These associations were substantially reduced after adjustment for MS symptom severity. CONCLUSIONS: Comorbidities substantially impact employment outcomes and these effects were mainly mediated through MS symptom severity. This suggests that optimal and simultaneous management of comorbidities may be a viable strategy to reduce MS symptom severity, which in turn could improve employment outcomes.

Modelling the impact of multiple sclerosis on life expectancy, quality-adjusted life years and total lifetime costs: Evidence from Australia.

OBJECTIVES: To quantify life expectancy (LE), quality-adjusted life years (QALYs) and total lifetime societal costs for a hypothetical cohort of Australians with multiple sclerosis (MS). METHODS: A 4-state Markov model simulated progression from no/mild to moderate and severe disability and death for a cohort of 35-year-old women over a lifetime horizon. Death risks were calculated from Australian life tables, adjusted by disability severity. State-dependent relapse probabilities and associated disutilities were considered. Probabilities of MS progression and relapse were estimated from AusLong and TasMSL MS epidemiological databases. Annual societal (direct and indirect) costs (2017 Australian dollars) and health-state utilities for each state were derived from the Australian MS Longitudinal Study. Costs were discounted at 5% annually. RESULTS: Mean (95% confidence interval (CI)) LE from age 35 years was 42.7 (41.6-43.8) years. This was 7.5 years less than the general Australian population. Undiscounted QALYs were 28.2 (26.3-30.0), a loss of 13.1 QALYs versus the Australian population. Discounted lifetime costs were $942,754 ($347,856-$2,820,219). CONCLUSION: We have developed a health economics model of the progression of MS, calculating the impact of MS on LE, QALYs and lifetime costs in Australia. It will form the basis for future cost-effectiveness analyses of interventions for MS.

Change in multiple sclerosis prevalence over time in Australia 2010-2017 utilising disease-modifying therapy prescription data.

OBJECTIVE: Determine the prevalence of multiple sclerosis (MS) in Australia in 2017 using MS-specific disease-modifying therapy (DMT) prescription data and estimate the change in prevalence from 2010. METHODS: DMT prescriptions were extracted from Australia's Pharmaceutical Benefits Scheme (PBS) data for January-December 2017. Percentages of people with MS using DMTs (DMT penetrance) were calculated using data from the Australian MS Longitudinal Study. Prevalence was estimated by dividing the total number of monthly prescriptions by 12 (except alemtuzumab), adjusted for DMT penetrance and Australian population estimates. Prevalences in Australian states/territories were age-standardised to the Australian population. Comparisons with 2010 prevalence data were performed using Poisson regression. RESULTS: Overall DMT penetrance was 64%, and the number of people with MS in Australia in 2017 was 25,607 (95% confidence interval (CI): 24,874-26,478), a significant increase of 4324 people since 2010 (p < 0.001). The prevalence increased significantly from 95.6/100,000 (2010) to 103.7/100,000 (2017), with estimates highest in Tasmania in 2017 (138.7/100,000; 95% CI: 137.2-140.1) and lowest in Queensland (74.6/100,000; 95% CI: 73.5-75.6). From 2010 to 2017 using the median latitudes for each state/territory, the overall latitudinal variation in MS prevalence was an increase of 3.0% per degree-latitude. CONCLUSION: Consistent with global trends, Australia's MS prevalence has increased; this probably reflecting decreased mortality, increased longevity and increased incidence.

Predictors of Change in Employment Status and Associations with Quality of Life: A Prospective International Study of People with Multiple Sclerosis.

Purpose This prospective international study aimed to assess the changes in employment, and predictors thereof, and associated change in mental health quality of life in people with multiple sclerosis (MS). Methods People with MS were recruited online through social media, forums and newsletters to complete an online English-language survey in 2012 and again in 2015, to assess changes in employment and clinical characteristics. Results 1276 people with MS of working age were included of whom 35.9% were employed full time, 25.6% part-time, 3.1% were unemployed and seeking employment, 19.7% were retired due to disability and 15.7% were not in the labour force. Part/full time employment decreased from 61.4 to 57.1% of the sample 2.5 years later, and 25.5% experienced some change in employment status. Lower level of education and higher level of disability at baseline predicted loss of employment at follow-up. 62.0% of the sample indicated that MS impacted on employment over their lifetime, associated with a lower level of education and progressive MS at time of diagnosis. Retiring due to disability was predictive of a decreased mental health related QOL score. Conclusion Employment status was negatively impacted by MS for most participants. We showed for the first time that employment loss was prospectively associated with poorer mental health related quality of life. Employment support including vocational services, reasonable flexibility in the workplace, and legal protection against discrimination should be widely available to assist people with MS, especially for those with progressive onset MS, higher disability and lower levels of education who are at higher risk of employment loss.

Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. OBJECTIVE: We evaluated sex-specific and onset phenotype-specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. METHODS: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype-specific MSSS matrices. We compared matrices using permutation analysis. RESULTS: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data (p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix (p < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex. CONCLUSION: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.

Increasing prevalence of primary biliary cholangitis in Victoria, Australia.

BACKGROUND AND AIM: The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and in some parts of the world appears to be increasing. The aim of this study was to determine the 2013 prevalence of PBC in Victoria, Australia, and to determine the time trend by comparing it with previous studies undertaken in 1991 and 2002. METHODS: Four case-finding methods were used to identify cases of PBC in Victoria: (1) physicians' survey; (2) tertiary hospital search; (3) liver transplant database search; and (4) private pathology antimitochondrial antibody search. RESULTS: The prevalence of PBC in Victoria, Australia, is 189.0 per million using all four methods. The average annual increase in prevalence from 1991 to 2013 was 7.7 per million per year. Using the same case-finding methods as the 1991 Victorian prevalence study (methods 1 and 2), the prevalence of PBC increased from 19.1 per million in 1991 to 49.4 per million in 2002 (P < 0.001) and to 80.7 per million in 2013 (P < 0.001). CONCLUSIONS: The current prevalence of PBC in Victoria is significantly higher than previously reported. The use of private pathology-based case-finding methods is important in identifying the maximum number of PBC cases.

Validation of 0-10 MS symptom scores in the Australian multiple sclerosis longitudinal study.

BACKGROUND: Multiple sclerosis (MS) symptom measurements often use multiple-item scales per symptom, creating a high burden when multiple symptoms are assessed. We aimed to examine the validity, stability and responsiveness of single-item 0-10 numeric rating MS Symptom Scores (MSSymS). METHODS: The study included 1,985 participants from the Australian Multiple Sclerosis Longitudinal Study. Thirteen MS symptoms were assessed using the MSSymS, of which we were able to validate six (walking difficulties, fatigue, pain, feelings of anxiety, feelings of depression and vision problems). Comparison measures included Patient Determined Disease Steps (PDDS), Fatigue Severity Scale (FSS), Hospital Anxiety and Depression Scale (HADS), and Assessment of Quality of Life (AQoL). We used spearman rank correlation for concurrent validity, linear regression for predictive validity, intra-class correlations for stability, and percentage change for responsiveness. RESULTS: We found high correlations between walking difficulties and PDDS (r = 0.82), pain and AQoL-pain (r = 0.77), fatigue and FSS (r = 0.72); moderate correlations between feelings of anxiety and HADS-Anxiety (r = 0.68), feelings of depression and HADS-Depression (r = 0.63); and low correlation between vision and AQoL-vision (r = 0.43) For predictive validity, the graphs with quality of life were largely overlapping and the R2 of the regression lines were generally similar. The stability and responsiveness of the MSSymS were adequate. CONCLUSION: The six assessed symptoms of the MSSymS performed equally well compared to validated comparison measures in terms of concurrent and predictive validity, temporal stability and responsiveness.

Does a modifiable risk factor score predict disability worsening in people with multiple sclerosis?

BACKGROUND: Risk factors for chronic disease include smoking, hazardous alcohol consumption, physical inactivity, unhealthy body mass index and poor diet (SNAP factors). In multiple sclerosis (MS) SNAP factors are associated with health outcomes such as disability in cross-sectional studies, but longitudinal data are lacking. OBJECTIVE: The objective of this study was to assess whether a combined SNAP risk score predicts disability worsening. METHODS: Longitudinal self-reported data from two time-points 2.5 years apart from an international survey of 1225 people with MS were used in linear regression models adjusted for potential confounding. Disability worsening was measured using the patient-derived Multiple Sclerosis Severity Score. RESULTS: The majority (62%) had two or more risk factors, with insufficient fruit and vegetable intake (83%), unhealthy body mass index (42%) and physical inactivity (33%) most common. Some SNAP factors at follow-up were associated with disability at follow-up (cross-sectionally), and in addition there was some evidence that increasing risk factors was associated with disability worsening over the 2.5 year study period. Baseline SNAP score was not predictive of disability worsening at follow-up, however. CONCLUSION: Known risk factors for morbidity and mortality were common and associated with disability cross-sectionally, but not prospectively. Further studies using longer time frames, objective measures and interventions may elucidate potential benefits from changes in risk factors on MS outcomes.

Systemic predictors of adverse events in a national surgical mortality audit: analysis of peer-review data from Australia and New Zealand Audit of Surgical Mortality.

BACKGROUND: Peer review of surgical deaths can identify deficits in individual and systemic delivery of healthcare, ultimately informing quality improvement. METHODS: From 2008 to 2016, cases reported to the Australia and New Zealand Audit of Surgical Mortality were analysed. Variables associated with peer-judged adverse events were sought. RESULTS: Of 21 045 cases evaluated, 24.8% incurred at least one adverse event judgement. The proportion of cases with reported adverse event significantly decreased over time. Following adjustment for demographic and clinical characteristics, significant negative patient-related associations were advanced age, greater American Society of Anesthesiologists grade, and neurological and malignant comorbidities. Significant associations were also found with systemic or organizational factors, including state/territory, surgical specialty and hospital regionality. CONCLUSION: Examination of this peer-reviewed database revealed systemic or organizational predictors of adverse events that may have implications for quality improvement at an institutional or jurisdictional level. The extent to which these associations are due to the peer-review process itself should be the focus of further research.

On the path together: Experiences of partners of people with multiple sclerosis of the impact of lifestyle modification on their relationship.

Multiple sclerosis (MS) has a major impact on the relationship of couples living with the illness. Although some positives of dealing with MS as a couple have been identified, MS has been associated with higher rates of relationship breakdown and worse Quality of Life (QOL) for both people in the relationship, especially if the person with MS experiences a decline in mental or physical health or develops disability. Modification of lifestyle-related risk factors has been associated with improved outcomes for people with MS, including physical and mental health-related QOL, and these improved outcomes may lead to improved experiences for their partners. We aimed to explore the perspectives and experiences of the partners of people with MS, when the people with MS had undertaken an intensive residential workshop regarding healthy lifestyle, to understand the impact of MS and lifestyle modification on these partners' experiences of their relationship. Within the framework of Heidegger's interpretive phenomenology, semi-structured interviews were thematically analysed. Participants were in a spousal relationship with people with MS who had attended an intensive residential workshop regarding modification of lifestyle-related risk factors between 2002 and 2016. Participants lived in Australia, New Zealand, the United Kingdom and Europe. Three major themes were identified relating to the couple's relationships: providing support, remaining connected and togetherness. Aspects of these themes, not commonly previously reported, included the personal and relationship benefits experienced from providing support with lifestyle modification, improved communication, and the resultant greater sense of closeness. These experiences of partners of people with MS improve our understanding of both the complexities of living with MS and adopting lifestyle modification, and suggest some potential benefits to relationships.

Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis.

BACKGROUND: Cervical cancer screening might contribute to the prevention of anal cancer in women. We aimed to investigate if routine cervical cancer screening results-namely high-risk human papillomavirus (HPV) infection and cytohistopathology-predict anal HPV16 infection, anal high-grade squamous intraepithelial lesions (HSIL) and, hence, anal cancer. METHODS: We did a systematic review of MEDLINE, Embase, and the Cochrane library for studies of cervical determinants of anal HPV and HSIL published up to Aug 31, 2018. We centrally reanalysed individual-level data from 13 427 women with paired cervical and anal samples from 36 studies. We compared anal high-risk HPV prevalence by HIV status, cervical high-risk HPV, cervical cytohistopathology, age, and their combinations, using prevalence ratios (PR) and 95% CIs. Among 3255 women with anal cytohistopathology results, PRs were similarly calculated for all anal HSIL and HPV16-positive anal HSIL. FINDINGS: Cervical and anal HPV infections were highly correlated. In HIV-negative women, anal HPV16 prevalence was 41% (447/1097) in cervical HPV16-positive versus 2% (214/8663) in cervical HPV16-negative women (PR 16·5, 95% CI 14·2-19·2, p<0·0001); these values were 46% (125/273) versus 11% (272/2588) in HIV-positive women (4·4, 3·7-5·3, p<0·0001). Anal HPV16 was also associated with cervical cytohistopathology, with a prevalence of 44% [101/228] for cervical cancer in HIV-negative women (PR vs normal cytology 14·1, 11·1-17·9, p<0·0001). Anal HSIL was associated with cervical high-risk HPV, both in HIV-negative women (from 2% [11/527] in cervical high-risk HPV-negative women up to 24% [33/138] in cervical HPV16-positive women; PR 12·9, 95% CI 6·7-24·8, p<0·0001) and HIV-positive women (from 8% [84/1094] to 17% [31/186]; 2·3, 1·6-3·4, p<0·0001). Anal HSIL was also associated with cervical cytohistopathology, both in HIV-negative women (from 1% [5/498] in normal cytology up to 22% [59/273] in cervical HSIL; PR 23·1, 9·4-57·0, p<0·0001) and HIV-positive women (from 7% [105/1421] to 25% [25/101]; 3·6, 2·5-5·3, p<0·0001). Prevalence of HPV16-positive anal HSIL was 23-25% in cervical HPV16-positive women older than 45 years (5/20 in HIV-negative women, 12/52 in HIV-positive women). INTERPRETATION: HPV-based cervical cancer screening programmes might help to stratify anal cancer risk, irrespective of HIV status. For targeted secondary anal cancer prevention in high-risk groups, HIV-negative women with cervical HPV16, especially those older than 45 years, have a similar anal cancer risk profile to that of HIV-positive women. FUNDING: International Agency for Research on Cancer.

Latitude continues to be significantly associated with the prevalence of multiple sclerosis: an updated meta-analysis.

OBJECTIVES: Previous studies have demonstrated a strong latitudinal gradient in multiple sclerosis (MS) prevalence. Herein, we present a meta-analysis of the latitudinal gradient of MS prevalence including studies published since our 2011 review, seeking to assess the latitudinal gradient and whether it has changed since our previous analysis. METHODS: Studies published up to December 2018 were located via Embase, Web of Knowledge and PubMed, using standardised search terms; data were extracted from peer-reviewed studies and these studies added to those from our previous analysis. Where age-specific data were available, prevalence estimates were age-/sex-standardised to the 2009 European population. Prevalence estimates were adjusted for study prevalence year and ascertainment methods. The latitudinal association with MS prevalence was assessed by meta-regression. RESULTS: A total of 94 studies met inclusion criteria, yielding 230 new prevalence points and 880 altogether with those from the prior study. There was a significant positive gradient in time-corrected MS prevalence with increasing latitude (5.27/100 000 per degree latitude), attenuating slightly to 4.34/100 000 on age-standardisation, these associations persisting on adjustment for ascertainment method. Of note, the age-standardised gradient was consistently significantly enhanced from our previous study, regardless of whether it was as-measured, time-corrected or adjusted for ascertainment methods. Certain areas, such as the Scandinavian and Atlantic Coast/Central Europe regions, showed changes in MS prevalence gradient over time, but other regional gradients were similar. CONCLUSIONS: This new meta-analysis confirms that MS prevalence is still strongly positively associated with increasing latitude and that the gradient is increasing, suggesting that potentially modifiable environmental factors, such as sun exposure, are still strongly associated with MS risk.

Modifiable factors associated with depression and anxiety in multiple sclerosis.

OBJECTIVES: Modifiable lifestyle factors are implicated in multiple sclerosis (MS) symptoms but their role in mood is unclear. This study aimed to investigate associations between lifestyle and depression and anxiety in Australian participants with MS. MATERIALS AND METHODS: Self-reported data from the Australian Multiple Sclerosis Longitudinal Study included the Hospital Anxiety and Depression Scale (HADS) and lifestyle measurements from 1500 participants. SNAP score (range 0-5) was the sum of non-smoking, sufficient fruit/vegetable intake, non-hazardous alcohol consumption, sufficient physical activity and healthy BMI. Analyses by log-binomial and linear regression were adjusted for confounding. RESULTS: Symptoms of depression and anxiety were prevalent in 27% and 40%, respectively; 20% had both. Mean SNAP score was 2.7/5; only 3% met all healthy lifestyle recommendations. Only 10% reported adequate fruit/vegetable intake, and 22% reported a combination of unhealthy BMI, inadequate physical activity and inadequate nutrition. A healthier SNAP score was associated with lower depression prevalence (adjusted prevalence ratio 0.83 [95% CI 0.75, 0.92] per unit increase) and depression severity (adjusted ß-0.44 [95% CI -0.64, -0.24]), but not with anxiety. CONCLUSIONS: Modifiable lifestyle factors are associated with lower frequency and severity of depression, but not anxiety, in Australian people with multiple sclerosis. The associations between a healthier SNAP score and lower depression are likely bi-directional. SNAP risk factor prevalence and co-occurrence, especially inadequate nutrition and low physical activity, were high among Australians with MS.

Associations of demographic and clinical factors with depression over 2.5-years in an international prospective cohort of people living with MS.

BACKGROUND: Depression is highly prevalent among people with MS, and determinants thereof would be useful. OBJECTIVES: We examined the relationship of demographic and clinical factors with positive depression-screen and change in depression over 2.5 years in people with MS. METHODS: Positive depression-screen assessed by Patient Health Questionnaire (PHQ)-2 and PHQ-9. Associations of demographic and clinical factors with depression-screen and change thereof assessed using multivariable regression models, adjusted for age, sex, disability, fatigue, antidepressant use, and baseline PHQ-2, as appropriate. RESULTS: Overweight/obese BMI, comorbidity number, fatigue, and disability were associated with positive depression-screen, while married/partnered state, being employed, higher perceived socioeconomic status, and greater education were inversely associated with depression-screen. After adjustment, only marital status, socioeconomic status, antidepressant medication use, and fatigue were associated with risk of newly positive depression-screen. MS type, relapse number and immunomodulatory medication use were not associated with depression-screen after controlling for disability and fatigue. CONCLUSION: In a large prospective cohort study of depression in people with MS, we substantiated several potential determinants of a positive depression-screen and depression trajectory, particularly fatigue. Given that fatigue is the most common and most significant clinical symptom for people with MS, efforts to reduce fatigue may have follow-on benefits for reducing depression.

Differential multiple sclerosis treatment allocation between Australia and New Zealand associated with clinical outcomes but not mood or quality of life.

BACKGROUND: Differential treatment allocation may impact on clinical phenotype in MS and in turn upon quality of life (QoL). OBJECTIVES: (a) Investigate the association between disease-modifying drugs (DMDs) use and relapse frequency, disability, clinically significant fatigue, and physical and mental health-related QoL among participants with MS residing in Australia and New Zealand (NZ); (b) assess whether these associations differed between Australia and NZ. METHODS: Disability and fatigue were measured by PDDS and FSS, respectively. QoL was assessed by MSQOL-54. Associations were assessed by binomial and multinomial logistic regression, as appropriate. Multivariable models were adjusted for demographic and clinical covariates, as appropriate. RESULTS: 837 participants (627 from Australia; 210 from NZ) were identified from an online cohort of people with MS. First- and second-generation DMD use was associated with higher adjusted-odds of fatigue and disability, though not with 12-month relapse number. DMD use was not independently associated with physical or mental QoL. The association of first-generation DMD use with moderate disability differed between nations, such that treatment was associated with lower odds in Australia but not in NZ; a similar but a small difference was found for severe disability. No differences were seen in the DMD association with relapse number, nor with fatigue or QoL, between Australia and NZ. CONCLUSION: The differential treatment allocation associations in NZ are evident in the DMD-disability association, but there is no evidence that this treatment regimen has negative associations with fatigue, mood, or QoL.

Lipid-related genetic polymorphisms significantly modulate the association between lipids and disability progression in multiple sclerosis.

OBJECTIVE: To investigate whether lipid-related or body mass index (BMI)-related common genetic polymorphisms modulate the associations between serum lipid levels, BMI and disability progression in multiple sclerosis (MS). METHODS: The association between disability progression (annualised Expanded Disability Status Scale (EDSS) change over 5 years, ΔEDSS) and lipid-related or BMI-related genetic polymorphisms was evaluated in a longitudinal cohort (n=184), diagnosed with MS. We constructed a cumulative genetic risk score (CGRS) of associated polymorphisms (p<0.05) and examined the interactions between the CGRS and lipid levels (measured at baseline) in predicting ΔEDSS. All analyses were conducted using linear regression. RESULTS: Five lipid polymorphisms (rs2013208, rs9488822, rs17173637, rs10401969 and rs2277862) and one BMI polymorphism (rs2033529) were nominally associated with ΔEDSS. The constructed lipid CGRS showed a significant, dose-dependent association with ΔEDSS (ptrend=1.4×10-6), such that participants having ≥6 risk alleles progressed 0.38 EDSS points per year faster compared with those having ≤3. This CGRS model explained 16% of the variance in ΔEDSS. We also found significant interactions between the CGRS and lipid levels in modulating ΔEDSS, including high-density lipoprotein (HDL; pinteraction=0.005) and total cholesterol:high-density lipoprotein ratio (TC:HDL; pinteraction=0.030). The combined model (combination of CGRS and the lipid parameter) explained 26% of the disability variance for HDL and 27% for TC:HDL. INTERPRETATION: In this prospective cohort study, both lipid levels and lipid-related polymorphisms individually and jointly were associated with significantly increased disability progression in MS. These results indicate that these polymorphisms and tagged genes might be potential points of intervention to moderate disability progression.

Role of PCK1 gene on oil tea-induced glucose homeostasis and type 2 diabetes: an animal experiment and a case-control study.

BACKGROUND: Oil tea is a type of traditional tea beverage used for treating various ailments in minority population in Guangxi, China. Our previous study showed oil tea improved glucose and lipid levels in type 2 diabetic mice. Yet, the underling molecular mechanisms are still not understood. This study aimed at assessing the effect of oil tea on glucose homeostasis and elucidating the molecular mechanisms underlying the oil tea-induced antidiabetic effects. METHODS: Twenty seven db/db mice were gavaged with saline, metformin and oil tea for 8 weeks with measurement of biochemical profiles. A real-time2 (RT2) profiler polymerase chain reaction (PCR) array comprising 84 genes involved in glucose metabolism was measured and validated by quantitative PCR (qPCR). The association between the candidate genes and type 2 diabetes were further analyzed in a case-control study in the Chinese minority population. RESULTS: Oil tea treatment facilitated glucose homeostasis by decreasing fasting blood glucose and total cholesterol, and improving glucose tolerance. Suppressing phosphoenolpyruvate carboxykinase 1 (PCK1) expression was observed in the oil tea treatment group and the expression was significantly correlated with fasting blood glucose levels. Target prediction and functional annotation by WEB-based GEne SeT AnaLysis Toolkit (WebGestalt) revealed that PCK1 mainly involved in the glycolysis/gluconeogenesis pathway among the top Kyoto Encyclopedia of Genes and Genomes (KEGG) database pathways. Both rs707555 and rs2071023 in PCK1 were significantly associated with type 2 diabetes in the minority population of Guangxi. CONCLUSION: Our findings indicated oil tea improved glucose homeostasis via down-regulation of PCK1 and PCK1 may be a genetic marker for the treatment of type 2 diabetes.

Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.

BACKGROUND: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity. OBJECTIVES: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry. STUDY SELECTION: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected. STUDY APPRAISAL: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity. RESULTS: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality. LIMITATIONS: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately. CONCLUSIONS: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013953. FUNDING: The National Institute for Health Research Health Technology Assessment programme.