Epididymitis rates in Australian hospitals 2009-2018: ecological analysis.

OBJECTIVES: To investigate rates of acute epididymitis diagnosed in Australian hospital settings. METHODS: Yearly hospital admission and emergency department (ED) rates of epididymitis as primary diagnoses were calculated for 15-44-year-old men for three states (Victoria, New South Wales, Queensland) from 2009 to 2014 using population denominators. Zero inflated Poisson regression models were used to analyse variation in rates by year, age, and residential area. Additionally, we investigated national epididymitis admission trends from 2009 to 2018 using generalised linear models. RESULTS: Between 2009 and 2014, there was a total of 7375 admissions and 17 281 ED presentations for which epididymitis was the main reason for care. Most epididymitis diagnoses (94.0% in admissions, 99.7% in EDs) were without abscess, and 2.5% of admissions were for chlamydial epididymitis. Almost a quarter (23.3%) of epididymitis diagnosed in EDs resulted in hospital admission. In 2014, the epididymitis rate per 100 000 men was 38.7 in admissions and 91.9 in EDs. Comparing 2014 with 2009, the overall epididymitis diagnosis rate increased in admissions by 32% (adjusted incident rate ratio (aIRR) 1.32, 95% CI 1.20 to 1.44) and in ED attendances by 40% (aIRR 1.40, 95% CI 1.31 to 1.49). By age, the highest rates were among men 35-44 years in admissions and men 15-24 years in EDs. National admission rates of epididymitis during 2009-2018 showed a similar pattern. CONCLUSION: Rates of epididymitis diagnosis in hospital admission and ED presentations increased. Different age-related rates in these settings suggest a different aetiology or differential severity by age group.

Multiple imputation methods for handling missing values in longitudinal studies with sampling weights: Comparison of methods implemented in Stata.

Many analyses of longitudinal cohorts require incorporating sampling weights to account for unequal sampling probabilities of participants, as well as the use of multiple imputation (MI) for dealing with missing data. However, there is no guidance on how MI and sampling weights should be implemented together. We simulated a target population based on the Australian Bureau of Statistics Estimated Resident Population and drew 1000 random samples dependent on three design variables to mimic the Longitudinal Study of Australian Children. The target analysis was the weighted prevalence of overweight/obesity over childhood. We evaluated the performance of several MI approaches available in Stata, based on multivariate normal imputation (MVNI), fully conditional specification (FCS) and twofold FCS: a weighted imputation model, imputing missing data separately for each quintile sampling weight grouping, including the design stratum indicator in the imputation model, and using sampling weights as a covariate in the imputation model. Approaches based on available cases and inverse probability weighting (IPW), with time-varying weights, were also compared. We observed severe issues of convergence with FCS and twofold FCS. All MVNI-based approaches performed similarly, producing minimal bias and nominal coverage, except for when imputation was conducted separately for each quintile sampling weight group. IPW performed equally as well as MVNI-based approaches in terms of bias, however, was less precise. In similar longitudinal studies, we recommend using MVNI with the design stratum as a covariate in the imputation model. If this is unknown, including the sampling weight as a covariate is an appropriate alternative.

Effectiveness of Exercise Interventions for Pain Reduction in People With Multiple Sclerosis: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To systematically review the evidence of the effect of exercise compared with passive control on pain in people with multiple sclerosis. DATA SOURCE AND STUDY SELECTION: Five electronic databases were searched for randomized controlled trials published up to March 2017 that recruited people with multiple sclerosis where exercise was the intervention and pain was an outcome (PROSPERO registration number CRD42017060489). STATISTICAL ANALYSIS: A random-effects meta-analysis was conducted to estimate the standardized mean difference of the effect of exercise on pain between treatment and control groups. We assessed risk of bias, fitted meta-regression models to explore heterogeneity between studies, and assessed small study effects. DATA SYNTHESIS: Ten studies met the inclusion criteria (total sample size=389), and all studies were at high risk of bias. We found that exercise interventions were associated with less pain compared with passive control groups (standardized mean difference=-.46; 95% CI, -.92 to .00). There was high between-study heterogeneity (I2=77.0%), which was not explained by the prespecified study characteristics. There was also some evidence of small study effects. CONCLUSION: This is the first systematic review of the effect of exercise interventions on pain in people with multiple sclerosis, a chronic neurological disorder that affects 2.5 million people. We found some evidence that exercise compared with passive control alleviates pain in this population, but there were limitations in reporting and study quality with high risk of bias of individual studies and heterogeneity between studies.

Trends in diagnosis of pelvic inflammatory disease in an Australian sexual health clinic, 2002-16: before and after clinical audit feedback.

Background A 2006 Australian sexual health clinic audit of pelvic inflammatory disease (PID) diagnosis rates found variability between doctors. Doctors were given audit feedback towards increasing diagnosis and reducing variability. The clinic implemented other improvements to increase capacity. This study investigated PID diagnosis time trends before and after feedback. METHODS: Yearly PID diagnosis rates for women aged 16-49 years attending the clinic (2002-16) were calculated. Using multivariable generalised linear mixed models, adjusted for patient risk and lower genital infection (any of chlamydia, gonorrhoea, Mycoplasma genitalium, bacterial vaginosis) and stratified by before (2002-June 2007) and after (July 2007-2016) feedback, we assessed if PID rates changed over time, accounting for between-doctor variability. RESULTS: During 2002-16, 144 doctors undertook 84476 female consultations and diagnosed 1755 (2.1%, 95% confidence interval (CI) 2.0-2.2) with PID. Comparing 2002-03 to 2015-16, the yearly PID rate increased; 0.8% (37/4836) to 2.9% (209/7088). Comparing before and after feedback more women reported any symptoms at triage (35.1%-47.2%) or had a lower genital infection diagnosed (10.1%-14.9%). After feedback, PID rates increased by 8% yearly (incidence rate ratio (IRR) 1.08, 95% CI 1.06-1.11), but were unchanged (adjusted IRR (aIRR) 1.01, 95% CI 0.98-1.03) after adjustment for patient characteristics. Factors associated with PID were self-reported symptoms, younger age and a lower genital infection. Lower variability in doctor-specific rates was observed after feedback. CONCLUSIONS: Increasing PID diagnosis rates appeared to be driven by a greater female patient risk profile, influenced by increased capacity following service improvements.

NormalizeMets: assessing, selecting and implementing statistical methods for normalizing metabolomics data.

INTRODUCTION: In metabolomics studies, unwanted variation inevitably arises from various sources. Normalization, that is the removal of unwanted variation, is an essential step in the statistical analysis of metabolomics data. However, metabolomics normalization is often considered an imprecise science due to the diverse sources of variation and the availability of a number of alternative strategies that may be implemented. OBJECTIVES: We highlight the need for comparative evaluation of different normalization methods and present software strategies to help ease this task for both data-oriented and biological researchers. METHODS: We present NormalizeMets-a joint graphical user interface within the familiar Microsoft Excel and freely-available R software for comparative evaluation of different normalization methods. The NormalizeMets R package along with the vignette describing the workflow can be downloaded from https://cran.r-project.org/web/packages/NormalizeMets/ . The Excel Interface and the Excel user guide are available on https://metabolomicstats.github.io/ExNormalizeMets . RESULTS: NormalizeMets allows for comparative evaluation of normalization methods using criteria that depend on the given dataset and the ultimate research question. Hence it guides researchers to assess, select and implement a suitable normalization method using either the familiar Microsoft Excel and/or freely-available R software. In addition, the package can be used for visualisation of metabolomics data using interactive graphical displays and to obtain end statistical results for clustering, classification, biomarker identification adjusting for confounding variables, and correlation analysis. CONCLUSION: NormalizeMets is designed for comparative evaluation of normalization methods, and can also be used to obtain end statistical results. The use of freely-available R software offers an attractive proposition for programming-oriented researchers, and the Excel interface offers a familiar alternative to most biological researchers. The package handles the data locally in the user's own computer allowing for reproducible code to be stored locally.

Rates of pelvic inflammatory disease and ectopic pregnancy in Australia, 2009-2014: ecological analysis of hospital data.

OBJECTIVE: To analyse yearly rates of pelvic inflammatory disease (PID) and ectopic pregnancy (EP) diagnosed in hospital settings in Australia from 2009 to 2014. METHODS: We calculated yearly PID and EP diagnosis rates in three states (Victoria, New South Wales, Queensland) for women aged 15-44 years using hospital admissions and emergency department (ED) attendance data, with population and live birth denominators. We stratified PID diagnoses as chlamydial-related or gonorrhoeal-related (Chlamydia trachomatis (CT)-related or Neisseria gonorrhoeae (NG)-related), acute, unspecified and chronic, and analysed variations by year, age and residential area using Poisson regression models. RESULTS: For PID, the rate of all admissions in 2014 was 63.3 per 100 000 women (95% CI 60.8 to 65.9) and of all presentations in EDs was 97.0 per 100 000 women (95% CI 93.9 to 100.2). Comparing 2014 with 2009, the rate of all PID admissions did not change, but the rate of all presentations in EDs increased (adjusted incidence rate ratio (aIRR) 1.34, 95% CI 1.24 to 1.45), and for admissions by PID category was higher for CT-related or NG-related PID (aIRR 1.73, 95% CI 1.31 to 2.28) and unspecified PID (aIRR 1.09, 95% CI 1.00 to 1.19), and lower for chronic PID (aIRR 0.84, 95% CI 0.74 to 0.95). For EP, in 2014 the rate of all admissions was 17.4 (95% CI 16.9 to 17.9) per 1000 live births and of all ED presentations was 15.6 (95% CI 15.1 to 16.1). Comparing 2014 with 2009, the rates of all EP admissions (aIRR 1.06, 95% CI 1.04 to 1.08) and rates in EDs (aIRR 1.24, 95% CI 1.18 to 1.31) were higher. CONCLUSIONS: PID and EP remain important causes of hospital admissions for female STI-associated complications. Hospital EDs care for more PID cases than inpatient departments, particularly for young women. Updated primary care data are needed to better understand PID epidemiology and healthcare usage.

Characteristics of pelvic inflammatory disease where no sexually transmitted infection is identified: a cross-sectional analysis of routinely collected sexual health clinic data.

OBJECTIVES: Pelvic inflammatory disease (PID) occurs when pathogens, often sexually transmitted, ascend to the upper genital tract, yet a causative pathogen is not detected in a substantial proportion of diagnosed PID. We assessed the characteristics associated with PID in women in whom chlamydia, gonorrhoea, Mycoplasma genitalium (MG) and bacterial vaginosis (BV) were not detected ('pathogen-negative-PID'). METHODS: Cross-sectional analysis of routinely collected clinical data from new female patients attending a sexual health clinic between 2006 and 2013. Women were eligible if they had been diagnosed with PID and tested for genital chlamydia, gonorrhoea, MG and BV. Logistic regression was conducted to identify characteristics associated with pathogen-negative-PID. RESULTS: Among 330 women with clinically diagnosed PID, 204 (61.8%, 95% CI 56.3% to 67.1%) had pathogen-negative-PID. Compared with pathogen-positive-PID, pathogen-negative-PID cases were more likely to be aged ≥30 years (adjusted odds ratio (AOR) 1.7, 95% CI 1.0 to 3.0), had less evidence of vaginal inflammation (AOR 0.5, 95% CI 0.3 to 0.9) and reported less unprotected sex (AOR 0.6, 95% CI 0.4 to 1.0). CONCLUSIONS: These findings highlight uncertainties around PID diagnosis and aetiology. Pathogen-negative-PID could represent (i) a false positive diagnosis where the woman does not have a sexually transmitted infection (STI) or PID, (ii) PID of another microbiological aetiology or associated with a past STI or (iii) PID where the cervical infection has cleared. However, until diagnostic biomarkers are available, PID treatment should be based on clinical features and sexual risk.

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.

The effect of breastfeeding on lung function at 12 and 18†years: a prospective cohort study.

The objective was to assess associations between duration of total and exclusive breastfeeding and lung function up to adolescence.A birth cohort (Melbourne Atopy Cohort Study) of 620 infants with a family history of allergic disease was recruited. Mothers were encouraged to breastfeed exclusively for 6 months. Lung function was assessed at 12 and 18 years of age. Associations between breastfeeding and lung function were investigated using multivariable linear regression and path analysis was used to assess the potential mediating factors.Duration of breastfeeding (total and exclusive) was not associated with most assessed lung function outcomes. However, there was a trend for increased pre-bronchodilator mid-expiratory flow (MEF) at both 12 (adjusted mean difference (95% CI) per week of breastfeeding of 10 (-1-20) mL·s(-1)) and 18 years (11 (-1-22) mL·s(-1)) (p-values of 0.07 and 0.08, respectively). There was a strong indirect effect of height on these observed associations.Duration of breastfeeding does not appear to greatly influence lung function outcomes in children with a family history of allergic diseases. Longer duration of exclusive breastfeeding may be associated with an increase in MEF, partly due to greater attained height of the child.

Population attributable fraction of pelvic inflammatory disease associated with chlamydia and gonorrhoea: a cross-sectional analysis of Australian sexual health clinic data.

OBJECTIVES: Pelvic inflammatory disease (PID) is an important cause of female infertility and can occur when micro-organisms such as chlamydia or gonorrhoea ascend to the upper genital tract. PID has been used as an outcome measure in chlamydia screening trials; however, few data have quantified the PID burden that could be avoided by preventing chlamydia. We estimated the population attributable fraction (PAF) of PID associated with a current chlamydia or gonorrhoea infection among females 16-49 years attending an Australian sexual health clinic (SHC) (2006-2013). METHODS: Using multivariable logistic regression, PAF estimates were adjusted for age and behavioural factors. Two separate analyses were undertaken: one among 'chlamydia-tested' women and one among a subset of chlamydia-tested women who were also tested for gonorrhoea ('chlamydia+gonorrhoea-tested'). A sensitivity analysis using multiple imputation was conducted to assess the impact of missing data on results. RESULTS: Among 15 690 chlamydia-tested women, 1279 (8.2%, 95% CI 7.7% to 8.6%) were chlamydia positive, 436 (2.8%, 95% CI 2.5% to 3.0%) had PID diagnosed and the adjusted PAF for chlamydia was 14.1% (95% CI 9.9% to 18.0%). Among the chlamydia+gonorrhoea-tested subset (n=8839), 681 (7.7%, 95% CI 7.2% to 8.3%) tested positive for chlamydia only, 30 (0.3%, 95% CI 0.2% to 0.5%) for gonorrhoea only, 22 (0.2%, 95% CI 0.2% to 0.4%) for chlamydia and gonorrhoea and 419 (4.7%, 95% CI 4.3% to 5.2%) had PID diagnosed. The adjusted PAF was highest for chlamydia only (12.4%, 95% CI 8.4% to 16.2%) compared with gonorrhoea only (0.9%, 95% CI -0.1% to 1.8%) or concurrent infections (1.0%, 95% CI 0.0% to 1.9%). CONCLUSIONS: In this high chlamydia prevalence SHC population, eliminating a current chlamydia infection might at most reduce PID by about 14%.

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.

Sexual function in multiple sclerosis and associations with demographic, disease and lifestyle characteristics: an international cross-sectional study.

BACKGROUND: Sexual dysfunction (SD) is very common in people with multiple sclerosis (PwMS) and contributes a significant burden of disease, particularly for young people. SD has direct neurological contributions from depression and fatigue, which occur commonly in PwMS. Modifiable factors may represent potential targets for treatment and prevention of SD. We aimed to assess the prevalence of SD and explore associations between SD and demographic and modifiable risk factors, as well as depression and fatigue in a large cohort of PwMS. METHODS: We analysed self-reported data from a large, international sample of PwMS recruited via Web 2.0 platforms, including demographic, lifestyle and disease characteristics. Specific sexual function questions included 4 items from the sexual function scale and 1 item regarding satisfaction with sexual function, part of the MS Quality of Life-54 instrument. RESULTS: 2062 PwMS from 54 countries completed questions on sexual function. 81.1 % were women, mean age was 45 years, most (62.8 %) reported having relapsing-remitting MS. The majority (54.5 %) reported one or more problems with sexual function and were classified as having SD. Lack of sexual interest (41.8 % of women), and difficulty with erection (40.7 % of men) were most common. The median total sexual function score was 75.0 out of 100, and 43.7 % were satisfied with their sexual function. Regression modeling revealed independent associations between sexual function and satisfaction and a range of demographic factors, including age, as well as depression risk, antidepressant use, and fatigue in PwMS. CONCLUSION: This cross-sectional study shows that SD and lack of satisfaction with sexual function are associated with depression risk and fatigue, as well as modifiable lifestyle factors diet and physical activity (after adjusting for depression and fatigue). Planned longitudinal follow-up of this sample may help clarify these associations and the underlying mechanisms. There is potential to prevent and treat SD in PwMS by addressing depression and fatigue and their determinants. Clinicians and PwMS should be aware of SD and associated factors as part of a comprehensive preventive approach to managing MS.

Statistical methods for handling unwanted variation in metabolomics data.

Metabolomics experiments are inevitably subject to a component of unwanted variation, due to factors such as batch effects, long runs of samples, and confounding biological variation. Although the removal of this unwanted variation is a vital step in the analysis of metabolomics data, it is considered a gray area in which there is a recognized need to develop a better understanding of the procedures and statistical methods required to achieve statistically relevant optimal biological outcomes. In this paper, we discuss the causes of unwanted variation in metabolomics experiments, review commonly used metabolomics approaches for handling this unwanted variation, and present a statistical approach for the removal of unwanted variation to obtain normalized metabolomics data. The advantages and performance of the approach relative to several widely used metabolomics normalization approaches are illustrated through two metabolomics studies, and recommendations are provided for choosing and assessing the most suitable normalization method for a given metabolomics experiment. Software for the approach is made freely available.

Models for the analysis of repeated continuous outcome measures in clinical trials.

Repeated continuous outcome measures are common in clinical trials. In this tutorial style paper, using data collected from a trial evaluating an intervention for managing asthma and chronic obstructive pulmonary disease, we demonstrate ways of statistically analysing such data to answer frequently encountered clinical research questions. We illustrate the use of linear mixed effects modelling in doing so and discuss its advantages over several other commonly used approaches. The methods described in this paper can easily be carried out using standard statistical software.

Normalizing and integrating metabolomics data.

Metabolomics research often requires the use of multiple analytical platforms, batches of samples, and laboratories, any of which can introduce a component of unwanted variation. In addition, every experiment is subject to within-platform and other experimental variation, which often includes unwanted biological variation. Such variation must be removed in order to focus on the biological information of interest. We present a broadly applicable method for the removal of unwanted variation arising from various sources for the identification of differentially abundant metabolites and, hence, for the systematic integration of data on the same quantities from different sources. We illustrate the versatility and the performance of the approach in four applications, and we show that it has several advantages over the existing normalization methods.

An Interactive Web Application for the Statistical Analysis of Continuous Glucose Monitoring Data in Epidemiological Studies.

MOTIVATION: Continuous glucose monitoring (CGM) systems are an essential part of novel technology in diabetes management and care. CGM studies have become increasingly popular among researchers, healthcare professionals, and people with diabetes due to the large amount of useful information that can be collected using CGM systems. The analysis of the data from these studies for research purposes, however, remains a challenge due to the characteristics and large volume of the data. RESULTS: Currently, there are no publicly available interactive software applications that can perform statistical analyses and visualization of data from CGM studies. With the rapidly increasing popularity of CGM studies, such an application is becoming necessary for anyone who works with these large CGM datasets, in particular for those with little background in programming or statistics. CGMStatsAnalyser is a publicly available, user-friendly, web-based application, which can be used to interactively visualize, summarize, and statistically analyze voluminous and complex CGM datasets together with the subject characteristics with ease.

Evaluating the efficacy and safety of GKT137831 in adults with type 1 diabetes and persistently elevated urinary albumin excretion: a statistical analysis plan.

BACKGROUND: The investigational medicinal product GKT137831 is a selective inhibitor of NOX 1 and 4 isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes, which has the potential to ameliorate diabetic kidney disease. An investigator-initiated, double-blind, randomised, placebo-controlled, multicentre phase 2 clinical trial started recruitment in December 2017, with the aim of evaluating the efficacy and safety of GKT13783, in adults with type 1 diabetes mellitus and persistently elevated urinary albumin excretion over a period of 48 weeks. METHODS/DESIGN: The trial is currently recruiting in Australia and New Zealand, with recruitment expected to end on 30 June 2020. The primary outcome measure of the trial is the urinary albumin excretion level measured at 48 weeks of treatment. This statistical analysis plan presents an update to the published trial protocol and provides a comprehensive description of the statistical methods that will be used for the analysis of the data from this trial. In doing so, we follow the "Guidelines for the content of statistical analysis plans in clinical trials" to support transparency and reproducibility of the trial findings. DISCUSSION: With the use of this prior statistical analysis plan, we aim to minimise bias in the reporting of the findings of this trial, which evaluates the investigational medicinal product GKT137831. The results of the trial are expected to be published in 2022. TRIAL REGISTRATION: ANZCTR registry: ACTRN12617001187336. Registered on 14 July 2017. Universal Trial Number: U1111-1187-2609; Protocol number: T1DGKT137831; Genkyotex trial number: GSN000241.

Metabolomic Biomarkers of Multiple Sclerosis: A Systematic Review.

BACKGROUND: Magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and the McDonald's clinical criteria are currently utilized tools in diagnosing multiple sclerosis. However, a more conclusive, consistent, and efficient way of diagnosing multiple sclerosis (MS) is yet to be discovered. A potential biomarker, discovered using advances in high-throughput sequencing such as nuclear magnetic resonance (NMR) spectroscopy and other "Omics"-based techniques, may make diagnosis and prognosis more reliable resulting in a more personalized and targeted treatment regime and improved outcomes. The aim of this review was to systematically search the literature for potential biomarkers from any bodily fluid that could consistently and accurately diagnose MS and/or indicate disease progression. METHODS: A systematic literature review of EMBASE, PubMed (MEDLINE), The Cochrane Library, and CINAHL databases produced over a thousand potential studies. Inclusion criteria stated studies with potential biomarker outcomes for people with MS were to be included in the review. Studies were limited to those with human participants who had a clinically defined diagnosis of MS and published in English, with no limit placed on date of publication or the type of bodily fluid sampled. RESULTS: A total of 1,805 studies were recorded from the literature search. A total of 1,760 studies were removed based on their abstract, with a further 18 removed after considering the full text. A total of 30 studies were considered relevant and had their data retrieved and analyzed. Due to the heterogeneity of focus and results from the refined studies, a narrative synthesis was favored. CONCLUSION: Several promising candidate biomarkers suitable for clinical application in MS have been studied. It is recommended follow-up studies with larger sample sizes be completed on several potential biomarkers.

A physician-initiated double-blind, randomised, placebo-controlled, phase 2 study evaluating the efficacy and safety of inhibition of NADPH oxidase with the first-in-class Nox-1/4 inhibitor, GKT137831, in adults with type 1 diabetes and persistently elevated urinary albumin excretion: Protocol and statistical considerations.

PURPOSE: Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox - 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. DESIGN: This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. PRIMARY OUTCOME MEASURES: Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. CONCLUSION: This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.

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.