Neuropsychological outcomes following HSCT in MS: A systematic review.

BACKGROUND: Autologous haematopoietic stem cell transplant (HSCT) is considered an effective treatment for highly active multiple sclerosis (MS). To date, most research has focused primarily on disease outcome measures, despite the significant impact of neuropsychological symptoms on MS patients' quality of life. The current systematic review aimed to examine whether HSCT for MS impacts neuropsychological outcome measures such as cognition, fatigue, mood, and quality of life. METHODS: The review was registered with the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42023474214). Systematic searches were carried out in six databases (PsycINFO, PubMed, Embase, Scopus, CINAHL and Web of Science) based on the following inclusion criteria: (i) published in peer-reviewed journals in English; (ii) longitudinal studies of adults with MS (iii) at least one neuropsychological outcome was assessed pre- and post-HSCT using standardised measures. Risk of bias was assessed using the National Heart, Lung and Blood Institute (NHLBI) quality assessment tools. A narrative synthesis was used to present results. RESULTS: Eleven studies were included in the review. Long-term improvements in quality of life post-HSCT were identified. In terms of cognition and fatigue, the evidence was mixed, with some post-HSCT improvements identified. Decline in cognitive performance in the short-term post-HSCT was observed. No changes in mood were identified post-HSCT. Arguments for interpreting these results with caution are presented based on risk of bias. Arguments for interpreting these results with caution are presented based on risk of bias. Limitations of the evidence are discussed, such confounding variables and lack of statistical power. CONCLUSION: The evidence base for the impact of HSCT for MS on neuropsychological outcomes is limited. Further research is required to progress understanding to facilitate clinician and patient understanding of HSCT treatment for MS.

Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.

Comparative effectiveness in multiple sclerosis: A methodological comparison.

BACKGROUND: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. OBJECTIVE: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. METHODS: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. RESULTS: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. CONCLUSIONS: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Predictors of treatment switching in the Big Multiple Sclerosis Data Network.

Background: Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods. Objective: The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry. Methods: In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect. Results: Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006). Conclusion: Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.

Investigating the association of mood and fatigue with objective and subjective cognitive impairment in multiple sclerosis.

Discrepancies between subjective cognitive difficulties and objective measures of cognitive function in people with MS have been identified and may be related to mood and fatigue. The aim of the present study was to examine associations of depression and fatigue with discrepancies between subjective and objective cognitive functioning in pwMS. 177 participants with MS attending a University Hospital Department of Neurology MS Outpatient clinic completed the Brief International Cognitive Assessment for MS (BICAMS), MS Neuropsychological Questionnaire (MSNQ), Hospital Anxiety and Depression Scale (HADS) and Modified Fatigue Impact Scale (MFIS). To quantify the discrepancy between objective (BICAMS) and subjective (MSNQ) cognitive functioning, discrepancy scores were calculated by subtracting MSNQ z-score from composite BICAMS z-score. Based on their discrepancy score, participants were grouped as 'Underestimated', 'Overestimated' and 'Non-discrepant'. 39% of the total sample demonstrated poorer subjective cognitive functioning than their objective cognitive performance suggested ('Underestimated'). 23% of the total sample indicated lower objective scores than their subjective report suggests ('Overestimated'). 38% participants indicated relatively no discrepancy between objective and subjective cognitive measures ('Non-discrepant'). Significant differences were observed between the discrepancy groups in terms of depression and fatigue, with the 'Underestimated' group demonstrating greater levels of depression and fatigue (ps < .01). Regression analysis indicated that cognitive fatigue and depression significantly contributed to variance in subjective cognitive functioning. Our findings suggest that subjective reports of cognitive function may be influenced by depression and fatigue, emphasising the importance of cognitive, mood and fatigue screening as part of routine clinical care.

Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis: An International Registry Study.

BACKGROUND AND OBJECTIVES: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. METHODS: This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. RESULTS: The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (ß = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (ß = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (ß = - 0.5, 95% CI -0.6 to 0.4) and 18 years (ß = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (ß = -1.0, 95% CI -1.1 to 0.9). DISCUSSION: In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.

Estimated Dissemination Ratio-A Practical Alternative to the Reproduction Number for Infectious Diseases.

Policymakers require consistent and accessible tools to monitor the progress of an epidemic and the impact of control measures in real time. One such measure is the Estimated Dissemination Ratio (EDR), a straightforward, easily replicable, and robust measure of the trajectory of an outbreak that has been used for many years in the control of infectious disease in livestock. It is simple to calculate and explain. Its calculation and use are discussed below together with examples from the current COVID-19 outbreak in the UK. These applications illustrate that EDR can demonstrate changes in transmission rate before they may be clear from the epidemic curve. Thus, EDR can provide an early warning that an epidemic is resuming growth, allowing earlier intervention. A conceptual comparison between EDR and the commonly used reproduction number is also provided.

Differential item functioning of the Arm function in Multiple Sclerosis Questionnaire (AMSQ) by language, a study in six countries.

BACKGROUND: The Arm function in Multiple Sclerosis Questionnaire (AMSQ) has been developed as a self-reported measure of arm and hand functioning for patients with multiple sclerosis (MS). The AMSQ was originally developed in Dutch and to date translated into five languages (i.e. English, German, Spanish, French, and Italian). OBJECTIVE: The aim of this study was to evaluate differential item functioning (DIF) of the AMSQ in these languages. METHODS: We performed DIF analyses, using "language" as the polytomous group variable. To detect DIF, logistic regression and item response theory principles were applied. Multiple logistic regression models were evaluated. We used a pseudo R2 value of 0.02 or more as the DIF threshold. RESULTS: A total of 1733 male and female patients with all subtypes of MS were included. The DIF analysis for the whole dataset showed no uniform or non-uniform DIF on any of the 31 items. All R2 values were below 0.02. CONCLUSION: The AMSQ is validated in six languages. All items have the same meaning to MS patients in Dutch, English, German, Spanish, French, and Italian. This validation study enables use of the AMSQ in international studies, for monitoring treatment response and disease progression.

Perceived and objective cognitive impairment in newly diagnosed versus established multiple sclerosis: impact of disease duration.

BACKGROUND: Cognitive impairment (CI) is common in multiple sclerosis (MS), including newly diagnosed MS, where it is particularly underrecognised. Determining the presence of CI in the outpatient clinic often relies on patient-reported complaints, with limited time and resources in this setting. Prior studies have shown that self-reported cognition relates poorly to formal neuropsychological testing in the MS population and correlates more with factors such as anxiety, depression and fatigue. AIMS: In this study, we assess the prevalence of perceived cognitive dysfunction in newly diagnosed MS patients and compare results with an established MS cohort. RESULTS: Thirty-nine patients with newly diagnosed MS (12 months following diagnosis) and 24 patients with an established diagnosis (3 years) were included. Similar levels of perceived and objective CI were seen in both groups. There was a strong correlation of perceived cognitive dysfunction with anxiety, mood and fatigue. Perceived cognition did not correlate with objective CI, assessed using the Brief International Cognitive Assessment in MS (BICAMS), in either group. CONCLUSIONS: Study findings add to the literature of perceived cognition in MS, in a newly diagnosed cohort. Findings are consistent with previous research using detailed neuropsychological assessments, confirming the sensitivity of BICAMS, applicable in a routine clinical setting.

Risk factors for falling for people with Multiple Sclerosis identified in a prospective cohort study.

OBJECTIVE: To identify risk factors for falling for people with Multiple Sclerosis. DESIGN: Prospective cohort study. SETTING: Neurology service in a tertiary hospital. SUBJECTS: Participants were 101 people with Multiple Sclerosis and Expanded Disability Status Score of 3-6.5. One participant withdrew after the baseline assessment; data were analysed for 100 participants. INTERVENTIONS: No intervention. MAIN MEASURES: Outcome was rate of falls, and predictors were Timed Up and Go, Symbol Digit Modalities test, demographics and 15 self-report questions about various symptoms including fatigue, concentration, dual tasking, bladder and bowel control. Three-month prospective diaries recorded falls. RESULTS: There were 791 falls reported over the 3-month period from a total of 56 fallers. Falls rate per person-year was 32.08 falls. Following multivariable regression analysis, the model with the greatest levels of clinical utility and discriminative ability (sensitivity 88% and area under the receiving operating curve statistic = 0.72, 95% CI 0.62-0.82), included the variables of history of a fall, not having visual problems, problems with bladder control and a slower speed on the Timed Up and Go. CONCLUSION: This study confirms the high incidence of falls for people with Multiple Sclerosis and provides a risk prediction model including fall history, problems with bladder control, not having visual problems and a slower Timed Up and Go speed that may be used to identify those at greater risk and in need of tailored falls prevention intervention.

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.

Monocytes exposed to plasma from patients with Alzheimer's disease undergo metabolic reprogramming.

The search for a blood-based biomarker that identifies Alzheimer's disease (AD) and can replace current invasive and expensive diagnostic tests, continues. The most extensively-examined peripheral marker is ß-amyloid (Aß) but the results are inconsistent across studies and do not reflect the changes that take place in the brain. Several studies have assessed possible proteomic signatures but with inconsistent findings, although increases in circulating inflammatory molecules are generally observed. Here, rather than focus on identifying changes in the circulation, we evaluated the effect of plasma from patients with mild cognitive impairment (MCI) and AD on the human monocyte-like cell line, THP-1 cells, and plasma from an AD mouse model on a mouse monocyte-macrophage cell line, J774.2 cells. Plasma from AD patients and the AD mouse model increased inflammatory molecules in the cells and these changes were accompanied by an increase in glycolysis. Interestingly, plasma from MCI patients exerted no significant effect on THP-1 cells. The possibility therefore exists that evaluating the effect of plasma on IL-8 and TNFα mRNA in THP-1 cells combined with analysis of glycolysis in these cells, may be the basis of an indicator that discriminates between AD and MCI and normal controls, but is unlikely to be useful in identifying early pathological changes.

Discriminative ability and clinical utility of the Timed Up and Go (TUG) in identifying falls risk in people with multiple sclerosis: a prospective cohort study.

OBJECTIVE:: To investigate discriminative ability and clinical utility of the Timed Up and Go under single- and dual-task conditions between fallers and non-fallers in multiple sclerosis (MS). DESIGN:: Prospective cohort study. SETTING:: Neurology service in a tertiary hospital. SUBJECTS:: Participants were 101 people with MS and Expanded Disability Status Scale score of 3-6.5. One participant withdrew after the baseline assessment, and hence the data were analysed for 100 participants. INTERVENTIONS:: No specific intervention. MAIN MEASURES:: Timed Up and Go and Timed Up and Go-Cognitive. Three-month prospective diaries recorded falls. RESULTS:: Mean age was 52.6 (SD 10.7) and 66 were female. Majority of the participants had progressive MS (72) and 73 used a walking aid; 56 participants recorded 791 falls. The area under the receiver operating characteristic curve values for Timed Up and Go and Timed Up and Go-Cognitive in distinguishing fallers (person with ⩾1 fall) from non-fallers are 0.60 and 0.57, respectively, and in distinguishing multiple fallers (⩾2 falls) the values are 0.46 and 0.43. A Timed Up and Go score of ⩾9 seconds has a sensitivity of 0.82 and a specificity of 0.34 to identify fallers and a sensitivity of 0.79 and a specificity of 0.27 to identify multiple fallers. A Timed Up and Go-Cognitive score of ⩾11 seconds has a sensitivity of 0.77 and a specificity of 0.30 to identify fallers and a sensitivity of 0.71 and a specificity of 0.26 to identify multiple fallers. CONCLUSION:: The Timed Up and Go and Timed Up and Go-Cognitive do not demonstrate sufficient clinical utility or discriminative ability for assessing falls risk in MS.

Medication usage and falls in people with multiple sclerosis.

There is a need to identify modifiable risk factors for falls in people with multiple sclerosis (MS) to enable the design of successful falls prevention interventions. There is conflicting evidence regarding the association between medication use and occurrence of falls in MS. A total of 101 people with MS had medications classified using the Anatomical Therapeutic Classification system and number of falls prospectively monitored for 3 months. No association was noted between number of medications and falls. The use of genitourinary and sex hormones (odds ratio (OR) = 5.154, 95% confidence interval (CI) = 1.427-18.609, p = 0.012) and centrally acting muscle relaxant (OR = 5.181, 95% CI = 1.546-17.364, p = 0.008) medications were associated with an increased odds of being a faller.

Effects of vitamin D3 in clinically isolated syndrome and healthy control participants: A double-blind randomised controlled trial.

BACKGROUND: Lowserum vitamin D levels are associated with susceptibility to, and severity of, multiple sclerosis. High dose vitamin D has been proposed as a potential immunomodulator in multiple sclerosis. OBJECTIVES: We performed a single centre, investigator-led, exploratory, double-blind, randomised, placebo controlled, trial of vitamin D3 in clinically isolated syndrome and healthy control participants to assess its immunological effects. Secondary end-points included clinical and magnetic resonance imaging outcomes and safety. METHODS: Clinically isolated syndrome patients and healthy control participants were randomised to: placebo, 5000 IU or 10,000 IU vitamin D3/day (Vigantol oil). Study duration was 24 weeks. RESULTS: The trial did not meet its primary end point, with no difference in the frequency of pro-inflammatory CD4+ T cells (interleukin (IL)-17+/interferon (IFN)-γ+) seen. A higher level of disease freedom (67% versus 50%) was seen in those with serum 1,25 (OH) vitamin D levels>100 nmol/l but this did not reach significance. High dose vitamin D3 was well tolerated with no safety signal. CONCLUSIONS: High dose vitamin D3 over 24 weeks was well tolerated but without immunological, magnetic resonance imaging or clinical evidence of benefit. The hypothesised therapeutic effects in clinically isolated syndrome or multiple sclerosis patients may require longer periods of administration or may only be seen in patients treated with vitamin D3 as an adjunct to established disease modifying therapies.

Kinase-independent phosphoramidate S1P1 receptor agonist benzyl ether derivatives.

Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P1-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents.

Acid-suppression medications and bacterial gastroenteritis: a population-based cohort study.

AIMS: To investigate whether acid-suppression medicines (ASMs) increase the risk of bacterial gastroenteritis. METHODS: A population-based, propensity-score matched cohort study using a record-linkage database in Tayside, UK. The study consisted of 188 323 exposed to ASMs (proton-pump inhibitors and histamine-2 receptor antagonists) and 376 646 controls (a propensity-score matched cohort from the rest of population who were not exposed to ASMs) between 1999 and 2013. The main outcome measure was a positive stool test for Clostridium difficile, Campylobacter, Salmonella, Shigella or Escherichia coli O157. The association between ASMs and risk of bacterial gastroenteritis was assessed by a Cox regression model. RESULTS: There were 22 705 positive test results (15 273 C. difficile [toxin positive], 6590 Campylobacter, 852 Salmonella, 129 Shigella and 193 E. coli O157, not mutually exclusive) with a total of 5 729 743 person-years follow up time in Tayside, 1999-2013. The adjusted hazard ratios for culture positive diarrhoea for the proton-pump inhibitors and histamine-2 receptor antagonists exposed vs. unexposed cohort were 2.72 (95% confidence interval [CI] 2.33, 3.17) during follow-up time for samples submitted from the community and 1.28 (95% CI 1.08, 1.52) for samples submitted from hospitals. Compared with the unexposed cohort, patients in the exposed group had increased risks of C. difficile and Campylobacter [adjusted hazard ratios of 1.70 (95% CI 1.28, 2.25), 3.71 (95% CI 3.04, 4.53) for community samples, and 1.42 (95% CI 1.17, 1.71), 4.53 (95% CI 1.75, 11.8) for hospital samples, respectively]. CONCLUSIONS: The results suggest that community prescribed ASMs were associated with increased rates of C. difficile and Campylobacter positive gastroenteritis in both the community and hospital settings.