Background Diabetic retinopathy (DR) is a major sight-threatening microvascular complication in individuals with diabetes. Systemic inflammation combined with oxidative stress is thought to capture most of the complexities involved in the pathology of diabetic retinopathy. A high level of neutrophil–lymphocyte ratio (NLR) is an indicator of abnormal immune system activity. Current estimates of the association of NLR with diabetes and its complications are almost entirely derived from cross-sectional studies, suggesting that the nature of the reported association may be more diagnostic than prognostic. Therefore, in the present study, we examined the utility of NLR as a biomarker to predict the incidence of DR in the Scottish population. Methods The incidence of DR was defined as the time to the first diagnosis of R1 or above grade in the Scottish retinopathy grading scheme from type 2 diabetes diagnosis. The effect of NLR and its interactions were explored using a competing risks survival model adjusting for other risk factors and accounting for deaths. The Fine and Gray subdistribution hazard model (FGR) was used to predict the effect of NLR on the incidence of DR. Results We analysed data from 23,531 individuals with complete covariate information. At 10 years, 8416 (35.8%) had developed DR and 2989 (12.7%) were lost to competing events (death) without developing DR and 12,126 individuals did not have DR. The median (interquartile range) level of NLR was 2.04 (1.5 to 2.7). The optimal NLR cut-off value to predict retinopathy incidence was 3.04. After accounting for competing risks at 10 years, the cumulative incidence of DR and deaths without DR were 50.7% and 21.9%, respectively. NLR was associated with incident DR in both Cause-specific hazard (CSH = 1.63; 95% CI: 1.28–2.07) and FGR models the subdistribution hazard (sHR = 2.24; 95% CI: 1.70–2.94). Both age and HbA 1c were found to modulate the association between NLR and the risk of DR. Conclusions The current study suggests that NLR has a promising potential to predict DR incidence in the Scottish population, especially in individuals less than 65 years and in those with well-controlled glycaemic status.

Aims/hypothesis Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes may develop through a process referred to as habituation. Consistent with this, a single bout of high intensity interval exercise as a novel stress stimulus improves counterregulatory responses (CRR) to next-day hypoglycaemia, referred to as dishabituation. This longitudinal pilot study investigated whether 4 weeks of high intensity interval training (HIIT) has sustained effects on counterregulatory and symptom responses to hypoglycaemia in adults with type 1 diabetes and IAH. Methods HIT4HYPOS was a single-centre, randomised, parallel-group study. Participants were identified using the Scottish Diabetes Research Network (SDRN) and from diabetes outpatient clinics in NHS Tayside, UK. The study took place at the Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, UK. Participants were aged 18–55 years with type 1 diabetes of at least 5 years’ duration and HbA 1c levels <75 mmol/mol (<9%). They had IAH confirmed by a Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating [DAFNE] hypoglycaemia awareness rating of 2 or 3, and/or evidence of recurrent hypoglycaemia on flash glucose monitoring. Participants were randomly allocated using a web-based system to either 4 weeks of real-time continuous glucose monitoring (RT-CGM) or RT-CGM+HIIT. Participants and investigators were not masked to group assignment. The HIIT programme was performed for 20 min on a stationary exercise bike three times a week. Hyperinsulinaemic–hypoglycaemic (2.5 mmol/l) clamp studies with assessment of symptoms, hormones and cognitive function were performed at baseline and after 4 weeks of the study intervention. The predefined primary outcome was the difference in hypoglycaemia-induced adrenaline (epinephrine) responses from baseline following RT-CGM or RT-CGM+HIIT. Results Eighteen participants (nine men and nine women) with type 1 diabetes (median [IQR] duration 27 [18.75–32] years) and IAH were included, with nine participants randomised to each group. Data from all study participants were included in the analysis. During the 4 week intervention there were no significant mean (SEM) differences between RT-CGM and RT-CGM+HIIT in exposure to level 1 (28 [7] vs 22 [4] episodes, p =0.45) or level 2 (9 [3] vs 4 [1] episodes, p =0.29) hypoglycaemia. The CGM-derived mean glucose level, SD of glucose and glucose management indicator (GMI) did not differ between groups. During the hyperinsulinaemic–hypoglycaemic clamp studies, mean (SEM) change from baseline was greater for the noradrenergic responses (RT-CGM vs RT-CGM+HIIT: −988 [447] vs 514 [732] pmol/l, p =0.02) but not the adrenergic responses (–298 [687] vs 1130 [747] pmol/l, p =0.11) in those participants who had undergone RT-CGM+HIIT. There was a benefit of RT-CGM+HIIT for mean (SEM) change from baseline in the glucagon CRR to hypoglycaemia (RT-CGM vs RT-CGM+HIIT: 1 [4] vs 16 [6] ng/l, p =0.01). Consistent with the hormone response, the mean (SEM) symptomatic response to hypoglycaemia (adjusted for baseline) was greater following RT-CGM+HIIT (RT-CGM vs RT-CGM+HIIT: −4 [2] vs 0 [2], p <0.05). Conclusions/interpretation In this pilot clinical trial in people with type 1 diabetes and IAH, we found continuing benefits of HIIT for overall hormonal and symptomatic CRR to subsequent hypoglycaemia. Our findings also suggest that HIIT may improve the glucagon response to insulin-induced hypoglycaemia. Trial registration ISRCTN15373978. Funding Sir George Alberti Fellowship from Diabetes UK (CMF) and the Juvenile Diabetes Research Foundation. Graphical Abstract

Objective To assess the real-world cardiovascular (CV) safety for SU, in comparison with dipeptidylpeptidase-4 inhibitors (DPP4i) and thiazolidinediones (TZD) through development of robust methodology for causal inference in a whole nation study. Research Design and Methods A cohort study was performed including people with type 2 diabetes diagnosed in Scotland before 31 December 2017, who failed to reach HbA1c 48 mmol/mol despite metformin monotherapy and initiated second-line pharmacotherapy (SU/DPP4i/TZD) on or after 1 January 2010. The primary outcome was the composite major adverse cardiovascular events (MACE), including hospitalization for myocardial infarction (MI), ischemic stroke, heart failure, and CV death. Secondary outcomes were each individual endpoint and all-cause death. Multivariable Cox proportional hazards regression and an instrumental variable (IV) approach were used to control confounding in a similar way to the randomization process in a randomized control trial. Results Comparing SU to non-SU (DPP4i/TZD), the hazard ratio (HR) for MACE was 1.00 (95% CI: 0.91 to 1.09) from the multivariable Cox regression and 1.02 (0.91 - 1.13) and 1.03 (0.91- 1.16) using two different IVs. For all-cause death, the HR from Cox regression and the two IV analyses was 1.03 (0.94 - 1.13), 1.04 (0.93 - 1.17), and 1.03 (0.90 - 1.17). Conclusion Our findings contribute to the understanding that second-line SU for glucose lowering are unlikely to increase CV risk or all-cause mortality. Given their potent efficacy, microvascular benefits, cost effectiveness and widespread use, this study supports that SU should remain a part of the global diabetes treatment portfolio.Article

Type 2 diabetes (T2D) is a complex chronic disease characterized by considerable phenotypic heterogeneity. In this study, we applied a reverse graph embedding method to routinely collected data from 23,137 Scottish patients with newly diagnosed diabetes to visualize this heterogeneity and used partitioned diabetes polygenic risk scores to gain insight into the underlying biological processes. Overlaying risk of progression to outcomes of insulin requirement, chronic kidney disease, referable diabetic retinopathy and major adverse cardiovascular events, we show how these risks differ by patient phenotype. For example, patients at risk of retinopathy are phenotypically different from those at risk of cardiovascular events. We replicated our findings in the UK Biobank and the ADOPT clinical trial, also showing that the pattern of diabetes drug monotherapy response differs for different drugs. Overall, our analysis highlights how, in a European population, underlying phenotypic variation drives T2D onset and affects subsequent diabetes outcomes and drug response, demonstrating the need to incorporate these factors into personalized treatment approaches for the management of T2D.

Our aim was to investigate the association of glycated haemoglobin A1c (HbA1c) variability score (HVS) with estimated glomerular filtration rate (eGFR) slope in Chinese adults living with type 2 diabetes. This cohort study included adults with type 2 diabetes attending outpatient clinics between 2011 and 2019 from a large electronic medical record-based database of diabetes in China (WECODe). We estimated the individual-level visit-to-visit HbA1c variability using HVS, a proportion of changes in HbA1c of ≥0.5% (5.5 mmol/mol). We estimated the odds of people experiencing a rapid eGFR annual decline using a logistic regression and differences across HVS categories in the mean eGFR slope using a mixed-effect model. The analysis involved 2397 individuals and a median follow-up of 4.7 years. Compared with people with HVS ≤ 20%, those with HVS of 60% to 80% had 11% higher odds of experiencing rapid eGFR annual decline, with an extra eGFR decline of 0.93 mL/min/1.73 m2 per year on average; those with HVS > 80% showed 26% higher odds of experiencing a rapid eGFR annual decline, with an extra decline of 1.83 mL/min/1.73 m2 per year on average. Chinese adults with type 2 diabetes and HVS > 60% could experience a more rapid eGFR decline.

Background: Cognitive impairment is common in older people admitted to hospital, but previous research has focused on single conditions. Objective: This project sits in phase 0/1 of the Medical Research Council Framework for the Development and Evaluation of Complex Interventions. It aims to develop an understanding of current health-care outcomes. This will be used in the future development of a multidomain intervention for people with confusion (dementia and cognitive impairment) in general hospitals. The research was conducted from January 2015 to June 2018 and used data from people admitted between 2012 and 2013. Design: For the review of outcomes, the systematic review identified peer-reviewed quantitative epidemiology measuring prevalence and associations with outcomes. Screening for duplication and relevance was followed by full-text review, quality assessment and a narrative review (141 papers). A survey sought opinion on the key outcomes for people with dementia and/or confusion and their carers in the acute hospital (n = 78). For the analysis of outcomes including cost, the prospective cohort study was in a medical admissions unit in an acute hospital in one Scottish health board covering 10% of the Scottish population. The participants (n = 6724) were older people (aged ≥ 65 years) with or without a cognitive spectrum disorder who were admitted as medical emergencies between January 2012 and December 2013 and who underwent a structured nurse assessment. ‘Cognitive spectrum disorder’ was defined as any combination of delirium, known dementia or an Abbreviated Mental Test score of < 8 out of 10 points. The main outcome measures were living at home 30 days after discharge, mortality within 2 years of admission, length of stay, re-admission within 2 years of admission and cost. Data sources: Scottish Morbidity Records 01 was linked to the Older Persons Routine Acute Assessment data set. Results: In the systematic review, methodological heterogeneity, especially concerning diagnostic criteria, means that there is significant overlap in conditions of patients presenting to general hospitals with confusion. Patients and their families expect that patients are discharged in the same or a better condition than they were in on admission or, failing that, that they have a satisfactory experience of their admission. Cognitive spectrum disorders were present in more than one-third of patients aged ≥ 65 years, and in over half of those aged ≥ 85 years. Outcomes were worse in those patients with cognitive spectrum disorders than in those without: length of stay 25.0 vs. 11.8 days, 30-day mortality 13.6% vs. 9.0%, 1-year mortality 40.0% vs. 26.0%, 1-year mortality or re-admission 62.4% vs. 51.5%, respectively (all p < 0.01). There was relatively little difference by cognitive spectrum disorder type; for example, the presence of any cognitive spectrum disorder was associated with an increased mortality over the entire period of follow-up, but with different temporal patterns depending on the type of cognitive spectrum disorder. The cost of admission was higher for those with cognitive spectrum disorders, but the average daily cost was lower. Limitations: A lack of diagnosis and/or standardisation of diagnosis for dementia and/or delirium was a limitation for the systematic review, the quantitative study and the economic study. The economic study was limited to in-hospital costs as data for social or informal care costs were unavailable. The survey was conducted online, limiting its reach to older carers and those people with cognitive spectrum disorders. Conclusions: Cognitive spectrum disorders are common in older inpatients and are associated with considerably worse health-care outcomes, with significant overlap between individual cognitive spectrum disorders. This suggests the need for health-care systems to systematically identify and develop care pathways for older people with cognitive spectrum disorders, and avoid focusing on only condition-specific pathways. Future work: Development and evaluation of a multidomain intervention for the management of patients with cognitive spectrum disorders in hospital. Study registration: This study is registered as PROSPERO CRD42015024492. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.

Approximately 25% of people with type 1 diabetes have suppressed counterregulatory hormonal and symptomatic responses to insulin-induced hypoglycaemia, which renders them at increased risk of severe, disabling hypoglycaemia. This is called impaired awareness of hypoglycaemia (IAH), the cause of which is unknown. We recently proposed that IAH develops through habituation, a form of adaptive memory to preceding hypoglycaemia. Consistent with this hypothesis, we demonstrated restoration of defective counterregulatory hormonal responses to hypoglycaemia (referred to as dishabituation) in a rodent model of IAH following introduction of a novel stress stimulus (high intensity training [HIT]). In this proof-of-concept study we sought to further test this hypothesis by examining whether a single episode of HIT would amplify counterregulatory responses to subsequent hypoglycaemia in people with type 1 diabetes who had IAH (assessed by Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating (DAFNE) hypoglycaemia awareness rating 2 or 3). The primary outcome was the difference in adrenaline response to hypoglycaemia following both a single episode of HIT and rest. In this randomised, crossover study 12 participants aged between 18 and 55 years with type 1 diabetes for ≥5 years and an HbA1c <75 mmol/mol (9%) were recruited. Individuals were randomised using computer generated block randomisation to start with one episode of HIT (4 × 30 s cycle sprints [2 min recovery] at 150% of maximum wattage achieved during $$ \dot{V}{\mathrm{O}}_{2\mathrm{peak}} $$ assessment) or rest (control). The following day they underwent a 90 min hyperinsulinaemic–hypoglycaemic clamp study at 2.5 mmol/l with measurement of hormonal counterregulatory response, symptom scores and cognitive testing (four-choice reaction time and digit symbol substitution test). Each intervention and subsequent clamp study was separated by at least 2 weeks. The participants and investigators were not blinded to the intervention or measurements during the study. The investigators were blinded to the primary outcome and blood analysis results. All participants (six male and six female, age 19–54 years, median [IQR] duration of type 1 diabetes 24.5 [17.3–29.0] years, mean [SEM] HbA1c 56 [3.67] mmol/mol; 7.3% [0.34%]) completed the study (both interventions and two clamps). In comparison with the rest study, a single episode of HIT led to a 29% increase in the adrenaline (epinephrine) response (mean [SEM]) (2286.5 [343.1] vs 2953.8 [384.9] pmol/l); a significant increase in total symptom scores (Edinburgh Hypoglycaemia Symptom Scale: 24.25 [2.960 vs 27.5 [3.9]; p<0.05), and a significant prolongation of four-choice reaction time (591.8 [22.5] vs 659.9 [39.86] ms; p<0.01] during equivalent hypoglycaemia induced the following day. These findings are consistent with the hypothesis that IAH develops in people with type 1 diabetes as a habituated response and that introduction of a novel stressor can restore, at least partially, the adapted counterregulatory hormonal, symptomatic and cognitive responses to hypoglycaemia. ISRCTN15236211.

Objectives: to establish and quantify any observable association between the exposure to community prescriptions for quinine and acute kidney injury (AKI) events in a population of older adults. Design: two observational studies using the same dataset, a retrospective longitudinal cohort study and a self-controlled case series (SCCS). Setting: NHS health board in Scotland. Participants: older adults (60+ years) who received quinine prescriptions in Tayside, Scotland, between January 2004 and December 2015. The first study included 12,744 individuals. The SCCS cohort included 5,907 people with quinine exposure and more than or equal to one AKI event. Main outcome measured: in the first study, multivariable logistic regression was used to calculate odds ratios (ORs) for AM comparing between episodes with and without recent quinine exposure after adjustment for demographics, comorbidities and concomitant medications. The SCCS study divided follow-up for each individual into periods 'on' and 'off quinine, calculating incidence rate ratios (IRRs) for AM adjusting for age. Results: during the study period, 273,596 prescriptions for quinine were dispensed in Tayside. A total of 13,616 AKI events occurred during follow-up (crude incidence 12.5 per 100 person-years). In the first study, exposure to quinine before an episode of care was significantly associated with an increased probability ofAKI (adjusted OR = 1.27, 95% confidence interval (CI) 1.21-1.33). In the SCCS study, exposure to quinine was associated with an increased relative incidence of AKI compared to unexposed periods (IRR = 1.20, 95% CI 1.15-1.26), with the greatest risk observed within 30 days following quinine initiation (IRR =1.48, 95% CI 1.35-1.61). Conclusion: community prescriptions for quinine in an older adult population are associated with an increased risk of AM.

BACKGROUND There are few observational studies evaluating the risk of AKI in people with type 2 diabetes, and even fewer simultaneously investigating AKI and CKD in this population. This limits understanding of the interplay between AKI and CKD in people with type 2 diabetes compared with the nondiabetic population. METHODS In this retrospective, cohort study of participants with or without type 2 diabetes, we used electronic healthcare records to evaluate rates of AKI and various statistical methods to determine their relationship to CKD status and further renal function decline. RESULTS We followed the cohort of 16,700 participants (9417 with type 2 diabetes and 7283 controls without diabetes) for a median of 8.2 years. Those with diabetes were more likely than controls to develop AKI (48.6% versus 17.2%, respectively) and have preexisting CKD or CKD that developed during follow-up (46.3% versus 17.2%, respectively). In the absence of CKD, the AKI rate among people with diabetes was nearly five times that of controls (121.5 versus 24.6 per 1000 person-years). Among participants with CKD, AKI rate in people with diabetes was more than twice that of controls (384.8 versus 180.0 per 1000 person-years after CKD diagnostic date, and 109.3 versus 47.4 per 1000 person-years before CKD onset in those developing CKD after recruitment). Decline in eGFR slope before AKI episodes was steeper in people with diabetes versus controls. After AKI episodes, decline in eGFR slope became steeper in people without diabetes, but not among those with diabetes and preexisting CKD. CONCLUSIONS Patients with diabetes have significantly higher rates of AKI compared with patients without diabetes, and this remains true for individuals with preexisting CKD.

Real-time continuous glucose monitoring (rtCGM) is increasingly used in patients with type 1 diabetes because it provides real-time data with low glucose alarms in place to alert individuals or their carers to developing hypoglycemia. This technology may be especially useful for those with impaired awareness of hypoglycemia (IAH). However, there is limited reported evidence on the accuracy of these devices in the hypoglycemic range in these patients under controlled conditions (1). In an ongoing clinical study of people with type 1 diabetes and IAH we compared data collected from rtCGM with time-matched arterialized venous (AV) blood analyzed using a bedside plasma glucose analyzer and a standard blood glucose meter (used in self-monitoring of blood glucose [SMBG]) under experimental hypoglycemic conditions. Participants with type 1 diabetes and IAH were recruited to a parallel-group study during which they underwent a 90-min hyperinsulinemic-hypoglycemic (45 mg/dL) clamp. Throughout the clamp, AV blood samples were obtained every 5 min via a retrograde …

Background. Patients who survive an episode of acute kidney injury (AKI) are more likely to have further episodes of AKI. AKI is associated with increased mortality, with a further increase with recurrent episodes. It is not clear whether this is due to AKI or as a result of other patient characteristics. The aim of this study was to establish whether recurrence of AKI is an independent risk factor for mortality or if excess mortality is explained by other factors. Methods. This observational cohort study included adult people from the Tayside region of Scotland, with an episode of AKI between 1 January 2009 and 31 December 2009. AKI was defined using the creatinine-based Kidney Disease: Improving Global Outcomes definition. Associations between recurrent AKI and mortality were examined using a Cox proportional hazards model. Results. Survival was worse in the group identified to have recurrent AKI compared with those with a single episode of AKI [hazard ratio = 1.49, 95% confidence interval (CI) 1.37-1.63; P< 0.001]. After adjustment for comorbidities, stage of reference AKI, sex, age, medicines that predispose to renal impairment or, in the 3 months prior to the reference AKI, deprivation and baseline estimated glomerular filtration rate (eGFR), recurrent AKI was independently associated with an increase in mortality (hazard ratio = 1.25, 95% CI 1.14-1.37; P< 0.001). Increasing stage of reference AKI, age, deprivation, baseline eGFR, male sex, previous myocardial infarction, cerebrovascular disease and diuretic use were all associated with an increased risk of mortality in patients with recurrent AKI. Conclusions. Recurrent AKI is associated with increased mortality. After adjusting for patient characteristics, the increase in mortality is independently associated with recurrent AKI and is not solely explained by other risk factors.

Impaired awareness of hypoglycemia (IAH) affects approx. 20-25% of all people with type 1 diabetes (T1D) and is a major risk factor for severe hypoglycemia. We recently proposed that IAH may develop as a form of adaptive memory to repeated hypoglycemia; referred to as Habituation. Consistent with this hypothesis, we demonstrated restoration of defective counterregulatory (CRR) responses to hypoglycemia in a rodent model of IAH following introduction of a novel stress stimulus [high intensity exercise (HIT)]; referred to as Dishabituation. In this study we sought to further test our hypothesis by examining whether a single episode of HIT would amplify counterregulatory response to subsequent hypoglycemia in people with T1D who had IAH (assessed by Gold score ≥4, Modified Clark score≥4 or DAFNE hypoglycaemia awareness rating 2 or 3). We recruited 12 participants to a single-centre, randomized, cross-over study. Individuals were randomized to one episode of HIT (4 x 30 s cycle sprints [2 min recovery] at 150% of max Watts achieved during VO2peak assessment) or rest. The following day they underwent a 90-minute hyperinsulinaemic hypoglycemic clamp study at 2.5 mmol/l with measurement of hormonal CRR and symptom scores. Each clamp study was separated by at least 2-weeks. We found that a single episode of HIT led to a 30% increase in the epinephrine response [mean (SEM) 418.8 +/- 62.84 vs. 541.1 +/- 70.5 pg/ml; p<0.05] accompanied by a significant increase in total symptom scores (Edinburgh Hypoglycemia scale: 24.25 +/- 2.96 vs. 27.5 +/- 3.9, p<0.05) during equivalent hypoglycemia induced the following day. These findings are consistent with the hypothesis that IAH develops in people with T1D as a habituated response and that introduction of a novel stressor can restore, at least partially, the CRR response to hypoglycemia. HIT may represent a novel therapeutic intervention for people with IAH. Disclosure C.M. Farrell: None. D.J. West: Research Support; Self; Arla Foods Ingredients, Dexcom, Inc. S.M. Hapca: None. T. Jones: Research Support; Self; Dexcom, Inc., Medtronic MiniMed, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Roche Diabetes Care. A.D. McNeilly: None. R.J. McCrimmon: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Funding JDRF; Diabetes UK

Aims: Metformin uptake is transporter-dependent. Observational data indicates that reduced-function variants in organic cation transporter 1 (OCT1) and OCT1-inhibiting drugs increase risk of metformin intolerance. The ImpOCT study investigated impact of OCT1 genotype and use of omeprazole (an OCT1-inhibiting drug) on an individual’s metformin tolerance. Methods: This recruit-by-genotype, double-blind, randomised, placebo-controlled, crossover study recruited 61 nondiabetic individuals with homozygous reduced-function (null) or wild type (WT) OCT1 genotype. During two 4-week treatment periods, participants received metformin and concurrent omeprazole or placebo. Metformin was titrated weekly according to tolerance, assessed by interview and symptom severity scoring. The primary outcome was maximum tolerated dose of metformin (MTD) in each treatment period. Results were analysed using mixed effects modelling, assessing effect of genotype, treatment and gene x drug interaction on MTD. Results: Participants were well matched for age and gender. Median BMI was higher in OCT1 null (26.3 [IQR 24.1 - 28.1] vs. 29 [IQR 26.5 - 31.8], p<0.001), though these OCT1 variants are not associated with obesity. Frequency of tolerance was comparable (WT 60% vs. null 64.5%, p=0.7). We identified a significant gene x drug interaction (p=0.04) - OCT1 WT individuals have improved MTD whilst taking omeprazole, compared to placebo, p=0.008, whereas OCT1 null individuals show no improvement in MTD with omeprazole compared to placebo, p=0.87. BMI was not significant in the model of MTD, p=0.27. Conclusions: Reduced function SNPs in OCT1 are relatively common and can affect transporter efficacy. This study identified a gene x drug interaction, between OCT1, metformin and omeprazole. Our data indicates that OCT1 WT individuals may benefit from PPI treatment to improve symptoms of metformin intolerance - this benefit is lost in those with reduced OCT1 function. Disclosure L.J. McCreight: None. S.M. Hapca: None. E. Pearson: None. Funding UK Wellcome Trust (to E.P.)

To address a number of issues of great societal concern at the moment, like the sequestration of carbon, information is direly needed about interactions between soil architecture and microbial dynamics. Unfortunately, soils are extremely complex, heterogeneous systems comprising highly variable and dynamic micro-habitats that have significant impacts on the growth and activity of inhabiting microbiota. Data remain scarce on the influence of soil physical parameters characterizing the pore space on the distribution and diversity of bacteria. In this context, the objective of the research described in this article was to develop a method where X-ray microtomography, to characterize the soil architecture, is combined with fluorescence microscopy to visualize and quantify bacterial distributions in resin-impregnated soil sections. The influence of pore geometry (at a resolution of 13.4 pm) on the distribution of Pseudomonas fluorescens was analysed at macro- (5.2 mm x 5.2 mm), meso- (1 mm x 1 mm) and microscales (0.2 mm x 0.2 mm) based on an experimental setup simulating different soil architectures. The cell density of P. fiuorescens was 5.59 x 10(7)(SE 2.6 x 10(6)) cells g(-1) soil in 1-2 mm and 5.84 x 10(7)(SE 2.4 x 10(6)) cells g(-1) in 2-4 mm size aggregates soil. Solid-pore interfaces influenced bacterial distribution at micro- and macroscale, whereas the effect of soil porosity on bacterial distribution varied according to three observation scales in different soil architectures. The influence of soil porosity on the distribution of bacteria in different soil. architectures was observed mainly at the macroscale, relative to micro- and mesoscales. Experimental data suggest that the effect of pore geometry on the distribution of bacteria varied with the spatial scale, thus highlighting the need to consider an "appropriate spatial scale" to understand the factors that regulate the distribution of microbial communities in soils. The results obtained to date also indicate that the proposed method is a significant step towards a full mechanistic understanding of microbial dynamics in structured soils.

Abstract Introduction People with dementia experience poor outcomes after hospital admission, with mortality being particularly high. There is no cure for dementia; antidementia medications have been shown to improve cognition and function, but their effect on mortality in real‐world settings is little known. This study examines associations between treatment with antidementia medication and mortality in older people with dementia after an emergency admission. Methods The design is a retrospective cohort study of people aged ≥65 years, with a diagnosis of dementia and an emergency hospital admission between 01/01/2010 and 31/12/2016. Two classes of antidementia medication were considered: the acetylcholinesterase inhibitors and memantine. Mortality was examined using a Cox proportional hazards model with time‐varying covariates for the prescribing of antidementia medication before or on admission and during one‐year follow‐up, adjusted for demographics, comorbidity, and community prescribing including anticholinergic burden. Propensity score analysis was examined for treatment selection bias. Results There were 9142 patients with known dementia included in this study, of which 45.0% (n = 4110) received an antidementia medication before or on admission; 31.3% (n = 2864) were prescribed one of the acetylcholinesterase inhibitors, 8.7% (n = 798) memantine, and 4.9% (n = 448) both. 32.9% (n = 1352) of these patients died in the year after admission, compared to 42.7% (n = 2148) of those with no antidementia medication on admission. The Cox model showed a significant reduction in mortality in patients treated with acetylcholinesterase inhibitors (hazard ratio [HR] = 0.78, 95% CI 0.72–0.85) or memantine (HR = 0.75, 95% CI 0.66–0.86) or both (HR = 0.76, 95% CI 0.68–0.94). Sensitivity analysis by propensity score matching confirmed the associations between antidementia prescribing and reduced mortality. Discussion Treatment with antidementia medication is associated with a reduction in risk of death in the year after an emergency hospital admission. Further research is required to determine if there is a causal relationship between treatment and mortality, and whether “symptomatic” therapy for dementia does have a disease‐modifying effect.

Glutathione (GSH) is widely distributed among all living organisms and associated with diverse functions that include maintaining redox homeostasis and detoxification of xenobiotic compounds. The level of GSH within the cell varies with stress often involving changes in GSH content, which is consumed in reactions that protect the cell leading to formation of oxidized GSH (GSSG). Mosquitoes breeding in habitats located at agricultural and residential ecosystems may encounter different kinds of pesticides. Enzyme recycling assay method was used to determine glutathione levels in adults Anopheles gambiae (An. gambiae) reared from larvae collected from agricultural (zone A) and residential (zone B) sites. More than 70% of the GSH occur in the reduced form across the sampling sites. Significantly, higher levels of the oxidized form of GSH were recorded in mosquitoes from agricultural compared to residential sites. This may possibly be an adaptive response to strong selection pressure due to higher concentration of pesticides in the agro-ecosystem. Under normal physiological condition, GSH exists mostly in the reduced form but is converted to the oxidized form during oxidative stress. GSH is a substrate for the glutathione Stransferases system and becomes rate limiting when organisms are exposed to large amount of xenobiotics. The ratio of reduced GSH (rGSH) to GSSG levels often remain above 99% but can change markedly during oxidative stress. Thus, the study highlighted glutathione status may be mediating the response and possibly adaptation of An. gambiae exposure to insecticide. Keywords—Anopheles gambiae, Agricultural and Residential settings, Glutathione, Oxidative stress, Variations

Over the last 60 years, soil microbiologists have accumulated a wealth of experimental data showing that the bulk, macroscopic parameters (e.g., granulometry, pH, soil organic matter, and biomass contents) commonly used to characterize soils provide insufficient information to describe quantitatively the activity of soil microorganisms and some of its outcomes, like the emission of greenhouse gasses. Clearly, new, more appropriate macroscopic parameters are needed, which reflect better the spatial heterogeneity of soils at the microscale (i.e., the pore scale) that is commensurate with the habitat of many microorganisms. For a long time, spectroscopic and microscopic tools were lacking to quantify processes at that scale, but major technological advances over the last 15 years have made suitable equipment available to researchers. In this context, the objective of the present article is to review progress achieved to date in the significant research program that has ensued. This program can be rationalized as a sequence of steps, namely the quantification and modeling of the physical-, (bio)chemical-, and microbiological properties of soils, the integration of these different perspectives into a unified theory, its upscaling to the macroscopic scale, and, eventually, the development of new approaches to measure macroscopic soil characteristics. At this stage, significant progress has been achieved on the physical front, and to a lesser extent on the (bio)chemical one as well, both in terms of experiments and modeling. With regard to the microbial aspects, although a lot of work has been devoted to the modeling of bacterial and fungal activity in soils at the pore scale, the appropriateness of model assumptions cannot be readily assessed because of the scarcity of relevant experimental data. For significant progress to be made, it is crucial to make sure that research on the microbial components of soil systems does not keep lagging behind the work on the physical and (bio)chemical characteristics. Concerning the subsequent steps in the program, very little integration of the various disciplinary perspectives has occurred so far, and, as a result, researchers have not yet been able to tackle the scaling up to the macroscopic level. Many challenges, some of them daunting, remain on the path ahead. Fortunately, a number of these challenges may be resolved by brand new measuring equipment that will become commercially available in the very near future.

AIMSTo test the effectiveness of a theoretically based text-message intervention to reduce binge drinking among socially disadvantaged men.DESIGNA multi-centre parallel group, pragmatic, individually randomized controlled trial.SETTINGCommunity-based study conducted in four regions of Scotland.PARTICIPANTSA total of 825 men aged 25-44 years recruited from socially disadvantaged areas who had two or more episodes of binge drinking (> 8 UK units on a single occasion) in the preceding 28 days: 411 men were randomized to the intervention and 414 to the control.INTERVENTION AND COMPARATORA series of 112 interactive text messages was delivered by mobile phone during a 12-week period. The intervention was structured around the Health Action Process Approach, a comprehensive model which allows integration of a range of evidence-based behaviour change techniques. The control group received 89 texts on general health, with no mention of alcohol or use of behaviour change techniques.MEASUREMENTSThe primary outcome measure was the proportion of men consuming > 8 units on three or more occasions (in the previous 28 days) at 12 months post-intervention.FINDINGSThe proportion of men consuming > 8 units on three or more occasions (in the previous 28 days) was 41.5% in the intervention group and 47.8% in the control group. Formal analysis showed that there was no evidence that the intervention was effective [odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.57-1.08; absolute reduction 5.7%, 95% CI = -13.3 to 1.9]. The Bayes factor for this outcome was 1.3, confirming that the results were inconclusive. The retention was high and similar in intervention (84.9%) and control (86.5%) groups. Most men in the intervention group engaged with the text messages: almost all (92%) replied to text messages and 67% replied more than 10 times.CONCLUSIONSA theoretically based text-messaging intervention aimed at reducing binge drinking in disadvantaged men was not found to reduce prevalence of binge drinking at 12-month follow-up.