In situ remediation of atrazine contaminated groundwater

The natural attenuation of groundwater pesticides by biological degradation, is widely accepted to occur at concentrations > 1 mg 1-1. However from observations of groundwater monitoring data it can be indicated that the occurrence of pesticides in groundwater is primarily at trace μg 1-1 concentrations, with 45 % of UK groundwater samples that failed the EC Drinking Water Directives PV of 0.1 μg 1-1 between 1995 – 2000, accounting for an average concentration of 64 μg 1-1. However, there are limited directed studies of in situ biological degradation of pesticides at μg concentrations. Therefore, this work was designed provided an insight as to whether any prevalent microbial adaptation can occur to degrade atrazine at μg 1-1 concentrations in groundwater. Laboratory batch studies were performed using a groundwater exposed to 0.2 μg 1-1 of the herbicide atrazine, for an excess of 10 years. Bacterial enrichment using a glucose minimal salts medium resulted in no biological degradation of atrazine, when amended at concentrations between 10 μg to 50 mg 1-1. Batch studies using the atrazine degrader Pseudomonas sp. Strain ADP as a positive control, indicated a capability to degrade atrazine within sterilised groundwater, at 50 mg 1-1 (0.92 mg 1-1 day-1) and 1 mg 1-1 (0.14 mg 1-1 day-1), but no degradation of atrazine at 100 or 10 μg 1-1. Therefore, biological degradation of trace μg 1-1 concentrations of atrazine by groundwater in situ bacteria does not readily occur. It is expected that changes in atrazine groundwater concentrations, are resulting purely from dilution, sorption or chemical degradation. Consequently, it cannot be assumed that microbial adaptation can occur to degrade atrazine at μg 1-1 concentrations in groundwaters even if in situ bioaugmentation methods are applied.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Cerebrospinal fluid cortisol levels are higher in patients with delirium versus controls

<p>Abstract</p> <p>Background</p> <p>High plasma cortisol levels can cause acute cognitive and neuropsychiatric dysfunction, and have been linked with delirium. CSF cortisol levels more closely reflect brain exposure to cortisol, but there are no studies of CSF cortisol levels in delirium. In this pilot study we acquired CSF specimens at the onset of spinal anaesthesia in patients undergoing hip fracture surgery, and compared CSF and plasma cortisol levels in delirium cases versus controls.</p> <p>Findings</p> <p>Delirium assessments were performed the evening before or on the morning of operation with a standard battery comprising cognitive tests, mental status assessments and the Confusion Assessment Method. CSF and plasma samples were obtained at the onset of the operation and cortisol levels measured. Twenty patients (15 female, 5 male) aged 62 - 93 years were studied. Seven patients were diagnosed with delirium. The mean ages of cases (81.4 (SD 7.2)) and controls (80.5 (SD 8.7)) were not significantly different (p = 0.88). The median (interquartile range) CSF cortisol levels were significantly higher in cases (63.9 (40.4-102.1) nmol/L) than controls (31.4 (21.7-43.3) nmol/L; Mann-Whitney U, p = 0.029). The median (interquartile range) of plasma cortisol was also significantly higher in cases (968.8 (886.2-1394.4) nmol/L, than controls (809.4 (544.0-986.4) nmol/L; Mann Whitney U, p = 0.036).</p> <p>Conclusions</p> <p>These findings support an association between higher CSF cortisol levels and delirium. This extends previous findings linking higher plasma cortisol and delirium, and suggests that more definitive studies of the relationship between cortisol levels and delirium are now required.</p

Time trends in prescribing of type 2 diabetes drugs, glycaemic response and risk factors:a retrospective analysis of primary care data, 2010-2017

This is the author accepted manuscript. The final version is available on open access from Wiley via the DOI in this recordAim: Prescribing in type 2 diabetes has changed markedly in recent years, with increasing use of newer, more expensive glucose-lowering drugs. We aimed to describe population-level time trends in both prescribing patterns and short-term patient outcomes (HbA1c, weight, blood pressure, hypoglycemia and treatment discontinuation) after initiating new therapy. Materials and methods: We studied 81,532 UK patients with type 2 diabetes initiating a first to fourth line drug in primary care between 2010-2017 inclusive (Clinical Practice Research Datalink). Trends in new prescriptions and subsequent six and twelve-month adjusted changes in glycemic response (reduction in HbA1c), weight, blood pressure, and rates of hypoglycemia and treatment discontinuation were examined. Results: DPP4-inhibitor use second-line near doubled (41% of new prescriptions in 2017 vs. 22% 2010), replacing sulfonylureas as the most common second-line drug (29% 2017 vs. 53% 2010). SGLT2-inhibitors, introduced in 2013, comprised 17% of new first-fourth line prescriptions by 2017. First-line use of metformin remained stable (91% of new prescriptions in 2017 vs. 91% 2010). Over the study period there was little change in average glycemic response and treatment discontinuation. There was a modest reduction in weight second and third-line (second line 2017 vs. 2010: -1.5 kg (95%CI -1.9;-1.1), p<0.001), and a slight reduction in systolic blood pressure first to third-line (2017 vs. 2010 difference range -1.7 to -2.1 mmHg, all p<0.001). Hypoglycemia rates decreased second-line (incidence rate ratio 0.94 per-year (95%CI 0.88;1.00, p=0.04)), mirroring the decline in use of sulfonylureas. 4 Conclusions: Recent changes in prescribing of therapy in type 2 diabetes have not led to a change in glycemic response and have resulted in modest improvements in other population-level short-term patient outcomes.Medical Research Council (MRC)National Institute for Health Research (NIHR)Wellcome Trus

Costs and Treatment Pathways for Type 2 Diabetes in the UK:A Mastermind Cohort Study

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.INTRODUCTION: Medication therapy for type 2 diabetes has become increasingly complex, and there are few reliable data on the current state of clinical practice. We report treatment pathways and associated costs of medication therapy for people with type 2 diabetes in the UK, their variability and changes over time. METHODS: Prescription and biomarker data for 7159 people with type 2 diabetes were extracted from the GoDARTS cohort study, covering the period 1989-2013. Average follow-up was 10 years. Individuals were prescribed on average 2.4 (SD: 1.2) drugs with average annual costs of £241. We calculated summary statistics for first- and second-line therapies. Linear regression models were used to estimate associations between therapy characteristics and baseline patient characteristics. RESULTS: Average time from diagnosis to first prescription was 3 years (SD: 4.0 years). Almost all first-line therapy (98%) was monotherapy, with average annual cost of £83 (SD: £204) for 3.8 (SD: 3.5) years. Second-line therapy was initiated in 73% of all individuals, at an average annual cost of £219 (SD: £305). Therapies involving insulin were markedly more expensive than other common therapies. Baseline HbA1c was unrelated to future therapy costs, but higher average HbA1c levels over time were associated with higher costs. CONCLUSIONS: Medication therapy has undergone substantial changes during the period covered in this study. For example, therapy is initiated earlier and is less expensive than in the past. The data provided in this study will prove useful for future modelling studies, e.g. of stratified treatment approaches.The authors gratefully acknowledge funding by the Medical Research Council (MRC) and the Association of the British Pharma Industry (ABPI) for “Mastermind” (MRC APBI STratification and Extreme Response Mechanism IN Diabetes–MASTERMIND. Grant Ref.: MRIK005707/1). ERP holds Wellcome Trust New Investigator award 102820/Z/13/Z. GoDARTS was funded by the Wellcome Trust as the Wellcome Trust Type 2 diabetes case control study

Predicting post one-year durability of glucose-lowering monotherapies in patients with newly-diagnosed type 2 diabetes mellitus – A MASTERMIND precision medicine approach (UKPDS 87)

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record Aims: Predicting likely durability of glucose-lowering therapies for people with type 2 diabetes (T2D) could help inform individualised therapeutic choices. Methods: We used data from UKPDS patients with newly-diagnosed T2D randomised to first-line glucose-lowering monotherapy with chlorpropamide–glibenclamide–basal insulin or metformin. In 2339 participants who achieved one-year HbA1c values <7.5% (<59 mmol/mol)–we assessed relationships between one-year characteristics and time to monotherapy-failure (HbA1c ≥ 7.5% or requiring second-line therapy). Model validation was performed using bootstrap sampling. Results: Follow-up was median (IQR) 11.0 (8.0–14.0) years. Monotherapy-failure occurred in 72%–82%–75% and 79% for those randomised to chlorpropamide–glibenclamide–basal insulin or metformin respectively–after median 4.5 (3.0–6.6)–3.7 (2.6–5.6)–4.2 (2.7–6.5) and 3.8 (2.6– 5.2) years. Time-to-monotherapy-failure was predicted primarily by HbA1c and BMI values–with other risk factors varying by type of monotherapy–with predictions to within ±2.5 years for 55%–60%–56% and 57% of the chlorpropamide–glibenclamide–basal insulin and metformin monotherapy cohorts respectively. Conclusions: Post one-year glycaemic durability can be predicted robustly in individuals with newly-diagnosed T2D who achieve HbA1c values < 7.5% one year after commencing traditional monotherapies. Such information could be used to help guide glycaemic management for individual patients.Medical Research Council (MRC

Risk of anemia with metformin use in type 2 diabetes:A MASTERMIND study

Objective: To evaluate the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data. Research Design and Methods: Anemia was defined as a hemoglobin measure of &lt;11 g/dL. In the RCTs A Diabetes Outcome Progression Trial (ADOPT; n = 3,967) and UK Prospective Diabetes Study (UKPDS; n = 1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters. In the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population (n = 3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk. Results: In ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones. In UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin. In ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years. In UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments. At years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia. Conclusions: Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B12 deficiency alone

Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes:the TriMaster study

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordData availability: To minimize the risk of patient re-identification, de-identified individual patient-level clinical data are available under restricted access. Requests for access to anonymized individual participant data and study documents should be made to the corresponding author and will be reviewed by the Peninsula Research Bank Steering Committee. Access to data through the Peninsula Research Bank will be granted for requests with scientifically valid questions by academic teams with the necessary skills appropriate for the research. Data that can be shared will be released with the relevant transfer agreement.Code availability: Requests for access to code should be made to the corresponding author and will be reviewed by the Peninsula Research Bank Steering Committee. Access to code through the Peninsula Research Bank will be granted for requests with scientifically valid questions by academic teams with the necessary skills appropriate for the research. Code will be released by the lead statistician.Precision medicine aims to treat an individual based on their clinical characteristics. A differential drug response, critical to using these features for therapy selection, has never been examined directly in type 2 diabetes. In this study, we tested two hypotheses: (1) individuals with body mass index (BMI) > 30 kg/m2, compared to BMI ≤ 30 kg/m2, have greater glucose lowering with thiazolidinediones than with DPP4 inhibitors, and (2) individuals with estimated glomerular filtration rate (eGFR) 60-90 ml/min/1.73 m2, compared to eGFR >90 ml/min/1.73 m2, have greater glucose lowering with DPP4 inhibitors than with SGLT2 inhibitors. The primary endpoint for both hypotheses was the achieved HbA1c difference between strata for the two drugs. In total, 525 people with type 2 diabetes participated in this UK-based randomized, double-blind, three-way crossover trial of 16 weeks of treatment with each of sitagliptin 100 mg once daily, canagliflozin 100 mg once daily and pioglitazone 30 mg once daily added to metformin alone or metformin plus sulfonylurea. Overall, the achieved HbA1c was similar for the three drugs: pioglitazone 59.6 mmol/mol, sitagliptin 60.0 mmol/mol and canagliflozin 60.6 mmol/mol (P = 0.2). Participants with BMI > 30 kg/m2, compared to BMI ≤ 30 kg/m2, had a 2.88 mmol/mol (95% confidence interval (CI): 0.98, 4.79) lower HbA1c on pioglitazone than on sitagliptin (n = 356, P = 0.003). Participants with eGFR 60-90 ml/min/1.73 m2, compared to eGFR >90 ml/min/1.73 m2, had a 2.90 mmol/mol (95% CI: 1.19, 4.61) lower HbA1c on sitagliptin than on canagliflozin (n = 342, P = 0.001). There were 2,201 adverse events reported, and 447/525 (85%) randomized participants experienced an adverse event on at least one of the study drugs. In this precision medicine trial in type 2 diabetes, our findings support the use of simple, routinely available clinical measures to identify the drug class most likely to deliver the greatest glycemic reduction for a given patient. (ClinicalTrials.gov registration: NCT02653209 ; ISRCTN registration: 12039221 .).Medical Research Council (MRC)National Institute for Health and Care Research (NIHR

Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study

&lt;p&gt;Background: Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.&lt;/p&gt; &lt;p&gt;Methods and Findings: The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005–2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4–3.8, p&#60;0.001) than men (2.3: 2.0–2.7, p&#60;0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2–3.0, p&#60;0.001) in men and 2.7 (2.2–3.4, p&#60;0.001) in women. Between 2005–2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were &#60;40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60–69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of &#60;7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.&lt;/p&gt; &lt;p&gt;Conclusions: Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.&lt;/p&gt