Publications by authors named "Yue Ruan"

35 Publications

Muscarinic Acetylcholine Receptors in the Retina-Therapeutic Implications.

Int J Mol Sci 2021 May 8;22(9). Epub 2021 May 8.

Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

Muscarinic acetylcholine receptors (mAChRs) belong to the superfamily of G-protein-coupled receptors (GPCRs). The family of mAChRs is composed of five subtypes, M, M, M, M and M, which have distinct expression patterns and functions. In the eye and its adnexa, mAChRs are widely expressed and exert multiple functions, such as modulation of tear secretion, regulation of pupil size, modulation of intraocular pressure, participation in cell-to-cell signaling and modula-tion of vascular diameter in the retina. Due to this variety of functions, it is reasonable to assume that abnormalities in mAChR signaling may contribute to the development of various ocular diseases. On the other hand, mAChRs may offer an attractive therapeutic target to treat ocular diseases. Thus far, non-subtype-selective mAChR ligands have been used in ophthalmology to treat dry eye disease, myopia and glaucoma. However, these drugs were shown to cause various side-effects. Thus, the use of subtype-selective ligands would be useful to circumvent this problem. In this review, we give an overview on the localization and on the functional role of mAChR subtypes in the eye and its adnexa with a special focus on the retina. Moreover, we describe the pathophysiological role of mAChRs in retinal diseases and discuss potential therapeutic approaches.
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http://dx.doi.org/10.3390/ijms22094989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125843PMC
May 2021

A UK nationwide study of people with type 1 diabetes admitted to hospital with COVID-19 infection.

Diabetologia 2021 May 8. Epub 2021 May 8.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Aims/hypothesis: The aim of this work was to describe the clinical characteristics of adults with type 1 diabetes admitted to hospital and the risk factors associated with severe coronavirus disease-2019 (COVID-19) in the UK.

Methods: A retrospective cohort study was performed using data collected through a nationwide audit of people admitted to hospital with diabetes and COVID-19, conducted by the Association of British Clinical Diabetologists from March to October 2020. Prespecified demographic, clinical, medication and laboratory data were collected from the electronic and paper medical record systems of the participating hospitals by local clinicians. The primary outcome of the study, severe COVID-19, was defined as death in hospital and/or admission to the adult intensive care unit (AICU). Logistic regression models were used to generate age-adjusted ORs.

Results: Forty UK centres submitted data. The final dataset included 196 adults who were admitted to hospital and had both type 1 diabetes and COVID-19 on admission (male sex 55%, white 70%, with mean [SD] age 62 [19] years, BMI 28.3 [7.3] kg/m and last recorded HbA 76 [31] mmol/mol [9.1 (5.0)%]). The prevalence of pre-existing microvascular disease and macrovascular disease was 56% and 39%, respectively. The prevalence of diabetic ketoacidosis on admission was 29%. A total of 68 patients (35%) died or were admitted to AICU. The proportions of people that died were 7%, 38% and 38% of those aged <55, 55-74 and ≥75 years, respectively. BMI, serum creatinine levels and having one or more microvascular complications were positively associated with the primary outcome after adjusting for age.

Conclusions/interpretation: In people with type 1 diabetes and COVID-19 who were admitted to hospital in the UK, higher BMI, poorer renal function and presence of microvascular complications were associated with greater risk of death and/or admission to AICU. Risk of severe COVID-19 is reassuringly very low in people with type 1 diabetes who are under 55 years of age without microvascular or macrovascular disease. IN PEOPLE WITH TYPE 1 DIABETES AND COVID-19 ADMITTED TO HOSPITAL IN THE UK, BMI AND ONE OR MORE MICROVASCULAR COMPLICATIONS HAD A POSITIVE ASSOCIATION AND LOW SERUM CREATINE LEVELS HAD A NEGATIVE ASSOCIATION WITH DEATH/ADMISSION TO INTENSIVE CARE UNIT AFTER ADJUSTING FOR AGE.
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http://dx.doi.org/10.1007/s00125-021-05463-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106514PMC
May 2021

Ablation of lysozyme M-positive cells prevents aircraft noise-induced vascular damage without improving cerebral side effects.

Basic Res Cardiol 2021 04 30;116(1):31. Epub 2021 Apr 30.

Department of Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University, Building 605, Langenbeckstr. 1, 55131, Mainz, Germany.

Aircraft noise induces vascular and cerebral inflammation and oxidative stress causing hypertension and cardiovascular/cerebral dysfunction. With the present studies, we sought to determine the role of myeloid cells in the vascular vs. cerebral consequences of exposure to aircraft noise. Toxin-mediated ablation of lysozyme M (LysM) myeloid cells was performed in LysMCre mice carrying a cre-inducible diphtheria toxin receptor. In the last 4d of toxin treatment, the animals were exposed to noise at maximum and mean sound pressure levels of 85 and 72 dB(A), respectively. Flow cytometry analysis revealed accumulation of CD45, CD11b, F4/80, and Ly6GLy6C cells in the aortas of noise-exposed mice, which was prevented by LysM cell ablation in the periphery, whereas brain infiltrates were even exacerbated upon ablation. Aircraft noise-induced increases in blood pressure and endothelial dysfunction of the aorta and retinal/mesenteric arterioles were almost completely normalized by ablation. Correspondingly, reactive oxygen species in the aorta, heart, and retinal/mesenteric vessels were attenuated in ablated noise-exposed mice, while microglial activation and abundance in the brain was greatly increased. Expression of phagocytic NADPH oxidase (NOX-2) and vascular cell adhesion molecule-1 (VCAM-1) mRNA in the aorta was reduced, while NFκB signaling appeared to be activated in the brain upon ablation. In sum, we show dissociation of cerebral and peripheral inflammatory reactions in response to aircraft noise after LysM cell ablation, wherein peripheral myeloid inflammatory cells represent a dominant part of the pathomechanism for noise stress-induced cardiovascular effects and their central nervous counterparts, microglia, as key mediators in stress responses.
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http://dx.doi.org/10.1007/s00395-021-00869-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087569PMC
April 2021

Day-to-day variability of insulin requirements in the inpatient setting: Observations during fully closed-loop insulin delivery.

Diabetes Obes Metab 2021 Apr 6. Epub 2021 Apr 6.

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

The aim of this study was to characterize the variability of exogenous insulin requirements during fully closed-loop insulin delivery in hospitalized patients with type 2 diabetes or new-onset hyperglycaemia, and to determine patient-related characteristics associated with higher variability of insulin requirements. We retrospectively analysed data from two fully closed-loop inpatient studies involving adults with type 2 diabetes or new-onset hyperglycaemia requiring insulin therapy. The coefficient of variation quantified day-to-day variability of exogenous insulin requirements during up to 15 days using fully automated closed-loop insulin delivery. Data from 535 days in 67 participants were analysed. The coefficient of variation of day-to-day exogenous insulin requirements was 30% ± 16%, and was higher between nights than between any daytime period (56% ± 29% overnight [11:00 pm to 4:59 am] compared with 41% ± 21% in the morning [5:00 am to 10:59 am], 39% ± 15% in the afternoon [11:00 am to 4:59 pm] and 45% ± 19% during the evening [5:00 pm to 10:59 pm]; all P < 0.01). There is high day-to-day variability of exogenous insulin requirements in inpatients, particularly overnight, and diabetes management approaches should account for this variability.
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http://dx.doi.org/10.1111/dom.14396DOI Listing
April 2021

Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels.

Int J Mol Sci 2021 Jan 28;22(3). Epub 2021 Jan 28.

Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.
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http://dx.doi.org/10.3390/ijms22031296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866075PMC
January 2021

Coronavirus disease (COVID 2019): protocol for a living overview of systematic reviews.

Ann Palliat Med 2021 Feb 24;10(2):1488-1493. Epub 2020 Nov 24.

Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China; Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China.

Background: The coronavirus disease 2019 (COVID-19) pandemic continues to grow worldwide, and systematic reviews (SRs)/meta-analyses (MAs) on COVID-19 can efficiently guide evidence-based clinical practice. However, SRs/MAs with weaknesses can mislead clinical practice and pose harm to patients, and too many useless SRs/MAs could pose confusion and waste sources. A "living" overview of SRs/MAs aims to provide an open, accessible and frequently updated resource summarizing the highest-level evidence of COVID-19, that can help evidence-users to quickly identify trusted evidence to guide the practice. This study aims to systematically give an overview SRs/MAs of COVID-19, assess their quality, and identify the best synthesis of evidence.

Methods: Databases including Medline, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM) and WanFang were systematically searched on May 1, 2020 using relevant terms for identify SRs/MAs related to COVID-19. The study selection, data extraction and quality assessment will be performed by independent reviewers, and results will be crosschecked. The authoritative tools (AMSTAR-2, PRISMA and its extensions) will be used to assess the methodological quality and reporting quality of included SRs/MAs, and potential influence factors will be explored. The consistency of conclusions will be compared among reviews and the best evidence will be summarized. In addition, we will conduct exploratory meta-analyses (MAs) of individual studies when applicable. Data will be reported as number with (or) percentage, risk ratio (RR) or odds ratio (OR), mean difference (MD) or standardized mean difference (SMD) with 95% confidence interval (CI) according to the specific results. R3.6.1 and Microsoft Excel 2016 will be used to analyze and manage data.

Results: The results of this overview will be submitted to a peer-reviewed journal for publication.

Discussion: In this study, we will present for the first time, an overview of SRs/MAs, which provides a comprehensive, dynamic evidence landscape on prevalence, prevention, diagnosis, treatment, and prognosis of COVID-19.
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http://dx.doi.org/10.21037/apm-20-1130DOI Listing
February 2021

The Role of Adrenoceptors in the Retina.

Cells 2020 12 3;9(12). Epub 2020 Dec 3.

Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

The retina is a part of the central nervous system, a thin multilayer with neuronal lamination, responsible for detecting, preprocessing, and sending visual information to the brain. Many retinal diseases are characterized by hemodynamic perturbations and neurodegeneration leading to vision loss and reduced quality of life. Since catecholamines and respective bindings sites have been characterized in the retina, we systematically reviewed the literature with regard to retinal expression, distribution and function of alpha (α)-, alpha (α)-, and beta (β)-adrenoceptors (ARs). Moreover, we discuss the role of the individual adrenoceptors as targets for the treatment of retinal diseases.
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http://dx.doi.org/10.3390/cells9122594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761662PMC
December 2020

Inpatient hypoglycaemia in older people is associated with a doubling in the increased length of stay compared with the younger population.

Age Ageing 2021 02;50(2):576-580

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

Background: Hypoglycaemia during hospital admission is associated with poor outcomes including increased length of stay. In this study, we compared the incidence of inpatient hypoglycaemia and length of stays among people of three age groups: ≤65 years, 65-80 years and >80 years old.

Methods: The study was conducted using a 4-year electronic patient record dataset from Oxford University Hospitals NHS Foundation Trust. The dataset contains hospital admission data for people with diabetes. We analysed the blood glucose (BG) measurements and identified all level 1 (BG <4 mmol/l) and level 2 (BG <3 mmol/l) hypoglycaemic episodes. We compared the length of stays between different age groups and with different levels of hypoglycaemia.

Results: We analysed data obtained from 17,658 inpatients with diabetes who underwent 32,758 hospital admissions. The length of stays for admissions with no hypoglycaemia were 3[1,6], 3[1,8] and 4[2,11] (median[interquartile range]) days for age groups ≤65 years, 65-80 years and >80 years, respectively. These were statistically significantly lower (P < 0.01 for all pairwise comparisons) than the length of stays for admissions with level 1 hypoglycaemia, which were 6[3,13], 10[5,20] and 12[6,22] days, and level 2 hypoglycaemia, which were 7[3,14], 11[5,24] and 13[6,24] days.

Conclusions: In all age groups, admissions with either level 1 or level 2 hypoglycaemia were associated with an increased length of stay. However, in both the older groups, the length of stay increments were much higher (double) than the younger counterparts. The clinical consequences of hypoglycaemia were more severe in older people compared with the younger population.
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http://dx.doi.org/10.1093/ageing/afaa212DOI Listing
February 2021

Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies.

Antioxidants (Basel) 2020 Aug 17;9(8). Epub 2020 Aug 17.

Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

Many retinal diseases, such as diabetic retinopathy, glaucoma, and age-related macular (AMD) degeneration, are associated with elevated reactive oxygen species (ROS) levels. ROS are important intracellular signaling molecules that regulate numerous physiological actions, including vascular reactivity and neuron function. However, excessive ROS formation has been linked to vascular endothelial dysfunction, neuron degeneration, and inflammation in the retina. ROS can directly modify cellular molecules and impair their function. Moreover, ROS can stimulate the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) causing inflammation and cell death. However, there are various compounds with direct or indirect antioxidant activity that have been used to reduce ROS accumulation in animal models and humans. In this review, we report on the physiological and pathophysiological role of ROS in the retina with a special focus on the vascular system. Moreover, we present therapeutic approaches for individual retinal diseases targeting retinal signaling pathways involving ROS.
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http://dx.doi.org/10.3390/antiox9080761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465265PMC
August 2020

Anxiety and Depression of Nurses in a North West Province in China During the Period of Novel Coronavirus Pneumonia Outbreak.

J Nurs Scholarsh 2020 09 19;52(5):564-573. Epub 2020 Aug 19.

Professor, School of Nursing, Evidence-Based Nursing Center, School of Nursing, Lanzhou University, Lanzhou, Gansu, China.

Purpose: To investigate the anxiety and depression levels of frontline clinical nurses working in 14 hospitals in Gansu Province, China, during this period.

Design: A cross-sectional survey was conducted online between February 7 and 10, 2020, with a convenience sample of 22,034 nurses working in 14 prefecture and city hospitals in Gansu Province, located in northwest China.

Methods: A self-reported questionnaire with four parts (demographic characteristics, general questions related to novel coronavirus-infected pneumonia, self-rating anxiety scale, and self-rating depression scale) was administered. Descriptive statistics including frequencies, means, and SDs were computed. The associations between anxiety and depression with sociodemographic characteristics, work-related concerns, and impacts were analyzed, followed by multiple stepwise linear regression to identify factors that best predicted the nurses' anxiety and depression levels.

Findings: A total of 21,199 questionnaires were checked to be valid, with an effective recovery rate of 96.21%. The mean ± SD age of the respondents was 31.89 ± 7.084 years, and the mean ± SD length of service was 9.40 ± 7.638 years. The majority of the respondents were female (98.6%) and married (73.1%). Some demographic characteristics, related concerns, and impacts of COVID-19 were found to be significantly associated with both anxiety (p < .001) and depression (p < .001). Nurses who needed to take care of children or elderly relatives, took leave from work because they were worried about COVID-19, avoided contact with family and friends, and wanted to obtain more COVID-19-related knowledge had higher levels of both anxiety and depression.

Conclusions: Results show that nurses faced with the COVID-19 outbreak are at risk for experiencing anxiety and depression. Demographic background, psychosocial factors, and work-related factors predicted the psychological responses. The family responsibilities and burdens of women may explain the higher levels of anxiety and depression among nurses with these obligations as compared to those without. On the other hand, nurses who chose not to take leave from work or who did not avoid going to work during this period were less anxious and depressed.

Clinical Relevance: Professional commitment might be a protective factor for adverse psychological responses. It is pertinent to provide emotional support for nurses and recognize their professional commitment in providing service to people in need.
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http://dx.doi.org/10.1111/jnu.12590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405411PMC
September 2020

Predicting the Risk of Inpatient Hypoglycemia With Machine Learning Using Electronic Health Records.

Diabetes Care 2020 07 29;43(7):1504-1511. Epub 2020 Apr 29.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals National Health Service Foundation Trust, Oxford, U.K.

Objective: We analyzed data from inpatients with diabetes admitted to a large university hospital to predict the risk of hypoglycemia through the use of machine learning algorithms.

Research Design And Methods: Four years of data were extracted from a hospital electronic health record system. This included laboratory and point-of-care blood glucose (BG) values to identify biochemical and clinically significant hypoglycemic episodes (BG ≤3.9 and ≤2.9 mmol/L, respectively). We used patient demographics, administered medications, vital signs, laboratory results, and procedures performed during the hospital stays to inform the model. Two iterations of the data set included the doses of insulin administered and the past history of inpatient hypoglycemia. Eighteen different prediction models were compared using the area under the receiver operating characteristic curve (AUROC) through a 10-fold cross validation.

Results: We analyzed data obtained from 17,658 inpatients with diabetes who underwent 32,758 admissions between July 2014 and August 2018. The predictive factors from the logistic regression model included people undergoing procedures, weight, type of diabetes, oxygen saturation level, use of medications (insulin, sulfonylurea, and metformin), and albumin levels. The machine learning model with the best performance was the XGBoost model (AUROC 0.96). This outperformed the logistic regression model, which had an AUROC of 0.75 for the estimation of the risk of clinically significant hypoglycemia.

Conclusions: Advanced machine learning models are superior to logistic regression models in predicting the risk of hypoglycemia in inpatients with diabetes. Trials of such models should be conducted in real time to evaluate their utility to reduce inpatient hypoglycemia.
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http://dx.doi.org/10.2337/dc19-1743DOI Listing
July 2020

Inpatient hypoglycaemia: understanding who is at risk.

Diabetologia 2020 07 17;63(7):1299-1304. Epub 2020 Apr 17.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals NHS Foundation Trust, Headington, Oxford, OX3 7LE, UK.

Aims/hypothesis: We analysed data obtained from the electronic patient records of inpatients with diabetes admitted to a large university hospital to understand the prevalence and distribution of inpatient hypoglycaemia.

Methods: The study was conducted using electronic patient record data from Oxford University Hospitals NHS Foundation Trust. The dataset contains hospital admission data for patients coded for diabetes. We used the recently agreed definition for a level 1 hypoglycaemia episode as any blood glucose measurement <4 mmol/l and a level 2 hypoglycaemia episode as any blood glucose measurement <3 mmol/l. Any two or more consecutive low blood glucose measurements within a 2 h time window were considered as one single hypoglycaemic episode.

Results: We analysed data obtained from 17,658 inpatients with diabetes (1696 with type 1 diabetes, 14,006 with type 2 diabetes, and 1956 with other forms of diabetes; 9277 men; mean ± SD age, 66 ± 18 years) who underwent 32,758 hospital admissions between July 2014 and August 2018. The incidence of level 1 hypoglycaemia was 21.5% and the incidence of level 2 hypoglycaemia was 9.6%. Recurrent level 1 and level 2 hypoglycaemia occurred, respectively, in 51% and 39% of hospital admissions in people with type 2 diabetes with at least one hypoglycaemic episode, and in 55% and 45% in those with type 1 diabetes. The incidence of level 2 hypoglycaemia in people with type 2 diabetes, when corrected for the number of people who remained in hospital, remained constant for the first 100 h at approximately 0.15 events per h per admission. With regards to the hypoglycaemia distribution during the day, after correcting for the number of blood glucose tests per h, there were two clear spikes in the rate of hypoglycaemia approximately 3 h after lunch and after dinner. The highest rate of hypoglycaemia per glucose test was seen between 01:00 hours and 05:00 hours. Medication had a significant impact on the incidence of level 2 hypoglycaemia, ranging from 1.5% in people with type 2 diabetes on metformin alone to 33% in people treated with a combination of rapid-acting insulin analogue, long-acting insulin analogue and i.v.-administered insulin.

Conclusions/interpretation: Retrospective analysis of data from electronic patient records enables clinicians to gain a greater understanding of the incidence and distribution of inpatient hypoglycaemia. This information should be used to drive evidence-based improvements in the glycaemic control of inpatients through targeted medication adjustment for specific populations at high risk of hypoglycaemia.
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http://dx.doi.org/10.1007/s00125-020-05139-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286944PMC
July 2020

Different metabolism of EPA, DPA and DHA in humans: A double-blind cross-over study.

Prostaglandins Leukot Essent Fatty Acids 2020 07 12;158:102033. Epub 2019 Nov 12.

Institute of Nutrition and Health, Qingdao University, Qingdao, China; Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China. Electronic address:

This study aimed to compare eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) incorporated into red blood cells (RBC) phospholipids (PL), plasma PL, plasma triglyceride (TAG), and plasma cholesteryl ester (CE) fractions, and the metabolomics profiles in a double-blind cross-over study. Twelve female healthy subjects randomly consumed 1 g per day for 6 days of pure EPA, DPA, or DHA. The placebo treatment was olive oil. The fasting venous blood was taken at days 0, 3 and 6, and the RBC PL and plasma lipid fractions were separated for fatty acid determination using thin layer chromatography followed by gas chromatography. Plasma metabolites were analyzed by UHPLC-Q-Exactive Orbitrap/MS. Supplemental EPA significantly increased the concentrations of EPA in RBC PL (days 3 and 6). For subjects consuming the DPA supplement, the concentrations of both DPA and EPA were significantly increased in RBC PL over a 6-day period, respectively. For plasma PL fraction, EPA and DPA supplementation significantly increased the concentrations of EPA and DPA at both days 3 and 6, respectively. Supplemental DHA significantly increased the concentrations of DHA in plasma PL at day 6. For plasma TAG fraction, supplementation with EPA and DPA significantly increased the concentrations of EPA and DPA at both days 3 and 6, respectively. After DHA supplementation, significant increases in the concentrations of DHA were found relative to baseline at both days 3 and 6. For plasma CE fraction, EPA supplementation significantly increased the concentrations of EPA (days 3 and 6) and DPA (days 6), respectively. Supplemental DPA significantly increased the concentrations of EPA at day 6. Meanwhile, the concentrations of DHA were significantly increased over a 6-day period of intervention after subjects consuming the DHA supplements. There were a total of 922 plasma metabolites identified using metabolomics analyses. Supplementation with DPA and DHA significantly increased the levels of sphingosine 1-phosphate (P  = 0.025, P  = 0.029) and 15-deoxy-Δ12,14-prostaglandin A1 (P  = 0.034; P  = 0.021) in comparison with olive oil group. Additionally, supplementation with EPA (P = 0.007) and DHA (P = 0.005) significantly reduced the levels of linoleyl carnitine, compared with olive oil group. This study shows that DPA might act as a reservoir of n-3 LCP incorporated into blood lipid fractions, metabolized into DHA, and retro-converted back to EPA. Metabolomics analyses indicate that supplemental EPA, DPA and DHA have shared and differentiated metabolites. The differences of these metabolic biomarkers should be investigated in additional studies.
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http://dx.doi.org/10.1016/j.plefa.2019.102033DOI Listing
July 2020

Short-term fully closed-loop insulin delivery using faster insulin aspart compared with standard insulin aspart in type 2 diabetes.

Diabetes Obes Metab 2019 12 8;21(12):2718-2722. Epub 2019 Oct 8.

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

We evaluated the efficacy and safety of short-term fully closed-loop insulin delivery using faster versus standard insulin aspart in type 2 diabetes. Fifteen adults with insulin-treated type 2 diabetes underwent 22 hours of closed-loop insulin delivery with either faster or standard insulin aspart in a double-blind randomized crossover design. Basal-bolus regimen was replaced by model predictive control algorithm-directed insulin delivery based on sensor glucose levels. The primary outcome was time with plasma glucose in target range (5.6-10.0 mmol/L) and did not differ between treatments (mean difference [95% CI] 3.3% [-8.2; 1.7], P = 0.17). Mean glucose and glucose variability were comparable, as was time spent below and above target range. Hypoglycaemia (<3.5 mmol/L) occurred once with faster insulin aspart and twice with standard insulin aspart. Mean total insulin dose was higher with faster insulin aspart (mean difference [95% CI] 3.7 U [0.7; 6.8], P = 0.021). No episodes of severe hypoglycaemia or other serious adverse events occurred. In conclusion, short-term fully closed-loop in type 2 diabetes may require higher dose of faster insulin aspart compared with standard insulin aspart to achieve comparable glucose control.
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http://dx.doi.org/10.1111/dom.13861DOI Listing
December 2019

Reliability of periocular anthropometry using three-dimensional digital stereophotogrammetry.

Graefes Arch Clin Exp Ophthalmol 2019 Nov 12;257(11):2517-2531. Epub 2019 Aug 12.

Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.

Purpose: Non-invasive three-dimensional (3D) stereophotogrammetry is becoming increasingly popular in many fields. However, few studies have focused on its periocular application. We aimed to provide evidence for the periocular application of a novel anthropometric procedure using 3D stereophotogrammetry by evaluating its reliability.

Methods: Fifty-one Caucasians were recruited (102 eyes; mean age, 31.9 ± 13.6 years). Two sets of 3D images were acquired for each subject, and two measurement sessions were performed on each image by two raters. Fifty-two periocular landmarks were identified, and then 49 corresponding linear, curvilinear, and angular measurements were evaluated for intrarater, interrater, and intramethod reliability.

Results: Our findings showed highly reliable results for mean absolute difference (0.59 and 0.68 unit), relative error measurement (2.66% and 3.08%), technical error of measurement (0.59 and 0.66 unit), relative technical error of measurement (2.71% and 2.96%), and intraclass correlation coefficient (0.98) for intrarater 1 and intrarater 2 reliability; respectively 0.94 unit, 4.06%, 0.89 unit, and 3.94%, as well as 0.97 for interrater reliability; and respectively 0.98 unit, 4.66%, 0.96 unit, and 4.64%, as well as 0.96 for intramethod reliability.

Conclusions: This imaging system and the landmark identification protocol are highly reliable. The collected measurements and their errors can be applied for the comparison of reliability among various 3D imaging systems and populations. It could be utilized for planning surgeries and evaluating treatment outcomes for physicians in ophthalmology, plastic and esthetic surgery, and in the maxillofacial field where periocular morphology alterations are made.
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http://dx.doi.org/10.1007/s00417-019-04428-6DOI Listing
November 2019

Fully closed-loop insulin delivery improves glucose control of inpatients with type 2 diabetes receiving hemodialysis.

Kidney Int 2019 09 20;96(3):593-596. Epub 2019 Mar 20.

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK. Electronic address:

Inpatient diabetes management of those on hemodialysis poses a major challenge. In a post hoc analysis of a randomized controlled clinical trial, we compared the efficacy of fully automated closed-loop insulin delivery vs. usual care in patients undergoing hemodialysis while in hospital. Compared to control patients receiving conventional subcutaneous insulin therapy, those patients receiving closed-loop insulin delivery significantly increased the proportion of time when a continuous glucose monitor was in the target range of 5.6-10.0 mmol/l by 37.6 percent without increasing the risk of hypoglycemia. Thus, closed-loop insulin delivery offers a novel way to achieve effective and safe glucose control in this vulnerable patient population.
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http://dx.doi.org/10.1016/j.kint.2019.03.006DOI Listing
September 2019

Charged particle radiobiology beamline using tandem accelerator-based MeV protons and carbon ions: a pilot study on the track-end radiation quality, variable biological effectiveness and Bayesian beam dosimetry.

Phys Med Biol 2019 08 14;64(16):165004. Epub 2019 Aug 14.

Institute of Modern Physics, Fudan University, Shanghai 200433, People's Republic of China. Key Laboratory of Nuclear Physics and Ion-beam Application (MOE), Fudan University, Shanghai 200433, People's Republic of China. Co-first authors having equal contribution to this work.

For in vitro cell irradiation using tandem accelerator-based MeV protons and carbon ions, by TOPAS simulation, a pilot study of performance evaluation is presented on a collimation beamline for 3 MeV protons and 10 MeV carbon ions from a 2  ×  3 MV tandem accelerator. Based on the elements and source parameters, a collimated beam of 2.8 MeV protons or 2.5 MeV carbon ions, with 5.175 mm or 5.166 mm full width tenth maximum (FWTM), respectively, can be delivered to the target cell dish. TOPAS simulations and/or deterministic algorithms present a Bragg curve of linear energy transfer (LET) (10-70 keV μm) along a 138 μm range of the proton beam, and a declining LET of the carbon beam (900-100 keV μm) within 4 μm range. Based on the biophysical models for relative biological effectiveness (RBE) of protons, TOPAS RBE scorers presents a set of depth-variation curves of the proton RBE (for V79 and DU145 cells), linearly related to the Bragg curve of the proton LET. Based on the microdosimetric-kinetic (MK) theory, in the 4 μm range for a monolayer cell thickness, the mean RBEα (V79 cells) of the carbon ion beam is estimated as 3.612 (late S phase) and 1.737 (G /S phase) for the mean LET of 492 keV μm. For practical irradiations, a tunable proton RBE can be acquired by changing the thickness of the cell dish. For the low-energy high-fluence (rate) beams, indirect beam measurements are proposed to detect the proton-beam induced scattering/recoil protons from a beam-intercepting Mylar film, and the carbon-beam induced backscattered electrons from a gold-deposited Havar-foil beam window. Statistical dosimetry for the indirect measurement is established, using a Bayesian model based on the preset number of detection counts, by which the mean value of the whole-dish dose can be prescribed and the uncertainty introduced in the survival data can be corrected.
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http://dx.doi.org/10.1088/1361-6560/ab21faDOI Listing
August 2019

Changes of urine metabolites in response to n-3 fatty acid supplements and their correlation with metabolic risk factors in patients with type 2 diabetes.

Food Funct 2019 May;10(5):2471-2479

Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China.

The present study aimed to investigate the effects of n-3 fatty acid supplements on urine metabolite profiling and their correlation with metabolic risk factors in Chinese T2D patients. A double-blind randomized controlled trial was conducted in 59 Chinese patients with T2D, who were randomized to receive fish oil (FO), flaxseed oil (FSO) or corn oil (CO, serving as a control group) capsules for 180 days. Morning urine samples were collected before and after the intervention and were analyzed for metabolomics by UHPLC-Q-Exactive Orbitrap/MS in positive and negative ionization modes. In the FO group, levels of 2-hexenoylcarnitine (C6:1) (p < 0.001) and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) (p = 0.004) were significantly increased while hydroxyisovaleroyl carnitine (C5:OH) (p < 0.001) was significantly decreased compared with the CO group. In addition, geranylacetone (p = 0.023) and citronellyl propionate (p = 0.038) levels were significantly elevated, while dihydrojasmonic acid (p = 0.003) was significantly reduced in the FSO group compared with that in the CO group. Moreover, increased C6:1 was correlated with decreased serum triglycerides (r = -0.340, p = 0.020). The change of urine CMPF showed inverse correlation with blood urea nitrogen (BUN) (r = -0.338, p = 0.020), while C5:OH was positively correlated with apolipoprotein B (APOB) and BUN (r = 0.386, p = 0.015; r = 0.327, p = 0.025). Besides, the change of urine CMPF was positively correlated with serum CMPF (r = 0.646, p < 0.001). In conclusion, the present study confirmed that CMPF is a strong biomarker of fish oil, and indicated that marine n-3 PUFA intake might have a beneficial effect on lipid metabolism and renal function in patients with T2D.
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http://dx.doi.org/10.1039/c9fo00048hDOI Listing
May 2019

Mixed-meal tolerance test to assess residual beta-cell secretion: Beyond the area-under-curve of plasma C-peptide concentration.

Pediatr Diabetes 2019 05 19;20(3):282-285. Epub 2019 Feb 19.

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Aims: Residual beta-cell secretion in type 1 diabetes is commonly assessed by area-under-curve of plasma C-peptide concentration (AUC ) following mixed-meal tolerance test (MMTT). We aimed to investigate alternative measures of beta-cell responsiveness.

Methods: We analyzed data from 32 youth (age 7 to 17 years) undergoing MMTT within 6 months of type 1 diabetes diagnosis. We related AUC with (a) validated mechanistic index of postprandial beta-cell responsiveness M accounting for glucose level during MMTT, and (b) pragmatic marker calculated as baseline plasma C-peptide concentration corrected for baseline plasma glucose concentration.

Results: Postprandial responsiveness M was correlated with age and BMI SDS (R = 0.66 and 0.44, P < 0.01 and P < 0.05) and was more correlated with glycated hemoglobin than AUC (R = 0.79, P = 0.04). The pragmatic marker was highly correlated with AUC (R = 0.94, P < 0.01).

Conclusions: Postprandial responsiveness M may be more relevant to glucose control than AUC . Baseline C-peptide corrected for baseline glucose appears to be a suitable surrogate of AUC if MMTT is not performed.
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http://dx.doi.org/10.1111/pedi.12816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487945PMC
May 2019

Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial.

Lancet 2018 10 3;392(10155):1321-1329. Epub 2018 Oct 3.

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK. Electronic address:

Background: The achievement of glycaemic control remains challenging for patients with type 1 diabetes. We assessed the effectiveness of day-and-night hybrid closed-loop insulin delivery compared with sensor-augmented pump therapy in people with suboptimally controlled type 1 diabetes aged 6 years and older.

Methods: In this open-label, multicentre, multinational, single-period, parallel randomised controlled trial, participants were recruited from diabetes outpatient clinics at four hospitals in the UK and two centres in the USA. We randomly assigned participants with type 1 diabetes aged 6 years and older treated with insulin pump and with suboptimal glycaemic control (glycated haemoglobin [HbA] 7·5-10·0%) to receive either hybrid closed-loop therapy or sensor-augmented pump therapy over 12 weeks of free living. Training on study insulin pump and continuous glucose monitoring took place over a 4-week run-in period. Eligible subjects were randomly assigned using central randomisation software. Allocation to the two study groups was unblinded, and randomisation was stratified within centre by low (<8·5%) or high (≥8·5%) HbA. The primary endpoint was the proportion of time that glucose concentration was within the target range of 3·9-10·0 mmol/L at 12 weeks post randomisation. Analyses of primary outcome and safety measures were done in all randomised patients. The trial is registered with ClinicalTrials.gov, number NCT02523131, and is closed to accrual.

Findings: From May 12, 2016, to Nov 17, 2017, 114 individuals were screened, and 86 eligible patients were randomly assigned to receive hybrid closed-loop therapy (n=46) or sensor-augmented pump therapy (n=40; control group). The proportion of time that glucose concentration was within the target range was significantly higher in the closed-loop group (65%, SD 8) compared with the control group (54%, SD 9; mean difference in change 10·8 percentage points, 95% CI 8·2 to 13·5; p<0·0001). In the closed-loop group, HbA was reduced from a screening value of 8·3% (SD 0·6) to 8·0% (SD 0·6) after the 4-week run-in, and to 7·4% (SD 0·6) after the 12-week intervention period. In the control group, the HbA values were 8·2% (SD 0·5) at screening, 7·8% (SD 0·6) after run-in, and 7·7% (SD 0·5) after intervention; reductions in HbA percentages were significantly greater in the closed-loop group compared with the control group (mean difference in change 0·36%, 95% CI 0·19 to 0·53; p<0·0001). The time spent with glucose concentrations below 3·9 mmol/L (mean difference in change -0·83 percentage points, -1·40 to -0·16; p=0·0013) and above 10·0 mmol/L (mean difference in change -10·3 percentage points, -13·2 to -7·5; p<0·0001) was shorter in the closed-loop group than the control group. The coefficient of variation of sensor-measured glucose was not different between interventions (mean difference in change -0·4%, 95% CI -1·4% to 0·7%; p=0·50). Similarly, total daily insulin dose was not different (mean difference in change 0·031 U/kg per day, 95% CI -0·005 to 0·067; p=0·09) and bodyweight did not differ (mean difference in change 0·68 kg, 95% CI -0·34 to 1·69; p=0·19). No severe hypoglycaemia occurred. One diabetic ketoacidosis occurred in the closed-loop group due to infusion set failure. Two participants in each study group had significant hyperglycaemia, and there were 13 other adverse events in the closed-loop group and three in the control group.

Interpretation: Hybrid closed-loop insulin delivery improves glucose control while reducing the risk of hypoglycaemia across a wide age range in patients with suboptimally controlled type 1 diabetes.

Funding: JDRF, NIHR, and Wellcome Trust.
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http://dx.doi.org/10.1016/S0140-6736(18)31947-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182127PMC
October 2018

Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care.

N Engl J Med 2018 Aug 25;379(6):547-556. Epub 2018 Jun 25.

From the Departments of Diabetes, Endocrinology, Clinical Nutrition, and Metabolism (L.B., E.A., C.S.) and General Internal Medicine (L.B., M.M.W.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; and the Wellcome Trust-MRC Institute of Metabolic Science (L.B., H.T., Y.R., M.E.W., M.L.E., A.P.C., R.H.) and the Department of Pediatrics (M.E.W., R.H.), University of Cambridge, and the Wolfson Diabetes and Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust (S.H., M.L.E., A.P.C.), Cambridge, and the Manchester University Hospitals NHS Foundation, Manchester Academic Health Science Centre (H.T.), and the Division of Diabetes, Endocrinology, and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester (H.T.), Manchester - all in the United Kingdom.

Background: In patients with diabetes, hospitalization can complicate the achievement of recommended glycemic targets. There is increasing evidence that a closed-loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabetes. We wanted to investigate whether a closed-loop system could also improve glycemic control in patients with type 2 diabetes who were receiving noncritical care.

Methods: In this randomized, open-label trial conducted on general wards in two tertiary hospitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed-loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge.

Results: The mean (±SD) percentage of time that the sensor glucose measurement was in the target range was 65.8±16.8% in the closed-loop group and 41.5±16.9% in the control group, a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001); values above the target range were found in 23.6±16.6% and 49.5±22.8% of the patients, respectively, a difference of 25.9±3.4 percentage points (95% CI, 19.2 to 32.7; P<0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P<0.001). There was no significant between-group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P=0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P=0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group.

Conclusions: Among inpatients with type 2 diabetes receiving noncritical care, the use of an automated, closed-loop insulin-delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565 .).
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http://dx.doi.org/10.1056/NEJMoa1805233DOI Listing
August 2018

Flavonoid subclasses and type 2 diabetes mellitus risk: a meta-analysis of prospective cohort studies.

Crit Rev Food Sci Nutr 2019 21;59(17):2850-2862. Epub 2019 Jan 21.

Institute of Nutrition and Health, Qingdao University , Qingdao , China.

Epidemiological studies have suggested controversial associations between flavonoid subclasses and type 2 diabetes mellitus (T2DM) risk. The aim of the present meta-analysis was to quantitatively estimate these associations with prospective cohort study. A systematic literature search in PubMed and Scopus databases was performed up to May 2018. Multivariate-adjust relative risks (RRs) with corresponding 95% confidence intervals (CIs) for the highest versus the lowest category were pooled by using a random-effects model. Using restricted cubic spline regression model, non-linear dose-response analysis was estimated. Nine independent prospective cohort studies with 172,058 participants and 16910 events were included. Dietary intakes of flavanols, flavonols, flavan-3-ols and isoflavones were inversely associated with T2DM risk, and the summary RRs were 0.86 (95%CI: 0.77, 0.97), 0.91 (95%CI: 0.85, 0.98), 0.90 (95%: 0.82, 0.99) and 0.91 (95%CI: 0.84, 0.98), respectively. Dose-response analysis showed that 135 mg/day increment of flavanols (95%CI: 0.92, 0.96; P for trend <0.001), 50 mg/day increment of flavonols (95%CI: 0.88, 0.99, for trend = 0.021), 68 mg/day increment of flavan-3-ols (95%CI: 0.92, 0.96, for trend <0.001), or 1.8 mg/day increment of isoflavones (95%CI: 0.92, 0.97, for trend <0.001) were associated with 6% reduction in T2DM risk. Non-significant association was observed with respect to flavanones and flavones. The present meta-analysis provides substantial evidence that dietary intakes of flavanols, flavonols, flavan-3-ols and isoflavones were inversely associated with T2DM risk, respectively. Higher dietary intakes of flavanol-, flavonol-, flavan-3-ol- and isoflavone-foods would have beneficial effects for protection against T2DM.
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http://dx.doi.org/10.1080/10408398.2018.1476964DOI Listing
February 2020

Dietary Fat Intake and Risk of Alzheimer's Disease and Dementia: A Meta-Analysis of Cohort Studies.

Curr Alzheimer Res 2018 ;15(9):869-876

Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China.

Background: Epidemiological studies showed that dietary fat intake is associated with Alzheimer's disease (AD) and dementia risk, however, the association remain inconsistent. This metaanalysis aimed to systematically examine the association of dietary fat intake with AD and dementia risk.

Methods: We have systematically searched PubMed, Embase and the Cochrane Library up to May 1st 2017. Prospective cohort studies were included if they reported on the association of dietary fat intake with AD and dementia risk. Multivariate-adjusted relative risks (RRs) for the highest versus lowest category were pooled by using a random-effects model.

Results: A total of 8630 participants and 633 cases from four independent prospective cohort studies were included in the present meta-analysis. A higher dietary saturated fat intake was significantly associated with an increased risk of 39% and 105% for AD (RR: 1.39; 95% CI: 1.00, 1.94) and dementia (RR: 2.05; 95% CI: 1.06, 3.98), respectively. Dose-response analysis indicated a 4 g/day increment of saturated fat intake was related to 15% higher risk of AD (RR: 1.15; 95% CI: 1.01, 1.31). However, there was no significant association found between dietary intake of total, monounsaturated, polyunsaturated fat and AD or dementia risk.

Conclusions: This meta-analysis provides significant evidence of positive association between higher saturated fat intake and AD and dementia risk.
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http://dx.doi.org/10.2174/1567205015666180427142350DOI Listing
August 2019

Hypoglycaemia incidence and recovery during home use of hybrid closed-loop insulin delivery in adults with type 1 diabetes.

Diabetes Obes Metab 2018 08 16;20(8):2004-2008. Epub 2018 Apr 16.

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Glucose excursion was assessed prior to and post hypoglycaemia to increase understanding of hypoglycaemia incidence and recovery during hybrid closed-loop insulin delivery. We retrospectively analysed data from 60 adults with type 1 diabetes who received, in a crossover randomized design, day-and-night hybrid closed-loop insulin delivery and insulin pump therapy, the latter with or without real-time continuous glucose monitoring. Over 4-week study periods, we identified hypoglycaemic episodes, defined as sensor glucose <3.0 mmol/L, and analysed sensor glucose relative to the onset of hypoglycaemia. We identified 377 hypoglycaemic episodes during hybrid closed-loop intervention vs 662 during control intervention (P < .001), with a predominant reduction of nocturnal hypoglycaemia. The slope of sensor glucose prior to hypoglycaemia was steeper during closed-loop intervention than during control intervention (P < .01), while insulin delivery was reduced (P < .01). During both day and night, participants recovered from hypoglycaemia faster when treated by closed-loop intervention. At 120 minutes post hypoglycaemia, sensor glucose levels were higher during closed-loop intervention compared to the control period (P < .05). In conclusion, closed-loop intervention reduces the risk of hypoglycaemia, particularly overnight, with swift recovery from hypoglycaemia leading to higher 2-hour post-hypoglycaemia glucose levels.
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http://dx.doi.org/10.1111/dom.13304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043360PMC
August 2018

Lorcaserin improves glycemic control via a melanocortin neurocircuit.

Mol Metab 2017 10 21;6(10):1092-1102. Epub 2017 Jul 21.

Department of Pharmacology, University of Cambridge, Cambridge, UK; The Rowett Institute, University of Aberdeen, Aberdeen, UK. Electronic address:

Objective: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HTR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved.

Methods: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control.

Results: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4R) to exert its effects on glucose homeostasis. In contrast, MC4R signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity.

Conclusions: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.
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http://dx.doi.org/10.1016/j.molmet.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641625PMC
October 2017

Application of Bayesian analysis to the doubly labelled water method for total energy expenditure in humans.

Rapid Commun Mass Spectrom 2018 Jan;32(1):23-32

MRC Elsie Widdowson Laboratory (formerly MRC Human Nutrition Research), Fulbourn Road, Cambridge, CB1 9NL, UK.

Rationale: The doubly labelled water (DLW) method is the reference method for the estimation of free-living total energy expenditure (TEE). In this method, where both H and O are employed, different approaches have been adopted to deal with the non-conformity observed regarding the distribution space for the labels being non-coincident with total body water. However, the method adopted can have a significant effect on the estimated TEE.

Methods: We proposed a Bayesian reasoning approach to modify an assumed prior distribution for the space ratio using experimental data to derive the TEE. A Bayesian hierarchical approach was also investigated. The dataset was obtained from 59 adults (37 women) who underwent a DLW experiment during which the H and O enrichments were measured using isotope ratio mass spectrometry (IRMS).

Results: TEE was estimated at 9925 (9106-11236) [median and interquartile range], 9646 (9167-10540), and 9,638 (9220-10340) kJ·day for women and at 13961 (12851-15347), 13353 (12651-15088) and 13211 (12653-14238) kJ·day for men, using normalized non-Bayesian, independent Bayesian and hierarchical Bayesian approaches, respectively. A comparison of hierarchical Bayesian with normalized non-Bayesian methods indicated a marked difference in behaviour between genders. The median difference was -287 kJ·day for women, and -750 kJ·day for men. In men there is an appreciable compression of the TEE distribution obtained from the hierarchical model compared with the normalized non-Bayesian methods (range of TEE 11234-15431 kJ·day vs 10786-18221 kJ·day ). An analogous, yet smaller, compression is seen in women (7081-12287 kJ·day vs 6989-13775 kJ·day ).

Conclusions: The Bayesian analysis is an appealing method to estimate TEE during DLW experiments. The principal advantages over those obtained using the classical least-squares method is the generation of potentially more useful estimates of TEE, and improved handling of outliers and missing data scenarios, particularly if a hierarchical model is used.
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http://dx.doi.org/10.1002/rcm.8013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765481PMC
January 2018

Faster insulin action is associated with improved glycaemic outcomes during closed-loop insulin delivery and sensor-augmented pump therapy in adults with type 1 diabetes.

Diabetes Obes Metab 2017 10 23;19(10):1485-1489. Epub 2017 Jun 23.

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

We aimed to evaluate the relationship between insulin pharmacodynamics and glycaemic outcomes during closed-loop insulin delivery and sensor-augmented pump therapy. We retrospectively analysed data from a multicentre randomized control trial involving 32 adults with type 1 diabetes receiving day-and-night closed-loop insulin delivery and sensor-augmented pump therapy over 12 weeks. We estimated time-to-peak insulin action (t ) and insulin sensitivity ( S ) during both interventions, and correlated these with demographic factors and glycaemic outcomes. During both interventions, t was positively correlated with pre- and post-intervention HbA1c (r = 0.50-0.52, P  < .01) and mean glucose (r = 0.45-0.62, P  < .05), and inversely correlated with time sensor glucose, which was in target range 3.9 to 10 mmol/L (r = -0.64 to -0.47, P  < .05). Increased body mass index was associated with higher t and lower S (both P  < .05). During closed-loop insulin delivery, t was positively correlated with glucose variability ( P  < .05). Faster insulin action is associated with improved glycaemic control during closed-loop insulin delivery and sensor-augmented pump therapy.
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http://dx.doi.org/10.1111/dom.12956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638091PMC
October 2017

Modeling Day-to-Day Variability of Glucose-Insulin Regulation Over 12-Week Home Use of Closed-Loop Insulin Delivery.

IEEE Trans Biomed Eng 2017 06 8;64(6):1412-1419. Epub 2016 Sep 8.

Parameters of physiological models of glucose-insulin regulation in type 1 diabetes have previously been estimated using data collected over short periods of time and lack the quantification of day-to-day variability. We developed a new hierarchical model to relate subcutaneous insulin delivery and carbohydrate intake to continuous glucose monitoring over 12 weeks while describing day-to-day variability. Sensor glucose data sampled every 10-min, insulin aspart delivery and meal intake were analyzed from eight adults with type 1 diabetes (male/female 5/3, age 39.9 ± 9.5 years, BMI 25.4 ± 4.4kg/m, HbA1c 8.4 ± 0.6% ) who underwent a 12-week home study of closed-loop insulin delivery. A compartment model comprised of five linear differential equations; model parameters were estimated using the Markov chain Monte Carlo approach within a hierarchical Bayesian model framework. Physiologically, plausible a posteriori distributions of model parameters including insulin sensitivity, time-to-peak insulin action, time-to-peak gut absorption, and carbohydrate bioavailability, and good model fit were observed. Day-to-day variability of model parameters was estimated in the range of 38-79% for insulin sensitivity and 27-48% for time-to-peak of insulin action. In conclusion, a linear Bayesian hierarchical approach is feasible to describe a 12-week glucose-insulin relationship using conventional clinical data. The model may facilitate in silico testing to aid the development of closed-loop insulin delivery systems.
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http://dx.doi.org/10.1109/TBME.2016.2590498DOI Listing
June 2017

Sensor Life and Overnight Closed Loop: A Randomized Clinical Trial.

J Diabetes Sci Technol 2017 05 11;11(3):513-521. Epub 2016 Nov 11.

1 Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Background: Closed-loop (CL) systems direct insulin delivery based on continuous glucose monitor (CGM) sensor values. CGM accuracy varies with sensor life, being least accurate on day 1 of sensor insertion. We evaluated the effect of sensor life (enhanced Enlite, Medtronic MiniMed, Northridge, CA) on overnight CL.

Methods: In an open-label, randomized, 2-period, inpatient crossover pilot study, 12 adolescents on insulin pump (age 16.7 ± 1.9 years; HbA1c 66 ± 10 mmol/mol) attended a clinical research facility on 2 overnight occasions. In random order, participants received CL on day 1 or on day 3-4 after sensor insertion. During both periods, glucose was automatically controlled by a model predictive control algorithm informed by sensor glucose. Plasma glucose was measured every 30 to 60 min.

Results: During overnight CL (22:30 to 07:30), the proportion of time with plasma glucose readings in the target range (3.9-8.0 mmol/l, primary endpoint) when initiated on day 1 of sensor insertion vs day 3-4 were comparable (58 ± 32% day 1 vs 56 ± 36% day 3-4; P = .34), and there were no significant differences between interventions in terms of mean plasma glucose ( P = .26), percentage time above 8.0 mmol/l ( P = .49), and time spent below 3.9 mmol/l ( P = .93). Sensor accuracy varied with sensor life (mean absolute relative difference 19.8 ± 15.0% on day 1 and 13.7 ± 10.2% on day 3 to 4). Sensor glucose tended to under-read plasma glucose inflating benefits of CL on glucose control.

Conclusions: In spite of differences in sensor accuracy, overnight CL glucose control informed by sensor glucose on day 1 or day 3-4 after sensor insertion was comparable. The model predictive controller appears to mitigate against sensor inaccuracies.
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http://dx.doi.org/10.1177/1932296816678631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505426PMC
May 2017

Closed-loop insulin delivery in inpatients with type 2 diabetes: a randomised, parallel-group trial.

Lancet Diabetes Endocrinol 2017 02 9;5(2):117-124. Epub 2016 Nov 9.

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK. Electronic address:

Background: We assessed whether fully closed-loop insulin delivery (the so-called artificial pancreas) is safe and effective compared with standard subcutaneous insulin therapy in patients with type 2 diabetes in the general ward.

Methods: For this single-centre, open-label, parallel-group, randomised controlled trial, we enrolled patients aged 18 years or older with type 2 diabetes who were receiving insulin therapy. Patients were recruited from general wards at Addenbrooke's Hospital, Cambridge, UK. Participants were randomly assigned (1:1) by a computer-generated minimisation method to receive closed-loop insulin delivery (using a model-predictive control algorithm to direct subcutaneous delivery of rapid-acting insulin analogue without meal-time insulin boluses) or conventional subcutaneous insulin delivery according to local clinical guidelines. The primary outcome was time spent in the target glucose concentration range of 5·6-10·0 mmol/L during the 72 h study period. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774565.

Findings: Between Feb 20, 2015, and March 24, 2016, we enrolled 40 participants, of whom 20 were randomly assigned to the closed-loop intervention group and 20 to the control group. The proportion of time spent in the target glucose range was 59·8% (SD 18·7) in the closed-loop group and 38·1% (16·7) in the control group (difference 21·8% [95% CI 10·4-33·1]; p=0·0004). No episodes of severe hypoglycaemia or hyperglycaemia with ketonaemia occurred in either group. One adverse event unrelated to study devices occurred during the study (gastrointestinal bleed).

Interpretation: Closed-loop insulin delivery without meal-time boluses is effective and safe in insulin-treated adults with type 2 diabetes in the general ward.

Funding: Diabetes UK; European Foundation for the Study of Diabetes; JDRF; National Institute for Health Research Cambridge Biomedical Research Centre; Wellcome Trust.
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http://dx.doi.org/10.1016/S2213-8587(16)30280-7DOI Listing
February 2017