Prediction of photodynamics of 200 nm excited cyclobutanone with linear response electronic structure and ab initio multiple spawning.

Simulations of photochemical reaction dynamics have been a challenge to the theoretical chemistry community for some time. In an effort to determine the predictive character of current approaches, we predict the results of an upcoming ultrafast diffraction experiment on the photodynamics of cyclobutanone after excitation to the lowest lying Rydberg state (S2). A picosecond of nonadiabatic dynamics is described with ab initio multiple spawning. We use both time dependent density functional theory (TDDFT) and equation-of-motion coupled cluster singles and doubles (EOM-CCSD) theory for the underlying electronic structure theory. We find that the lifetime of the S2 state is more than a picosecond (with both TDDFT and EOM-CCSD). The predicted ultrafast electron diffraction spectrum exhibits numerous structural features, but weak time dependence over the course of the simulations.

Efficient analytical gradients of property-based diabatic states: Geometry optimizations for localized holes.

We present efficient analytical gradients of property-based diabatic states and couplings using a Lagrangian formalism. Unlike previous formulations, the method achieves a computational scaling that is independent of the number of adiabatic states used to construct the diabats. The approach is generalizable to other property-based diabatization schemes and electronic structure methods as long as analytical energy gradients are available and integral derivatives with the property operator can be formed. We also introduce a scheme to phase and reorder diabats to ensure their continuity between molecular configurations. We demonstrate this for the specific case of Boys diabatic states obtained from state-averaged complete active space self-consistent field electronic structure calculations with GPU acceleration in the TeraChem package. The method is used to test the Condon approximation for the hole transfer in an explicitly solvated model DNA oligomer.

Evidence for Water Antibonding Orbital Mixing in the Hydrated Electron from Its Oxygen 1s X-ray Absorption Spectrum.

The X-ray absorption spectrum (XAS) of the hydrated electron (e(aq)-) has been simulated using time-dependent density functional theory with a quantum mechanics/molecular mechanics description. A unique XAS peak at 533 eV is observed with an energy and intensity in quantitative agreement with recent time-resolved experiments, allowing its assignment as arising from water O1s transitions to the singly occupied molecular orbital (SOMO) in which the excess electron resides. The transitions acquire oscillator strength due to the SOMO comprising an admixture of a cavity-localized orbital and water 4a1 and 2b2 antibonding orbitals. The mixing of antibonding orbitals has implications for the strength of couplings between e(aq)- and intramolecular modes of water.

The transCampus Metabolic Training Programme Explores the Link of SARS-CoV-2 Virus to Metabolic Disease.

Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society. A modern training programme in diabetes and metabolism does not only involve a thorough understanding of classical physiology, biology and clinical diabetology but has to bring together an interdisciplinary team. With the arrival of the coronavirus pandemic, this prestigious and unique metabolic training programme is facing new challenges but also new opportunities. The consortium of the training programme has recognized early on the need for a guidance and for practical recommendations to cope with the COVID-19 pandemic for the community of patients with metabolic disease, obesity and diabetes. This involves the optimal management from surgical obesity programmes to medications and insulin replacement. We also established a global registry analyzing the dimension and role of metabolic disease including new onset diabetes potentially triggered by the virus. We have involved experts of infectious disease and virology to our faculty with this metabolic training programme to offer the full breadth and scope of expertise needed to meet these scientific challenges. We have all learned that this pandemic does not respect or heed any national borders and that we have to work together as a global community. We believe that this transCampus metabolic training programme provides a prime example how an international team of established experts in the field of metabolism can work together with students from all over the world to address a new pandemic.

Active orbital preservation for multiconfigurational self-consistent field.

We introduce Active Orbital Preservation for Multiconfigurational Self-Consistent Field (AOP-MCSCF), an automated approach to improving the consistency of active space orbitals over multiple molecular configurations. Our approach is based on maximum overlap with a reference set of active space orbitals taken from a single geometry of a chromophore in the gas phase and can be used to automatically preserve the appropriate orbitals of the chromophore across multiple thermally sampled configurations, even when the chromophore is solvated by quantum-mechanically treated water molecules. In particular, using the singular value decomposition of a Molecular Orbital (MO) overlap matrix between the system and reference, we rotate the MOs of the system to align with the reference active space orbitals and use the resulting rotated orbitals as an initial guess to a MCSCF calculation. We demonstrate the approach on aqueous p-hydroxybenzylidene-imidazolinone (HBI) and find that AOP-MCSCF converges to the "correct" orbitals for over 90% of 3000 thermally sampled configurations. In addition, we compute the linear absorption spectrum and find excellent agreement with new experimental measurements up to 5.4 eV (230 nm). We show that electrostatic contributions to the solvation energy of HBI largely explain the observed state-dependent solvatochromism.

Recurrent diabetic ketoacidosis and a brief history of brittle diabetes research: contemporary and past evidence in diabetic ketoacidosis research including mortality, mental health and prevention.

Pharmacological, technological and educational approaches have advanced the treatment of Type 1 diabetes in the last four decades and yet diabetic ketoacidosis (DKA) continues to be a leading cause of admission in Type 1 diabetes. This article begins by reviewing the contemporary epidemiological evidence in DKA. It highlights a rise in DKA episodes in the last two decades, with DKA continuing to be the leading cause of death in young people with Type 1 diabetes, and that DKA episodes are a marker for subsequent all-cause mortality. It also summarizes the limited evidence base for DKA prevention and associations with psychopathology. To emphasize the importance of this group with high-risk Type 1 diabetes and the degree to which they have been overlooked in the past two decades, the article summarizes the research literature of recurrent DKA during 1976-1991 when it was extensively investigated as part of the phenomenon of 'brittle diabetes'. This period saw numerous basic science studies investigating the pathophysiology of recurrent DKA. Subsequently, research centres published their experiences of brittle diabetes research participants manipulating their treatment under research conditions. Unfortunately, the driver for this behaviour and whether it was indicative of other people with ketoacidosis was not pursued. In summary, we suggest there has been a stasis in the approach to recurrent DKA prevention, which is likely linked to historical cases of mass sabotage of brittle diabetes research. Further investigation is required to clarify possible psychological characteristics that increase the risk of DKA and thereby targets for DKA prevention.

Depression and change in occupational functioning in type 2 diabetes.

BACKGROUND: The effect of depression on both employment and productivity in type 2 diabetes (T2D) is poorly understood. AIMS: We tested whether depressive symptoms at diagnosis of T2D are associated with change in employment status and productivity over 2-year follow-up. METHODS: In a prospective analysis of working-age (18-63 years) people with newly diagnosed T2D recruited from primary care, we tested the association between depressive symptoms at diagnosis of T2D (baseline) and employment rates over 2 years. Using the Patient Health Questionnaire-9, depressive symptoms were measured categorically (depression caseness score ≥10) and continuously. In those employed, we measured changes in presenteeism and absenteeism using the World Health Organization (WHO) Health and Work Performance Questionnaire in univariate and multivariate models, respectively, including and excluding part-time workers. RESULTS: Of 1202 people aged 18-63 at baseline, 982 (82%) provided employment information; the mean age was 50.3 (SD 8.1) years, 44% were female, 59% of non-white ethnicity and 16% had depression. After adjustment for age, sex, ethnicity, socio-economic status, diabetes control and depression treatment, depression caseness was associated with worsening unemployment over 2 years only in full-time workers (odds ratio 0.43 (95% CI 0.20, 0.96), P < 0.05). In those employed full-time or part-time, total depressive symptoms were associated with worsening presenteeism over 2 years after full adjustment (ß = -2.63 (95% CI -4.81, -0.45), P < 0.05), despite no association with worsening absenteeism. CONCLUSIONS: In newly diagnosed T2D, depressive symptoms demonstrate an association with worsening employment rate and decline in work productivity over 2-year follow-up.

Optimal prandial timing of bolus insulin in diabetes management: a review.

The inability to achieve optimal diabetes glucose control in people with diabetes is multifactorial, but one contributor may be inadequate control of postprandial glucose. In patients treated with multiple daily injections of insulin, both the dose and timing of meal-related rapid-acting insulin are key factors in this. There are conflicting opinions and evidence on the optimal time to administer mealtime insulin. We performed a comprehensive literature search to review the published data, focusing on the use of rapid-acting insulin analogues in patients with Type 1 diabetes. Pharmacokinetic and pharmacodynamic studies of rapid-acting insulin analogues, together with postprandial glucose excursion data, suggest that administering these 15-20 min before food would provide optimal postprandial glucose control. Data from clinical studies involving people with Type 1 diabetes receiving structured meals and rapid-acting insulin analogues support this, showing a reduction in post-meal glucose levels of ~30% and less hypoglycaemia when meal insulin was taken 15-20 min before a meal compared with immediately before the meal. Importantly, there was also a greater risk of postprandial hypoglycaemia when patients took rapid-acting analogues after eating compared with before eating.

The attitude of healthcare professionals plays an important role in the uptake of diabetes self-management education: analysis of the Barriers to Uptake of Type 1 Diabetes Education (BUD1E) study survey.

AIM: To explore reasons for the poor uptake of accredited diabetes self-management education (DSME) in adults with Type 1 diabetes. METHODS: The study was set in an urban population in South London, UK. A cross sectional survey gathered demographic, diabetes service-use data, psychological scores and reasons for non-attendance at locally-available DSME. In addition, 56 healthcare professionals were surveyed. RESULTS: Responses to surveys were returned by 496 adults with Type 1 diabetes (33% response rate), of whom 263 had attended DSME (53%). Multivariable analysis adjusted for significant variables identified four key variables influencing attendance. Non-attendance was associated with men (OR 0.55 CI 0.37-0.84, p = 0.005), lower educational attainment (OR 0.45 CI 0.28-0.73, p = 0.001), higher glycated haemoglobin (OR 1.74 CI 1.03-2.94, p = 0.04) and healthcare professional encouragement to attend (OR 1.7 CI 1.28-2.3, p = 0.001). The most frequently reported barriers to attendance were work (37%) and time (14%) commitments. Only 49% of healthcare professionals (HCPs) correctly identified the most likely barriers. Those HCPs who had observed courses believed more in their efficacy, with higher uptake within their clinic population. CONCLUSIONS: Social determinants of health, particularly educational attainment and gender, increase health inequalities by influencing decisions to attend evidence-based education courses. Healthcare professional communication is paramount to encourage attendance, and observation of a course may facilitate this.

Proportion of daily capillary blood glucose readings required in the target range for target glycaemic control: shift of focus from target range to proportion in range.

AIM: Most guidelines provide people with Type 1 diabetes with pre- and post-meal capillary blood glucose (CBG) targets to achieve optimal glycaemic control. We evaluated the proportion of daily CBG readings between 4 and 10 mmol/l in people achieving different HbA1c levels. METHOD: We analysed CBG data from routine pump/meter downloads from 201 adults treated with continuous subcutaneous insulin infusion (CSII) at a single hospital clinic. Exclusion criteria were CSII < 6 months, < 3 CBG/day, pregnancy, haemoglobinopathy and continuous sensor use. People were categorized into three groups based on HbA1c : < 58 mmol/mol, < 7.5% (n = 58); 58-74 mmol/mol, 7.5-8.9% (n = 107); and ≥ 75 mmol/mol, ≥ 9.0% (n = 36). RESULTS: Participants had a mean age of 43 ± 13 years and mean HBA1c of 64 mmol/mol (8.0 ± 1.1%). 47% of people started CSII for raised HbA1c , 25% due to hypoglycaemia and the rest during pregnancy. Downloads contained a mean of 22 ± 6.8 days of data per participant. CBG frequency was similar between the three groups (5.6 ± 2.0, 5.6 ± 1.9 and 5.4 ± 1.2 CBG/day; P = 0.468). The proportion of CBG readings between 4 and 10 mmol/l (72-180 mg/dl) was 57.3 ± 25.4%, 50.6 ± 11.1% and 39.9 ± 16.5% (P < 0.0001); < 4 mmol was 13.8%, 8.8% and 4.4% (P < 0.0001) and > 10 mmol/l was 28.9 ± 16.5%, 40.6 ± 12.1% and 55.6 ± 17.9% (P < 0.0001) in the three groups respectively. CONCLUSIONS: Participants achieving HBA1c < 58 mmol/mol (< 7.5%) had ~ 60% of CBG readings in range (4-10 mmol/l), with up to 30% of readings > 10 mmol/l. This target of achieving 60% or more readings within target, and being permissive with up to 30% readings > 10 mmol/l may be a novel target for people with diabetes, and may reduce anxiety associated with readings out of range.

Factors influencing attendance at structured education for Type 1 diabetes in south London.

AIM: To investigate the factors influencing uptake of structured education for people with Type 1 diabetes in our local population in order to understand why such uptake is low. METHODS: We conducted a cross-sectional database study of adults with Type 1 diabetes in two south London boroughs, analysed according to Dose Adjustment For Normal Eating (DAFNE) attendance or non-attendance. Demographics, glycaemic control and service use, with subset analysis by ethnicity, were compared using univariate analysis. An exploratory regression model was used to identify influencing factors. RESULTS: The analysis showed that 73% of adults had not attended the DAFNE programme. For non-attenders vs attenders, male gender (59 vs 48%; P = 0.002), older age (39 vs 35 years; P < 0.001), non-white ethnicity (30 vs 20%; P = 0.001) and coming from an area of social deprivation (index of multiple deprivation score 31 vs 28; P < 0.001) were associated with non-attendance. The difference in gender (88% men vs 70% women; P < 0.001) and age (43 vs 34 years) persisted in the non-white group. Regression analysis showed that higher baseline HbA1c level (odds ratio 1.96; P = 0.004), younger age (odds ratio 0.98; P = 0.001) and lower social deprivation (odds ratio 0.52; P = 0.001) was associated with attendance. CONCLUSION: Socio-economic status and factors perceived as indicating greater severity of disease (HbA1c ) influence attendance at DAFNE. More work is necessary to understand the demography of non-attenders to aid future service design and alternative engagement strategies for these groups.

Patient explanations for non-attendance at structured diabetes education sessions for newly diagnosed Type 2 diabetes: a qualitative study.

AIM: To determine the reasons for non-attendance at structured education sessions among people with a recent diagnosis of Type 2 diabetes. METHODS: This was a qualitative study using semi-structured interviews to elicit the main themes explaining non-attendance. A thematic framework method was applied to analyse the data. People who had not attended structured education were recruited from a population cohort of newly diagnosed Type 2 diabetes from South London (the South London Diabetes cohort study), UK. RESULTS: A sample of 30 people was interviewed. Three main themes emerged from the qualitative data explaining non-attendance at structured education: (1) lack of information/perceived benefit of the programme (e.g. not being informed about the course by their health professional); (2) unmet personal preferences (e.g. parking, timing); and (3) shame and stigma of diabetes (e.g. not wishing to tell others of diabetes diagnosis). CONCLUSION: This is the first time that reasons for non-attendance have been explored in depth among people who have newly diagnosed Type 2 diabetes. Novel reasons identified included non-attendance because of shame and stigma of diabetes. To improve uptake at structured education we need to: consider how health professionals in primary care communicate with their patients on the subject of structured diabetes education; offer alternatives to the traditional group education format; and understand that diabetes is associated with health-related stigma, which may affect participation.

Sustained benefit of continuous subcutaneous insulin infusion on glycaemic control and hypoglycaemia in adults with Type 1 diabetes.

AIM: To evaluate the sustainability of the benefits of continuous subcutaneous insulin infusion therapy in routine practice in a cohort of adults with diabetes. METHODS: The clinical records of all adults starting continuous subcutaneous insulin infusion over 12 years at our centre were included in this study. Baseline and mean annual HbA(1c) levels were recorded. The frequency of mild-to-moderate and severe hypoglycaemia and hypoglycaemia awareness were analysed in a subgroup. RESULTS: Adequate data were available from 327 patients, of whom 71% were female. The patients' mean ± sd age was 41 ± 14 years, the mean ± sd (range) follow-up for continuous subcutaneous insulin infusion was 4.3 ± 2.7 (1-12) years. The mean ± sd HbA(1c) concentration fell by 8 ± 5 mmol/mol (0.7 ± 0.5%) at year 1 [to 63 ± 12 mmol/mol from 70 ± 18 mmol/mol (7.9 ± 1.1% from 8.6 ± 1.6%); P < 0.0005], sustained to year 5. In patients with initial poor control, HbA(1c) dropped by 12 ± 11 mmol/mol (1.1 ± 1.0%; P < 0.0005) at year 1, sustained to year 6. The percentage of patients with ≥ 5 mild to moderate hypoglycaemic episodes per week fell from 29 to 12% (n = 163; P = 0.006). In the subgroup (n = 87; follow-up 2.5 ± mean ± sd 1.1 years), the frequency of severe hypoglycaemia fell from 0.6 ± 1.7 episodes per patient per year to 0.3 ± 0.9 (P = 0.047). Of 24 patients with impaired awareness of hypoglycaemia (Gold score ≥ 4), the mean ± sd Gold score improved from 4.9 ± 0.9 to 3.8 ± 1.7 (P = 0.011). Nine people regained awareness. No deterioration in HbA(1c) was seen in the hypoglycaemia-prone groups. CONCLUSIONS: The benefits of continuous subcutaneous insulin infusion with regard to improving glycaemic control and reducing hypoglycaemia frequency, along with improvement in hypoglycaemia awareness without deterioration in glycaemic control, can be sustained over several years in clinical practice.

Twice- rather than once-daily basal insulin is associated with better glycaemic control in Type 1 diabetes mellitus 12 months after skills-based structured education in insulin self-management.

AIM: This study investigates the relationship between basal insulin regimen and glycaemic outcomes 12 months after skills-based structured education in the UK Dose Adjustment for Normal Eating (DAFNE) programme for Type 1 diabetes mellitus. METHOD: Retrospective analysis of data from 892 DAFNE participants from 11 UK centres. RESULTS: Mean HbA1c 12 months after DAFNE was lower in those using twice- rather than once-daily basal insulin after correcting for differences in baseline HbA1c , age and duration of diabetes; difference -2 (95% CI -3 to -1) mmol/mol [-0.2 (-0.3 to -0.1)%], P = 0.009. The greatest fall in HbA1c of -5 (-7 to -3) mmol/mol [-0.4 (-0.6 to -0.3)%], P < 0.001 occurred in those with less good baseline control, HbA1c  ≥ 58 mmol/mol, who switched from once- to twice-daily basal insulin. There was no difference in the 12-month HbA1c between users of glargine, detemir and NPH insulin after correcting for other variables. Relative risk of severe hypoglycaemia fell by 76% and ketoacidosis by 63% 12 months after DAFNE. The rate of severe hypoglycaemia fell from 0.82 to 0.23 events/patient year in twice-daily basal insulin users. In the group with greatest fall in HbA1c , the estimated relative risk for severe hypoglycaemia in twice-daily basal insulin users versus once daily at 12 months was 1.72 (0.88-3.36, P = 0.110). CONCLUSION: After structured education in adults with Type 1 diabetes mellitus, use of basal insulin twice rather than once daily was associated with lower HbA1c , independent of insulin type, with significant reductions in severe hypoglycaemia and ketoacidosis in all groups.

Psychosocial aspects of closed- and open-loop insulin delivery: closing the loop in adults with Type 1 diabetes in the home setting.

AIMS: To explore the psychosocial experiences of closed-loop technology and to compare ratings of closed- and open-loop technology for adults with Type 1 diabetes taking part in a randomized crossover study. METHODS: Adults (aged > 18 years) on insulin pump therapy were recruited to receive a first phase of either real-time continuous glucose monitoring with overnight closed-loop or real-time continuous glucose monitoring alone (open-loop) followed by a second phase of the alternative treatment in random order, at home for 4 weeks, unsupervised. Participants were invited to share their views in semi-structured interviews. The impact of the closed-loop technology, positive and negative aspects of living with the device overnight, along with the hopes and anxieties of the participants, were explored. RESULTS: The participants in the trial were 24 adults with a mean (sd) age of 43 (12) years, of whom 54% were men. The mean (range) interview duration was 26 (12-46) min. Content and thematic analysis showed the following key positive themes: improved blood glucose control (n = 16); reassurance/reduced worry (n = 16); improved overnight control leading to improved daily functioning and diabetes control (n = 16); and improved sleep (n = 8). The key negative themes were: technical difficulties (n = 24); intrusiveness of alarms (n = 13); and size of equipment (n = 7). Of the 24 participant, 20 would recommend the closed-loop technology. CONCLUSIONS: Closed-loop therapy has positive effects when it works in freeing participants from the demands of self-management. The downside was technical difficulties, particularly concerning the pump and 'connectivity', which it is hoped will improve. Future research should continue to explore the acceptability of the closed-loop system as a realistic therapy option, taking account of user concerns as new systems are designed. Failure to do this may reduce the eventual utility of new systems.

Outcomes for adults with type 1 diabetes referred with severe hypoglycaemia and/or referred for islet transplantation to a specialist hypoglycaemia service.

Islet transplantation alone (ITA) is indicated for patients with type 1 diabetes (T1D) with disabling severe hypoglycaemia (SH) despite optimised medical therapy. We examined outcomes for patients referred to an islet transplant unit with recurrent SH. Retrospective case note audit of 45 patients with ≥1 SH per year who were referred to our ITA unit between 2009-2012; 36 patients attended follow-up appointments. The cohort was 52.8% male, mean (± SD) age 43.9 (± 11.4) years, and duration of diabetes 26.5 (± 12.9) years. Baseline HbA1c was 8.3% (± 1.7) (67.2 mmol/mol), median (IQR) frequency of SH was 6.0 (2.0-24.0) per/patient/year and 83.3% had impaired awareness of hypoglycaemia (IAH). 80.6% of patients were referred from other secondary diabetes services, 22.2% had completed structured education, and 30.6% were using continuous subcutaneous insulin infusion (CSII). Seventeen patients were optimised with conventional therapy; SH reduced from 2.0 (1.5-9.0) to 0.0 (0.0-0.5) episodes/patient/year; p<0.001, and there was concurrent improvement in HbA1c (8.1-7.7%; 65.0 vs. 60.7 mmol/mol; p=0.072). Ten patients were listed for transplantation as they were not optimised despite structured education, CSII, and continuous glucose monitoring (CGM). The remaining 9 had a reduction in SH [7.0 (4.8-40.5) to 4.0 (2.5-6.3) episodes/patient/year; p=0.058] and either left the service (n=5) or are still being optimised (n=4). In conclusion, 47.2% of patients presenting with problematic hypoglycaemia resolved with optimal medical therapy, with a further 25% achieving clinically relevant improvement, however 27.8% required transplantation despite access to all therapies. Provision of expertise in hypoglycaemia management is essential to focus limited transplant resources on those who need it most.

Modification of human islet preparation: an effective approach to improve graft outcome after islet transplantation?

Revascularisation of transplanted islets is an essential prerequisite for graft survival and function. However, current islet isolation procedures deprive the islets of endothelial tubulets. This may have a detrimental effect on the revascularisation process of islets following transplantation. We hypothesise that modification of the isolation procedure that preserves islet endothelial vessels may improve the islet revascularisation process following transplantation. Here, we present a modified islet isolation method by which a substantial amount of endothelial cells still attached to the islets could be preserved. The islets with preserved endothelial cells isolated by this method were revascularised within 3 days, not observed in islets isolated by standard methods. Further, we observed that grafts of islets isolated by standard methods had more patches of dead tissue than islet grafts obtained by the modified method, indicating that attached endothelial cells may play an important role in the islet revascularisation process and potentially help to improve the transplantation outcome.

Unsupervised home use of an overnight closed-loop system over 3-4 weeks: a pooled analysis of randomized controlled studies in adults and adolescents with type 1 diabetes.

AIMS: To compare overnight closed-loop and sensor-augmented pump therapy in patients with type 1 diabetes by combining data collected during free-living unsupervised randomized crossover home studies. METHODS: A total of 40 participants with type 1 diabetes, of whom 24 were adults [mean ± standard deviation (s.d.) age 43 ± 12 years and glycated haemoglobin (HbA1c) 8.0 ± 0.9%] and 16 were adolescents (mean ± s.d. age 15.6 ± 3.6 years and HbA1c 8.1 ± 0.8%), underwent two periods of sensor-augmented pump therapy in the home setting, in combination with or without an overnight closed-loop insulin delivery system that uses a model predictive control algorithm to direct insulin delivery. The order of the two interventions was random; each period lasted 4 weeks in adults and 3 weeks in adolescents. The primary outcome was time during which sensor glucose readings were in the target range of 3.9-8.0 mmol/l. RESULTS: The proportion of time when sensor glucose was in the target range (3.9-8.0 mmol/l) overnight (between 24:00 and 08:00 hours) was 18.5% greater during closed-loop insulin delivery than during sensor-augmented therapy (p < 0.001). Closed-loop therapy significantly reduced mean overnight glucose levels by 0.9 mmol/l (p < 0.001), with no difference in glycaemic variability, as measured by the standard deviation of sensor glucose. Time spent above the target range was reduced (p = 0.001), as was time spent in hypoglycaemia (<3.9 mmol/l; p = 0.014) during closed-loop therapy. Lower mean overnight glucose levels during closed-loop therapy were brought about by increased overnight insulin delivery (p < 0.001) without changes to the total daily delivery (p = 0.84). CONCLUSION: Overnight closed-loop insulin therapy at home in adults and adolescents with type 1 diabetes is feasible, showing improvements in glucose control and reducing the risk of nocturnal hypoglycaemia.

Ageing diminishes the modulation of human brain responses to visual food cues by meal ingestion.

BACKGROUND/OBJECTIVES: Rates of obesity are greatest in middle age. Obesity is associated with altered activity of brain networks sensing food-related stimuli and internal signals of energy balance, which modulate eating behaviour. The impact of healthy mid-life ageing on these processes has not been characterised. We therefore aimed to investigate changes in brain responses to food cues, and the modulatory effect of meal ingestion on such evoked neural activity, from young adulthood to middle age. SUBJECTS/METHODS: Twenty-four healthy, right-handed subjects, aged 19.5-52.6 years, were studied on separate days after an overnight fast, randomly receiving 50 ml water or 554 kcal mixed meal before functional brain magnetic resonance imaging while viewing visual food cues. RESULTS: Across the group, meal ingestion reduced food cue-evoked activity of amygdala, putamen, insula and thalamus, and increased activity in precuneus and bilateral parietal cortex. Corrected for body mass index, ageing was associated with decreasing food cue-evoked activation of right dorsolateral prefrontal cortex (DLPFC) and precuneus, and increasing activation of left ventrolateral prefrontal cortex (VLPFC), bilateral temporal lobe and posterior cingulate in the fasted state. Ageing was also positively associated with the difference in food cue-evoked activation between fed and fasted states in the right DLPFC, bilateral amygdala and striatum, and negatively associated with that of the left orbitofrontal cortex and VLPFC, superior frontal gyrus, left middle and temporal gyri, posterior cingulate and precuneus. There was an overall tendency towards decreasing modulatory effects of prior meal ingestion on food cue-evoked regional brain activity with increasing age. CONCLUSIONS: Healthy ageing to middle age is associated with diminishing sensitivity to meal ingestion of visual food cue-evoked activity in brain regions that represent the salience of food and direct food-associated behaviour. Reduced satiety sensing may have a role in the greater risk of obesity in middle age.

Severe hypoglycaemia in type 1 diabetes mellitus: underlying drivers and potential strategies for successful prevention.

Hypoglycaemia remains an over-riding factor limiting optimal glycaemic control in type 1 diabetes. Severe hypoglycaemia is prevalent in almost half of those with long-duration diabetes and is one of the most feared diabetes-related complications. In this review, we present an overview of the increasing body of literature seeking to elucidate the underlying pathophysiology of severe hypoglycaemia and the limited evidence behind the strategies employed to prevent episodes. Drivers of severe hypoglycaemia including impaired counter-regulation, hypoglycaemia-associated autonomic failure, psychosocial and behavioural factors and neuroimaging correlates are discussed. Treatment strategies encompassing structured education, insulin analogue regimens, continuous subcutaneous insulin infusion pumps, continuous glucose sensing and beta-cell replacement therapies have been employed, yet there is little randomized controlled trial evidence demonstrating effectiveness of new technologies in reducing severe hypoglycaemia. Optimally designed interventional trials evaluating these existing technologies and using modern methods of teaching patients flexible insulin use within structured education programmes with the specific goal of preventing severe hypoglycaemia are required. Individuals at high risk need to be monitored with meticulous collection of data on awareness, as well as frequency and severity of all hypoglycaemic episodes.