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Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) containing the additional excipients niacinamide and L-arginine. The improved pharmacological profile and greater early glucose-lowering action of faster aspart compared with IAsp suggests that faster aspart may be advantageous for people with diabetes using continuous subcutaneous insulin infusion (CSII). The recent onset 5 trial was the first to evaluate the efficacy and safety of an ultra-fast-acting insulin in CSII therapy in a large number of participants with type 1 diabetes (T1D). Non-inferiority of faster aspart to IAsp in terms of change from baseline in HbA1c was confirmed, with an estimated treatment difference (ETD) of 0.09% (95% CI, 0.01; 0.17; P < 0.001 for non-inferiority [0.4% margin]). Faster aspart was superior to IAsp in terms of change from baseline in 1-hour post-prandial glucose (PPG) increment after a meal test (ETD [95% CI], -0.91 mmol/L [-1.43; -0.39]; P = 0.001), with statistically significant improvements also at 30 minutes and 2 hours. The overall rate of severe or blood glucose-confirmed hypoglycaemia was not statistically significantly different between treatments, with an estimated rate ratio of 1.00 (95% CI, 0.85; 1.16). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and the 4-week run-in periods (4 vs 0). Experience from clinical practice indicates that all pump settings should be reviewed when initiating faster aspart with CSII, and that the use of continuous glucose monitoring or flash glucose monitoring, along with a good understanding of meal content and bolus type, may also facilitate optimal use. This review summarizes the available clinical evidence for faster aspart administered via CSII and highlights practical considerations based on clinical experience that may help healthcare providers and individuals with T1D successfully initiate and adjust faster aspart with CSII. ispartof: DIABETES OBESITY & METABOLISM vol:21 issue:9 pages:2039-2047 ispartof: location:England status: published

The current literature credits Keech and Creech with the first report of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in 1997. Here we discuss what we consider is the first ever description of BIA-ALCL, a recently recognized entity by the WHO. We unearthed the description of a patient that was diagnosed with primary effusion lymphoma (PEL), surrounding a breast implant in 1996. In light of the current state of knowledge, we evaluated the evidence presented in 1996 and consider that BIA-ALCL is a more appropriate diagnosis rather than PEL. We base our proposal on the following features: 1). clinical presentation of effusion around a breast implant, 2). occurring in an HIV negative patient, 3). absence of EBV co-infection, and 4). a historically questionable demonstration of HHV8. In effect we further support that HHV8 is not related with BIA-ALCL based on the following facts: 1). An extensive review of the literature did not disclose a similar case in the next 24 years, 2). Use of state of the art HHV8 by immunohistochemistry did not disclose any positive case among 30 randomly tested cases. We believe this matter is of importance because in the current WHO, the assertion that PEL is a possible complication of breast implants may lead to a diagnosis with poor prognosis and susceptible of morbidity related with aggressive therapy, in contrast with BIA-ALCL that can be cured with surgery alone.

International audience; Aim: To evaluate the efficacy and safety of fast-acting insulin aspart (faster aspart) vs insulin aspart (IAsp) used in continuous subcutaneous insulin infusion (CSII) in participants with type 1 diabetes (T1D).Materials and methods: This was a double-blind, treat-to-target, randomized, 16-week trial investigating CSII treatment with faster aspart (n = 236) or IAsp (n = 236). All available information, regardless of treatment discontinuation, was used for the evaluation of effect.Results: Faster aspart was non-inferior to IAsp regarding the change from baseline in glycated haemoglobin (HbA1c; primary endpoint). The mean HbA1c changed from 58.4 mmol/mol (7.5%) at baseline to 57.8 mmol/mol (7.4%) with faster aspart and to 56.8 mmol/mol (7.4%) with IAsp after 16 weeks' treatment, with an estimated treatment difference (ETD) of 1.0 mmol/mol (95% confidence interval [CI] 0.14; 1.87) or 0.09% (95% CI 0.01; 0.17; P < 0.001) for non-inferiority (0.4% margin; P < 0.02 for statistical significance in favour of IAsp). Faster aspart was superior to IAsp in change from baseline in 1-hour postprandial glucose (PPG) increment after a meal test (ETD -0.91 mmol/L [95% CI -1.43; -0.39] or -16.4 mg/dL [95% CI -25.7; -7.0]; P = 0.001), with statistically significant reductions also at 30 minutes and 2 hours. The improvement in PPG was reflected in the change from baseline in 1-hour interstitial glucose increment after all meals (ETD -0.21 mmol/L [95% CI -0.31; -0.11] or -3.77 mg/dL [95% CI -5.53; -2.01]). There was no statistically significant difference in the overall rate of severe or blood glucose-confirmed hypoglycaemia (estimated rate ratio 1.00 [95% CI 0.85; 1.16]). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and 4-week run-in periods (4 vs 0).Conclusions: Faster aspart provides an effective and safe option for CSII treatment in T1D.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Human health courses at universities are facing different challenges to provide students with real laboratory experiences due to the combination of large course cohorts with a shortage of academic staff, resources and time. Future health professionals are encouraged to have a complete understanding of human anatomy and histology as well as to have some pathology and diagnostic skills including the necessary skills to use a microscope. However, students often find learning histology challenging as they usually need to learn how to use a microscope in a limited time during a practical timetabled with several peers, in which they are also required to undertake other activities such as tissue embedding, cutting and staining. To address these factors, different web-based resources have been made available to enhance learning of anatomy and histology, however they are directed to medical students so their use by non-medical students (e.g. pharmacy, biomedical science, nursing, etc.) is limited due to their complexity. As a result, De Montfort University (DMU, UK) is leading an international project to develop an on-line package for teaching and learning biology, named DMU e-Biology, which will cover not only the foundation but also the latest scientific knowledge on human biology. This novel resource is also equipped with a Virtual Microscope and a Virtual Laboratory. The Virtual Laboratory will present different subsections with a range of units regarding biomedical techniques and equipment, which will be developed following previous successful experience from the team. Units will be highly engaging and will contain short videos of academics and/or technicians working hands-on with equipment and/or techniques shown to bring the laboratory to the student’s house. Videos will be enhanced with audio and subtitles in English and the user will be able to complete a series of voluntary self-assessments throughout each unit to enhance engagement and self-assessment by providing the user with tools to evaluate their acquisition of knowledge. A subsection will cover all the elements to perform routine histological techniques in a biomedical laboratory, including the use and practicalities of the microtome, how to perform paraffin embedding and tissue sampling, and common staining techniques such as haematoxylin & eosin (H&E) and periodic acid–Schiff stain (PAS). The histology section will be publicly available from the DMU website in 2018 here http://parasitology.dmu.ac.uk/ebiology/biologyLaboratory_units.htm. Additionally, this resource is supported by a virtual microscope in which the user will be able to explore a library of virtual histological slides from different human tissues and organs; the virtual microscope will transfer the practicalities of a microscope to study human histology. These resources will be tested with first year BSc Biomedical Science and BMedSci Medical Science students enrolled in the module Basic Anatomy and Physiology at DMU by implementing blended learning, i.e. a pedagogy that integrates e-learning resources and materials with formal teaching (lectures, workshops and practicals), as different studies have pointed out that this pedagogy can enhance self-learning and facilitate acquisition of knowledge and long-term retention of information. This paper will provide a description of these novel resources and explore their practicalities with non-medical science students.

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.

BACKGROUND. Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic β cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs. METHODS. DILfrequency is a nonrandomized, open-label, response-adaptive study of participants, aged 18–70 years, with T1D. The initial learning phase allocated 12 participants to 6 different predefined regimens. Then, 3 cohorts of 8 participants were sequentially allocated dose frequencies, based on repeated interim analyses of all accumulated trial data. The coprimary endpoints were percentage change in Tregs and Teffs and CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. RESULTS. Thirty-eight participants were enrolled, with thirty-six completing treatment. The optimal regimen to maintain a steady-state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI –0.007 to 0.485) every 3 days. Tregs and CD25 were dose-frequency responsive, Teffs were not. The commonest adverse event was injection site reaction (464 of 694 events). CONCLUSIONS. Using a response-adaptive design, aldesleukin treatment can be optimized. Our methodology can generally be employed to immediately access proof of mechanism, thereby leading to more efficient and safe drug development. TRIAL REGISTRATION. International Standard Randomised Controlled Trial Number Register, ISRCTN40319192; ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02265809","term_id":"NCT02265809"}}NCT02265809. FUNDING. Sir Jules Thorn Trust, the Swiss National Science Foundation, Wellcome, JDRF, and NIHR Cambridge Biomedical Research Centre.

Objective: The cardiotocograph (CTG) or electronic fetal monitoring (EFM) was developed to prevent fetal asphyxia and subsequent neurological injury. From a public health perspective, it has failed these objectives while increasing emergency operative deliveries (emergency operative deliveries (EODs) – emergency cesarean delivery or operative vaginal delivery) for newborns, who in retrospect, actually did not require the assistance. EODs increase the risks of complications and stress for patients, families, and medical personnel. A safe reduction in the need for EOD will likely reduce both the overall Cesarean section rate as well as the risk of fetal neurological injury during labor to which it is related. We have developed the fetal reserve index (FRI), which is more comprehensive than CTG as a new screening method for early identification of the fetus at-risk of both neurological harm and the need to “rescue” by means of an EOD. Here, we compare prospectively the need for EOD in two groups of parturients undergoing a trial of labor at term. One group was managed conventionally, the other by the principles of the FRI. Study design: We compared the need for EOD of 800 parturients with singleton cases undergoing a trial of labor at term entering with normal CTG patterns (ACOG category 1). Patients were either treated routinely (400 – “early cases”) or in a second group seen later actively managed using the principles of the FRI (400 – “late cases”). The FRI includes measurements of five components of the CTG: rate, variability, decelerations, accelerations, and abnormal uterine activity combined with the presence of medical, obstetrical, and fetal risk factors. The 8-point metric categorizes cases as “green”, “yellow”, and “red” with the latter being at risk. Results: All 800 patients delivered babies, who were discharged in the usual time course with no untoward outcomes noted. The incidence of red zone scores was comparable in the two groups (≈25%), but the use of intrauterine resuscitation (IR) when reaching the red zone in the late group (47%) was more than double the incidence in the early group (20%) (p p 1 h in the red zone versus 0.5 h for non-EODs. Conclusions: The FRI may provide a metric to reduce EODs and by extension also reduce the risks of both cesarean delivery and adverse fetal/neonatal outcomes. The safe avoidance of EOD would seem to be an important metric to assess the quality of intrapartum management. This study represents the first attempt to apply the principles of the FRI “live” for the concurrent management of patients during labor. These promising results, if confirmed, in larger sample sizes, set the stage for our computerization of the FRI for widespread study. Benefits appear to come from identification and early, conservative management of fetal deterioration before the need to “rescue” the fetus by EOD.

Electronic fetal monitoring (EFM) is a poor predictor of outcomes attributable to delivery problems. Contextualizing EFM by adding maternal, obstetrical, and fetal risk-related information to create an index called the Fetal Reserve Index (FRI) improves the predictive capacity and facilitates the timing of interventions. Here, we test critical assumptions of FRI as a clinical tool. Our conceptualization implies that the earlier one reaches the red zone (FRI ≤25) and the longer one spends in the red zone, the greater the likelihood of emergency operative deliveries (EOD). Methods: We analyzed 1,402 patients using logistic regression predicting the probability of EOD and employed qualitative methodology techniques to refine predictive capabilities. Results: Reaching the red zone early and staying there > 1 h increases the probability of EOD. When these risk factors are paired with intrauterine resuscitation (IR) in Stage 1, the reduction of EOD is substantial. Conclusion: FRI is a capable predictor of EOD because it accurately identifies the level of malleable risk. FRI analysis increases the risk of using IR in Stage 1. Matching risk and resources dramatically reduces the chances of EOD. Earlier IR improves the outcomes if the calculated risk is high.

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

An international innovative teaching group from different EU Universities (De Montfort University, Leicester, UK; University of San Pablo CEU, Madrid, Spain; University of Miguel Hernandez, Elche, Spain) and biomedical scientists registered by the Health and Care Professions Council (HCPC, UK) are developing a complete e-learning package in medical parasitology for undergraduate and postgraduate students that study Health Sciences. This package, named DMU e-Parasitology, is accessible through the DMU website (http://parasitology.dmu.ac.uk) and will present different modules including a virtual laboratory module for the study of traditional and novel biomedical laboratory techniques and equipment for detecting, identifying and studying human pathogens, specifically parasites. These techniques could also be potentially used to study other pathogens such as bacteria or viruses. The virtual biomedical laboratory is under development, but is available in the DMU website here: http://parasitology.dmu.ac.uk/learn/laboratory.htm. To develop this new module of the DMU e-Parasitology, we are using Storyline 360 software and the scaffolding and methods used to build the theoretical module (Peña-Fernández et al., 2017) [1]. To facilitate the navigation, study and comprehension of the final user, we have divided the virtual laboratory into a series of sub-sections that include different units; the sub-sections so far are: microscopes (with units such as the electron microscope); molecular biology (e.g. polymerase chain reaction and gel electrophoresis); biological safety cabinets and cell/parasite culture; biochemical and immunological techniques (e.g. magnetic immunoseparation); histology (e.g. microtome) and staining techniques (e.g. Kinyoun staining). The virtual laboratory units are highly interactive and present short videos of academics and/or technicians working in real conditions with the different laboratory equipment such as a thermocycler, a microtome, or a biological safety cabinet, as well as performing a specific technique such as a staining to determine pathogens. Therefore, the user of this virtual environment will receive a complete and “real” experience of the work in a biomedical laboratory. The DMU e-Parasitology package, and specifically its virtual laboratory environment, could help technicians and students across the world to learn how to work in a biomedical laboratory as well as to perform techniques to identify and diagnose human pathogens such as microsporidia or Plasmodium spp. Thus, the virtual resource is supported by a virtual library that includes a real collection of clinical slides that will provide the user with the functionality of a light and/or an immunofluorescence microscope. In conclusion, the virtual laboratory may serve as a high quality and reliable on-line environment for the learning of techniques and equipment. These resources can be used to improve the learning of undergraduate and postgraduate students of human health sciences as well as to develop CPD training. Moreover, the virtual laboratory module may impact in the teaching of laboratory techniques and skills in developing countries due to their limited resources. This communication will explore the design and development of the virtual laboratory environment that will be publicly accessible by the end of 2018.

Aim: To examine the impact of different types of insulin pumps (CSII) on HbA1c lowering control in a large UK type 1 diabetes practice. Methods: Observational retrospective study of electronic database. We identified 597 adults (≥18 years) in our service who started on CSII between 2002 and 2017 with HbA1c data available at baseline and at 6 +/or 12 months after starting CSII. We classified by the starting pump model/manufacturer into traditional “tethered pumps” (Medtronic n=369; Roche n=79; Animas n=60) and “small pumps” (Omnipod n=79 and Cellnovo n=6). We examined change in HbA1c data (shown here in mmol/mol except where otherwise indicated) over the first year of CSII treatment. Results: In general, CSII improved HbA1c during the first 12 months (72±0.7 to 64±0.6 and 65±0.6 mmol/mol at baseline, 6 and 12 months). Despite similar starting HbA1c, those using tethered pumps achieved a significantly lower HbA1c compared with small pump users after 6 and 12 months CSII therapy. Conclusions: In real world data from a large pump service, we found significant differences in glycemic outcomes between different pumps. Those starting on tethered pumps had greater HbA1c lowering over first 12 months.HbA1c Outcomes for Tethered vs small PumpsPump typeInitial HbA1c range mol/mol (%)Baseline HbA1c6 months HbA1cp vs baseline12 months HbA1cp vs baselineTethered (n=509)All starting values71±0.763±0.6* Disclosure S.D. De Soysa: None. J. Grey: None. K.H. Davenport: Advisory Panel; Self; Novo Nordisk Inc. E.M. Gurnell: Advisory Panel; Spouse/Partner; AstraZeneca, Pfizer Inc. S. Hartnell: Speaker's Bureau; Self; Medtronic, Roche Pharma. M. Evans: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company, Cellnovo, Roche Pharma. Speaker's Bureau; Self; Abbott, Novo Nordisk A/S.

Despite being an established marker of glucose control, HbA1c does not provide insight into hypoglycemia and glycemic variability. As such, HbA1c does not capture these vital attributes of particular interest during closed-loop insulin delivery (CL). We developed a novel index using continuous glucose monitoring (CGM) data, named composite glucose index (COGI), which evaluates CL performance based on 3 key aspects: time in range 70-180mg/dl, hypoglycemia Disclosure H. Thabit: None. L. Leelarathna: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc.. Advisory Panel; Self; Roche Diabetes Care Health and Digital Solutions, Abbott. M.E. Wilinska: None. C. Benesch: None. S. Arnolds: None. J.K. Mader: Speaker's Bureau; Self; Roche Diabetes Care Health and Digital Solutions, Novo Nordisk A/S. Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Becton, Dickinson and Company. Speaker's Bureau; Self; Sanofi. Research Support; Self; ConvaTec Inc., Menarini Group. Speaker's Bureau; Self; Medtronic. Research Support; Self; Novo Nordisk A/S, Sanofi. T.R. Pieber: Consultant; Self; Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Employee; Self; CBmed. Research Support; Self; Novo Nordisk A/S, AstraZeneca. M. Evans: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company, Cellnovo, Roche Pharma. Speaker's Bureau; Self; Abbott, Novo Nordisk A/S. R. Hovorka: Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, AstraZeneca. Other Relationship; Self; B. Braun Medical Inc.. Research Support; Self; Medtronic. Other Relationship; Self; Medtronic. Research Support; Self; Abbott, JDRF, Diabetes UK, National Institute of Diabetes and Digestive and Kidney Diseases.

Following the recent communication from the European Societies of Toxicology (EUROTOX) advising that toxicology training and expertise is being eroded in the European Union, we have reviewed the teaching status of this subject in all the bioscience undergraduate courses offered at De Montfort University (DMU, UK). The courses reviewed were: Biomedical Science, Health and Wellbeing in Society, Speech and Language Therapy, Medical Science, Pharmaceutical and Cosmetic Science, Forensic Science and Pharmacy. None of these courses dedicate a complete module to the study of toxicology although they teach some aspects of toxicology following the subject-specific threshold standards described by the UK Quality Assurance Agency for Higher Education. Similar results are found in other UK Universities, although a comprehensive study on the status of toxicology teaching is needed. We have not found any undergraduate courses currently offered in the UK that contained the word “toxicology” in their title. These results are in agreement with EUROTOX, which indicated that toxicology has been generally integrated into other bioscience disciplines and is mainly offered as part of a taught postgraduate degree programme in Europe. Owing to these observations, our teaching group is performing different strategies to enhance the teaching of toxicology at DMU as we consider that the learning of this science is critically important to enable future health professionals to protect human health. These strategies included the development of specialised teaching/workshop sessions in toxicology that can be easily included in any undergraduate bioscience module. Thus, during 2016/17 we collected comprehensive feedback (during an Erasmus+ mobility grant for academics) from human health students about their views on the teaching of toxicology and one of the specialised workshops in a programme that does not offer a module in toxicology (BMedSci Medical Science, DMU) and one that does (MPharm. Pharmacy, University of San Pablo CEU, Spain). A high proportion of the students consulted requested more teaching of toxicology or the introduction of more specialised toxicology in their programmes. Thus, 85% of second year BMedSci students indicated that they would like to receive more toxicology training. Also, 42.9% (57.1% neither agree nor disagree) of fourth year MPharm. students suggested the incorporation of specialised environmental toxicology workshops within their course and all of them considered the environmental toxicology training relevant to their general toxicology module. Other strategies implemented include the enhancement of research in toxicology in our university by offering final projects on these topics to undergraduate and postgraduate students, as well as completion of PhDs. Finally, DMU has recently recruited two toxicologists as academic staff, allowing us to promote the teaching/research of toxicology as well as exploring the possibility of developing postgraduate content for the teaching of toxicology. More efforts should be considered to enhance the teaching of this subject in any bioscience programme, as the current status of toxicology in the UK has been eroded.

Automated fully closed-loop (CL) insulin delivery system without meal-bolusing was evaluated in medical and surgical non-critical care wards of two acute hospitals in Switzerland and United Kingdom. In a randomised controlled parallel design study, 136 adults with inpatient hyperglycaemia requiring subcutaneous (s/c) insulin were randomised to receive either CL-directed s/c insulin delivery (n=70) or conventional s/c insulin therapy as per local practice with masked continuous glucose monitoring (n=66) for up to 15-days. Participants consumed self-selected hospital meals and were matched for age (68±10 vs. 67±13 years; CL vs. control), HbA1c (7.8±2.5 vs. 8.0±1.9%) and BMI (32.7±8.2 vs. 32.3±8.1kg/m2). During CL, participant’s usual insulin and sulphonylurea therapy were withheld. In an intention to treat analysis, the proportion of time when sensor glucose was in target range from 5.6 to 10.0mmol/l was significantly higher during CL (p In conclusion, fully closed-loop without meal-bolusing is safe, and may improve glucose control in a heterogeneous inpatient population.Closed-loop insulin delivery (n=70)Conventional insulin therapy (n=66)PTime spent at sensor glucose levels (%)5.6 to 10.0 mmol/l65.7±16.841.5±16.910.0 mmol/l23.7±16.649.5±22.8 Disclosure L. Bally: None. H. Thabit: None. S. Hartnell: Speaker’s Bureau; Self; Medtronic, Roche Pharma. E. Andereggen: None. Y. Ruan: None. M.E. Wilinska: None. M. Evans: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company, Cellnovo, Roche Pharma. Speaker’s Bureau; Self; Abbott, Novo Nordisk A/S. M.M. Wertli: None. A.P. Coll: None. C. Stettler: None. R. Hovorka: Speaker’s Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company, AstraZeneca. Other Relationship; Self; B. Braun Medical Inc.. Research Support; Self; Medtronic. Other Relationship; Self; Medtronic. Research Support; Self; Abbott, JDRF, Diabetes UK, National Institute of Diabetes and Digestive and Kidney Diseases.

Presently, no single index exists that summarizes key aspects of continuous glucose monitoring (CGM) data. Such an index may be useful in evaluating outcomes in closed-loop (CL) as well as other novel diabetes technology studies utilizing CGM. Here we present a novel composite glucose index (COGI), encompassing three key elements of CGM (Table). The total index ranges from 0 to 100, where 100 approximates glucose profile of people without diabetes. One percent reduction of time Disclosure L. Leelarathna: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc.. Advisory Panel; Self; Roche Diabetes Care Health and Digital Solutions, Abbott. H. Thabit: None. L. Bally: None. M.E. Wilinska: None. J.K. Mader: Speaker's Bureau; Self; Roche Diabetes Care Health and Digital Solutions, Novo Nordisk A/S. Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Becton, Dickinson and Company. Speaker's Bureau; Self; Sanofi. Research Support; Self; ConvaTec Inc., Menarini Group. Speaker's Bureau; Self; Medtronic. Research Support; Self; Novo Nordisk A/S, Sanofi. T.R. Pieber: Consultant; Self; Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Employee; Self; CBmed. Research Support; Self; Novo Nordisk A/S, AstraZeneca. M. Evans: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company, Cellnovo, Roche Pharma. Speaker's Bureau; Self; Abbott, Novo Nordisk A/S. R. Hovorka: Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, AstraZeneca. Other Relationship; Self; B. Braun Medical Inc.. Research Support; Self; Medtronic. Other Relationship; Self; Medtronic. Research Support; Self; Abbott, JDRF, Diabetes UK, National Institute of Diabetes and Digestive and Kidney Diseases.

Astrocytes are involved in non-cell-autonomous pathogenic cascades in amyotrophic lateral sclerosis (ALS); however, their role is still debated. We show that astrocytic NF-κB activation drives microglial proliferation and leukocyte infiltration in the SOD1 (G93A) ALS model. This response prolongs the presymptomatic phase, delaying muscle denervation and decreasing disease burden, but turns detrimental in the symptomatic phase, accelerating disease progression. The transition corresponds to a shift in the microglial phenotype showing two effects that can be dissociated by temporally controlling NF-κB activation. While NF-κB activation in astrocytes induced a Wnt-dependent microglial proliferation in the presymptomatic phase with neuroprotective effects on motoneurons, in later stage, astrocyte NF-κB-dependent microglial activation caused an accelerated disease progression. Notably, suppression of the early microglial response by CB ₂ R agonists had acute detrimental effects. These data identify astrocytes as important regulators of microglia expansion and immune response. Therefore, stage-dependent microglia modulation may be an effective therapeutic strategy in ALS.

Aims/hypothesis Women with diabetes remain at increased risk of adverse pregnancy outcomes associated with poor pregnancy preparation. However, women with type 2 diabetes are less aware of and less likely to access pre-pregnancy care (PPC) compared with women with type 1 diabetes. We developed and evaluated a community-based PPC programme with the aim of improving pregnancy preparation in all women with pregestational diabetes. Methods This was a prospective cohort study comparing pregnancy preparation measures before and during/after the PPC intervention in women with pre-existing diabetes from 1 June 2013 to 28 February 2017. The setting was 422 primary care practices and ten National Health Service specialist antenatal diabetes clinics. A multifaceted approach was taken to engage women with diabetes and community healthcare teams. This included identifying and sending PPC information leaflets to all eligible women, electronic preconception care templates, online education modules and resources, and regional meetings and educational events. Key outcomes were preconception folic acid supplementation, maternal HbA1c level, use of potentially harmful medications at conception and gestational age at first presentation, before and during/after the PPC programme. Results A total of 306 (73%) primary care practices actively participated in the PPC programme. Primary care databases were used to identify 5075 women with diabetes aged 18–45 years. PPC leaflets were provided to 4558 (89.8%) eligible women. There were 842 consecutive pregnancies in women with diabetes: 502 before and 340 during/after the PPC intervention. During/after the PPC intervention, pregnant women with type 2 diabetes were more likely to achieve target HbA1c levels ≤48 mmol/mol (6.5%) (44.4% of women before vs 58.5% of women during/after PPC intervention; p = 0.016) and to take 5 mg folic acid daily (23.5% and 41.8%; p = 0.001). There was an almost threefold improvement in ‘optimal’ pregnancy preparation in women with type 2 diabetes (5.8% and 15.1%; p = 0.021). Women with type 1 diabetes presented for earlier antenatal care during/after PPC (54.0% vs 67.3% before 8 weeks’ gestation; p = 0.003) with no other changes. Conclusions/interpretation A pragmatic community-based PPC programme was associated with clinically relevant improvements in pregnancy preparation in women with type 2 diabetes. To our knowledge, this is the first community-based PPC intervention to improve pregnancy preparation for women with type 2 diabetes. Data availability Further details of the data collection methodology, individual clinic data and the full audit reports for healthcare professionals and service users are available from https://digital.nhs.uk/data-and-information/clinical-audits-and-registries/our-clinical-audits-and-registries/national-pregnancy-in-diabetes-audit. Electronic supplementary material The online version of this article (10.1007/s00125-018-4613-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

The last year has seen a continued uptake of insulin pump therapy in most countries. The USA is still a leader in pump use, with probably some 40% of type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII), but the large variation in usage within Europe remains, with relatively high use ( 15%) in, for example, Norway, Austria, Germany and Sweden and low use ( 5%) in Spain, the UK, Finland and Portugal. There is much speculation on the factors responsible for this variation, and the possibilities include physician attitudes to CSII and knowledge about its benefits and indications for its use (and inappropriate beliefs about dangers), the availability of reimbursement from insurance companies or funding from national health services, the availability of sufficient diabetes nurse educators and dietitians trained in pump procedures, and clear referral pathways for the pump candidate from general practitioner or general hospital to specialist pump centre. There are now several comprehensive national guidelines on CSII use (see ATTD Yearbook 2009) but more work needs to be done in unifying uptake and ensuring all those who can benefit do so. Technology developments recently include increasing use of pumps with continuous glucose monitoring (CGM) connectivity (see elsewhere in this volume) and the emergence of numerous manufacturers developing so-called 'patch pumps', often for the type 2 diabetes market. Interestingly, the evidence base for CSII in this group is not well established, and for this reason the selected papers on CSII in this section include several in this area. The use of CSII in diabetic pregnancy is a long-established practice, in spite of the lack of evidence that it is superior to multiple daily injections (MDI), and few randomised controlled trials have been done in recent years. Several papers in this field this year continue the debate about the usefulness of CSII in diabetic pregnancy and are reviewed here. It is pleasing to see more research on the psychosocial aspects of CSII during the year, both from the point of view of how psychological beliefs influence outcomes on CSII (is there a type of patient who does particularly well or poorly on CSII?) and how CSII affects psychological factors like mood, behaviour and quality of life. Quality of life is a difficult topic with doubts that the instruments always capture the aspects of quality of life important to the patient, and there have been conflicting results over the years about whether CSII alters quality of life. Patients in the clinic usually say that it does, and more evidence for quality of life improvement in pump therapy is reviewed here.

BACKGROUND: The feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established. METHODS: In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents. RESULTS: Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P

Objectives: Closed-loop (CL) systems modulate insulin delivery based on glucose levels measured by a continuous glucose monitor (CGM). Accuracy of the CGM affects CL performance and safety. We evaluated the accuracy of the Freestyle Navigator® II CGM (Abbott Diabetes Care, Alameda, CA) during three unsupervised, randomized, open-label, crossover home CL studies.\ud \ud Materials and Methods: Paired CGM and capillary glucose values (10,597 pairs) were collected from 57 participants with type 1 diabetes (41 adults [mean±SD age, 39±12 years; mean±SD hemoglobin A1c, 7.9±0.8%] recruited at five centers and 16 adolescents [mean±SD age, 15.6±3.6 years; mean±SD hemoglobin A1c, 8.1±0.8%] recruited at two centers). Numerical accuracy was assessed by absolute relative difference (ARD) and International Organization for Standardization (ISO) 15197:2013 15/15% limits, and clinical accuracy was assessed by Clarke error grid analysis.\ud \ud Results: Total duration of sensor use was 2,002 days (48,052 h). Overall sensor accuracy for the capillary glucose range (1.1–27.8 mmol/L) showed mean±SD and median (interquartile range) ARD of 14.2±15.5% and 10.0% (4.5%, 18.4%), respectively. Lowest mean ARD was observed in the hyperglycemic range (9.8±8.8%). Over 95% of pairs were in combined Clarke error grid Zones A and B (A, 80.1%, B, 16.2%). Overall, 70.0% of the sensor readings satisfied ISO criteria. Mean ARD was consistent (12.3%; 95% of the values fall within ±3.7%) and not different between participants (P=0.06) within the euglycemic and hyperglycemic range, when CL is actively modulating insulin delivery.\ud \ud Conclusions: Consistent accuracy of the CGM within the euglycemic–hyperglycemic range using the Freestyle Navigator II was observed and supports its use in home CL studies. Our results may contribute toward establishing normative CGM performance criteria for unsupervised home use of CL.

In this paper, I examine the relation between disclosure commitment and cost of equity capital using accelerated earnings announcement disclosures as a measure of commitment. In settings characterized by imperfect market competition, I find that firms which consistently disclose balance sheet detail in relatively timely earnings announcements have lower costs of capital compared to other firms. This result is statistically significant and economically meaningful, and is robust to various alternative measurements for cost of capital, and alternative designs addressing endogeneity and underlying information quality. Overall, this result is important because it highlights additional dimensions of disclosure commitment (consistency and timeliness), while incorporating important features from theoretical models (information quality and market competition). In particular, my results suggest that consistency and timeliness are salient features of firms' disclosure behavior that have predictable and robust relations with capital market outcomes. This result is robust to controlling for underlying information quality; however, consistent with theory, it is conditional on low levels of market competition. [ABSTRACT FROM AUTHOR]

Several isolated reports of fetal goiter treatment have shown limited generalizability of approaches and provide no real guidance for optimal timing, dosages, and treatment strategies. Graves' disease accounts for >60% of these cases. Maternal treatments of hyperthyroidism include antithyroid medications such as methimazole and more commonly propylthiouracil (PTU). Here, our management of a patient with a fetal thyroid goiter from maternal exposure to PTU diagnosed at 23.6 weeks' gestation and the management of other cases allow us propose a general strategy for treatment. Intrauterine therapy with 200 and then 400 μg of levothyroxine (3 weeks apart) showed an 85% reduction in fetal thyroid goiter volume. We collected amniotic fluid samples at the time of treatments and assayed thyroid hormones and associated antibodies which closely reflected the changes in thyroid goiter mass volume. Our observations suggest a weekly or biweekly therapeutic intervention schedule. Utilizing both goiter size as well as a novel approach in using amniotic fluid hormone levels to monitor therapy efficacy might improve the quality of treatments. Only with a standardized approach and collection of amniotic fluid thyroid panels do we have the opportunity to develop the database required to determine the number and timing of treatments needed.

Installation of hydrokinetic power-generating devices is currently being considered for the Yukon and Tanana rivers, two large and glacially turbid rivers in Alaska. We sampled downstream-migrating fish along the margins of both rivers, a middle island in the Yukon River, and mid-channel in the Tanana River in order to assess the temporal and spatial patterns of movement by resident and anadromous fishes and hence the potential for fish interactions with hydrokinetic devices. Results suggest that (1) river margins in the Yukon and Tanana rivers are primarily utilized by resident freshwater species, (2) the mid-channel is utilized by Pacific salmon Oncorhynchus spp. smolts, and (3) only Chum Salmon O. keta smolts utilize both river margin and mid-channel areas. Some species exhibited distinct peaks and trends in downstream migration timing, including Longnose Suckers Catostomus catostomus, whitefishes (Coregoninae), Arctic Grayling Thymallus arcticus, Lake Chub Couesius plumbeus, Chinook Salmon O. ...

Viridans streptococci are a grouping of multiple streptococcal species which do not possess Lancefield antigens, are alpha-hemolytic, and result in infective endocarditis. Despite intensive care with antimicrobial therapy, the mortality has remained high for these infections and post infection squeal. All the pathways of complement system culminate in the formation of C3 convertase enzymes that mediate deposition of C3b on foreign surfaces. The goal of this study, to assay interferes between alkaline protease (AprA) of viridans streptococci and complement activation. Our data found that alkaline protease potently blocked phagocytosis of viridans streptococci by neutrophils the AprA specifically blocked C3b deposition via 2-pathways; the classical and lectin pathways. Serum degradation assays revealed that AprA degrades both human C1s and C2. However, repletion assays demonstrated that the mechanism of action for complement inhibition is cleavage of C2. These results suggest a novel viridans streptococci mechanism, through AprA interferes with complement system pathway activation via cleavage of C2.

The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis. A series of new heterocyclic small-molecule CB2 receptor agonists were identified from a high-throughput screen. Lead optimization gave access to novel, highly potent, and selective (over CB1) triazolopyrimidine derivatives. A preliminary structure-activity relationship was established, and physicochemical properties in this compound class were significantly improved toward better solubility, lipophilicity, and microsomal stability. An optimized triazolopyrimidine derivative, (3S)-1-[5-tert-butyl-3-[(1-cyclopropyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol (39), was tested in a kidney ischemia-reperfusion model, in which it showed efficacy at a dose of 10 mg kg(-1) (p.o.). A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound 39 was also protective in a model of renal fibrosis. Oral treatment with 39 at 3 mg kg(-1) per day significantly decreased the amount of fibrosis by ∼ 40% which was induced by unilateral ureter obstruction.

Two intravenous studies with tanezumab, an anti-nerve growth factor monoclonal antibody, were conducted in pregnant cynomolgus monkeys to assess potential effects on pregnancy and pre- and postnatal development. Study 1 evaluated infants up to 12 months of age following weekly maternal dosing (0, 0.5, 4 or 30 mg/kg; 18 per group) from gestation day (GD) 20 through parturition. Study 2 evaluated infants 2 months postnatally following weekly maternal dosing (0, 0.5 or 30 mg/kg; 20-21 per group) from GD 20 through 48. In the absence of maternal toxicity, tanezumab increased stillbirth and post-birth infant mortality/morbidity, decreased infant growth and resulted in microscopic changes in the peripheral sympathetic and sensory nervous system of the infants at all doses. Decreased primary antibody responses and increased incidences in skin changes in infants were also observed. The no-observed-adverse-effect-level for maternal toxicity was 30 mg/kg and0.5 mg/kg for developmental toxicity.

There have been tremendous advances in the ability to screen for the "odds" of having a genetic disorder (both mendelian and chromosomal). With microarray analyses on fetal tissue now showing a minimum risk for any pregnancy being at least 1 in 150 and ultimately greater than 1%, it is thought that all patients, regardless of age, should be offered chorionic villus sampling/amniocentesis and microarray analysis. As sequencing techniques replace other laboratory methods, the only question will be whether these tests are performed on villi, amniotic fluid cells, or maternal blood.

In states of insulopaenic hyperglycaemia, counter-regulatory hormone (CRH) excess is a driver of ketogenesis and thus diabetic ketoacidosis. We present a case of hyperglycaemic hyperosmolar state in a patient with type 1 diabetes mellitus, associated with a mixed drug overdose including agents with documented CRH suppressive effects. We postulate that the drugs taken in overdose protected against diabetic ketoacidosis, and suggest further investigation of pharmacological therapies aimed at inhibiting CRH responses which may protect against this life-threatening complication in patients with type 1 diabetes. Copyright © 2016 John Wiley & Sons.

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

Objective Dietary proteins are sensed by hypothalamic neurons and strongly influence multiple aspects of metabolic health, including appetite, weight gain, and adiposity. However, little is known about the mechanisms by which hypothalamic neural circuits controlling behavior and metabolism sense protein availability. The aim of this study is to characterize how neurons from the mediobasal hypothalamus respond to a signal of protein availability: the amino acid l-leucine. Methods We used primary cultures of post-weaning murine mediobasal hypothalamic neurons, hypothalamic neurons derived from human induced pluripotent stem cells, and calcium imaging to characterize rapid neuronal responses to physiological changes in extracellular l-Leucine concentration. Results A neurochemically diverse subset of both mouse and human hypothalamic neurons responded rapidly to l-leucine. Consistent with l-leucine's anorexigenic role, we found that 25% of mouse MBH POMC neurons were activated by l-leucine. 10% of MBH NPY neurons were inhibited by l-leucine, and leucine rapidly reduced AGRP secretion, providing a mechanism for the rapid leucine-induced inhibition of foraging behavior in rodents. Surprisingly, none of the candidate mechanisms previously implicated in hypothalamic leucine sensing (KATP channels, mTORC1 signaling, amino-acid decarboxylation) were involved in the acute activity changes produced by l-leucine. Instead, our data indicate that leucine-induced neuronal activation involves a plasma membrane Ca2+ channel, whereas leucine-induced neuronal inhibition is mediated by inhibition of a store-operated Ca2+ current. Conclusions A subset of neurons in the mediobasal hypothalamus rapidly respond to physiological changes in extracellular leucine concentration. Leucine can produce both increases and decreases in neuronal Ca2+ concentrations in a neurochemically-diverse group of neurons, including some POMC and NPY/AGRP neurons. Our data reveal that leucine can signal through novel mechanisms to rapidly affect neuronal activity., Highlights • A neurochemically diverse group of mouse and human hypothalamic neurons rapidly sense and respond to l-leucine. • Leucine can produce neuronal activation or neuronal inhibition via distinct and novel Ca2+ signaling mechanisms. • Leucine activates 25% ARH POMC neurons. • Leucine inhibits 10% ARH NPY/AGRP neurons and reduces AGRP secretion from fasted mediobasal hypothalamic slices.

Even key opinion leaders now concede that electronic fetal monitoring (EFM) cannot reliably identify fetal acidemia which many vouch as the only labor mediated pathophysiologic precursor for cerebral palsy (CP). We have developed the "Fetal Reserve Index" - an algorithm combining five dynamic components of EFM (1. Rate, 2. Variability, 3. Accelerations, 4. Decelerations, and 5. Excessive uterine activity) considered individually that are combined with the presence of: 6. maternal, 7. obstetrical, and 8. fetal risk factors.Here, we compare this 8-point fetal reserve index (FRI) against the performance of ACOG monograph criteria and ACOG Category systems for predicting risk for both CP and the need for emergency operative delivery (EOD). We then studied how varied management for screen positives (Red zone-defined below) impacts the outcome of such cases.Four hundred twenty term patients were studied: all entered labor with normal EFMs and no apparent cause of harm except events of labor and delivery. Sixty subsequently developed CP, and 360 were apparently normal controls. An FRI, normal on all eight parameters scored 100%, 4 of the 8 was 50%, etc. We divided cases into Green zone50%, Yellow 50-26%, and Red ≤25%. An FRI in the Red zone was considered a positive screen. We then compared performance metrics for the three evaluation schemes and differences between controls that reached Red against those controls whose worst scores were Green/Yellow.For detection of injury during labor, the FRI performed much better than the ACOG Category criteria (sensitivity 28%), and Category III (45%) (p .001). All CP cases reached Red zone and were Red for a minimum of 2 hours (mean = 5.35 hours). Twenty-four% of controls reached Red, but were only Red for average of 1 hr. The incidence of low Apgar's, pH, FRI, and Lowest FRI increased progressively from Green/Yellow controls to red controls to CP cases. Irrespective, CP cases met ACOG Monograph criteria for labor injury less than 50% of the time. Only half of CP babies had umbilical artery pH values7.00, and less than 50% showed Category III patterns. The earlier in labor the Red zone was reached, the more likely for a baby to develop CP or the mother to require an EOD regardless of fetal outcome. Successful intrauterine resuscitations (IR) diminished time spent in the Red zone and the need for EODs.FRI shows better discrimination for adverse fetal outcome and EOD than traditional EFM interpretation. The Category system is a very poor, subjective screening method as the vast majority of CP babies never reach the "action point" result of Category III. While reaching the Red zone does not ordain a bad outcome, how it is managed, does. Compared to CP cases, Red controls were delivered faster, had higher FRIs, and often had prompt management including IR maneuvers, which improved the FRI and lowered the risk of EODs even for cases with normal outcomes. With further study and validation, the quantitative FRI approach may replace the current, very subjective interpretation with a quantitative "lab test" approach.

We present a case of unusual cardiac paraganglioma (PG) initially misdiagnosed as atypical carcinoid tumor of the lung and discuss key clinical and pathologic characteristics that guide surgical management of these rare chromaffin cell tumors. A 64-year-old female with persistent cough and back pain was found to have a 4 cm × 3 cm mass abutting multiple cardiopulmonary structures. A biopsy was performed at an outside institution and pathology reported "atypical neuroendocrine carcinoma, consistent with carcinoid". The patient was transferred to our institution and pericardial resection with right pneumonectomy was performed to excise the tumor. Histology of the mass was that of PG with multiple ethanol embolizations. Immunohistochemical examination revealed that type I (chief) cells were positive for neuroendocrine markers (chromogranin A and synaptophysin), while type II (sustentacular) cells were positive for S100. There was no evidence of atypical carcinoid tumor in the lung. PG is an entity of chromaffin cell tumors that often affects the adrenal glands and carotid body. PG rarely occurs in the thoracic region, accounting for just 1-2% of all PG. Proper diagnosis of cardiac PG is challenging owing to its rare prevalence, subtle symptoms of presentation, and the neuroendocrine histopathological features it shares with atypical carcinoids. These tumors are typically benign and are best treated by surgical resection. Our report examines the approach to appropriate diagnosis of cardiac PG vs. atypical carcinoid, preoperative management, and surgical treatment by describing successful resection through thoracotomy without the use of cardiopulmonary bypass.

SummaryBackgroundType 1 diabetes (T1D) results from loss of immune regulation leading to the development of autoimmunity to pancreatic beta-cells, involving autoreactive T effector cells (Teffs). Regulatory T cells (Tregs), that prevent autoimmunity, require Interleukin-2 (IL-2) for maintenance of immunosuppressive functions and, alterations in the IL-2 pathway predispose to T1D. Using an adaptive trial design we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of autoreactive Teffs.MethodsDILfrequency is a single-center, non-randomised, open-label, response-adaptive study of participants aged 18 to 70 years with T1D. The initial learning phase allocated 12 participants to six different predefined dose-frequency regimens. Then, three cohorts of 8 participants were sequentially allocated dose-frequencies, based on repeated interim analyses of all accumulated trial data. The co-primary endpoints were percentage change in Tregs, Teffs and, CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. Trial registration ISRCTN40319192 and ClinicalTrials.gov (NCT02265809).Findings115 participants were assessed between November 17th 2014 and May 22nd 2016, 38 participants were enrolled with 36 completing treatment. The optimal regimen to maintain a steady state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI (−0.007 to 0.485)) every 3 days (1.3 to 4.4). Tregs and CD25 were dose-frequency responsive, while Teffs were not. The commonest adverse event was injection site reaction (464/694 events), with a single participant developing transient eosinophilia at the highest dose (0.47 × 106 IU/m2).InterpretationThis response-adaptive trial defined a well-tolerated aldesleukin regimen that specifically induces Treg expansion that can now be trialled to treat T1D.FundingSir Jules Thorn Trust, Wellcome, JDRF, SNSF, NIHR

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link The BSc Biomedical Science (BMS) programme at De Montfort University (DMU, Leicester, UK) is accredited by the Institute of Biomedical Science (IBMS). Students enrolled within this programme acquire highly sought after skills related with human health sciences to work in: pathology departments in hospitals; research institutions; biotechnology and pharmaceutical industries; and the education sector to name a few. The degree recruits a large number of students with currently around 600 students enrolled on this programme at DMU. Despite pre-entry requirements of knowledge of subjects related to human biology, biology or chemistry, we have noted that first year students require basic support in STEM subjects (biology, chemistry and mathematics) in modules such as “Basic Microbiology”, “Basic Anatomy and Physiology” and “Chemistry for the Biosciences”. This support is especially necessary for students that come from non-traditional routes such as Business and Technology Education Council (BTEC) routes. Moreover, usually topics related with microbiology and human diseases are challenging for students, often causing stress impacting their overall performance and experience. A group of BMS academics at DMU in conjunction with universities in the European Union (EU; e.g. University of San Pablo CEU, Spain) have started to design, create and develop a series of e-learning resources or units in human biology and BMS for undergraduate students that study health sciences degrees in the EU. These units are being uploaded onto the DMU web server (http://parasitology.dmu.ac.uk/) and will be only accessible for students from participating universities during the first phase of this project (2017/18 course) in which comprehensive feedback will be collected. This web server space has three sections or modules (theoretical section, virtual laboratory and microscope) in which the new e-learning resources will be preliminary accommodated. These units will be interactive and easy to follow, and will cover basic human biology (e.g. cells, cell structure), human anatomy and physiology, histology and basic microbiology, which will be embedded in a theoretical module named DMU e-Biology within the above URL link. They will include formative assessments and case studies throughout each unit. In addition, a series of practical units are being developed which describe routine practical elements in any biomedical laboratory such as laboratory materials, pipetting, molecular techniques (e.g. PCR), cell culture (e.g. use of biological safety cabinet) and histological techniques (e.g. use of microtome, staining techniques). The development of this teaching and learning resource will cover a gap in the traditional teaching and learning methods that are currently used and provided in the participating universities. The DMU e-Biology will aid to our undergraduate students to gain knowledge in human biology and microbiology by promoting self-learning. We consider that the DMU e-Biology will help overcome spatiotemporal, equipment and resource barriers. Additionally, it may help student retention as currently about a 10% of our first year students fail to continue BMS at DMU. Finally, the creation of the DMU e-Biology will also provide support to the DMU Student Retention and Attainment Strategy 2016-2020 through the DMU Student Learning Hub, which is currently under development.

Little is known about the sexual health of male veterans. This study used nationally representative data from the 2011 to 2013 National Survey of Family Growth to compare sexual behaviors and history of sexually transmitted infections (STIs) between male veterans and nonveterans. The sample included 3,860 men aged 18 to 44 years who reported ever having sex with a man or woman. The key independent variable was veteran status. Sexual behavior outcomes included ≥6 lifetime female partners, ≥10 lifetime partners of either sex, ≥2 past-year partners of either sex, having past-year partners of both sexes, and condom nonuse at last vaginal sex. STI outcomes included past-year history of chlamydia, gonorrhea, or receiving any STI treatment; lifetime history of herpes, genital warts, or syphilis; and an aggregate measure capturing any reported STI history. Logistic regression models were used to evaluate associations between veteran status and each outcome. In models adjusting for age, race/ethnicity, education, income, and marital status, veterans had significantly greater odds than nonveterans of having ≥6 lifetime female partners ( OR = 1.5, 95% CI [1.02, 2.31]). In models adjusting for age and marital status, veterans had significantly greater odds of having partners of both sexes in the past year ( OR = 4.8, 95% CI [1.2, 19.8]), and gonorrhea in the past year ( OR = 3.2, 95% CI [1.2, 8.5]). Male veterans were thus significantly more likely than nonveterans to have STI risk factors. Health care providers should be aware that male veterans may be at higher risk for STIs and assess veterans’ sexual risk behaviors.

BackgroundInsulin is generally administered to people with type 1 diabetes mellitus (T1DM) using multiple daily injections (MDIs), but can also be delivered using infusion pumps. In the UK, pumps are recommended for patients with the greatest need and adult use is less than in comparable countries. Previous trials have been small, of short duration and have failed to control for training in insulin adjustment.ObjectiveTo assess the clinical effectiveness and cost-effectiveness of pump therapy compared with MDI for adults with T1DM, with both groups receiving equivalent structured training in flexible insulin therapy.DesignPragmatic, multicentre, open-label, parallel-group cluster randomised controlled trial, including economic and psychosocial evaluations. After participants were assigned a group training course, courses were randomly allocated in pairs to either pump or MDI.SettingEight secondary care diabetes centres in the UK.ParticipantsAdults with T1DM for > 12 months, willing to undertake intensive insulin therapy, with no preference for pump or MDI, or a clinical indication for pumps.InterventionsPump or MDI structured training in flexible insulin therapy, followed up for 2 years. MDI participants used insulin analogues. Pump participants used a Medtronic Paradigm®VeoTM(Medtronic, Watford, UK) with insulin aspart (NovoRapid, Novo Nordisk, Gatwick, UK).Main outcome measuresPrimary outcome – change in glycated haemoglobin (HbA1c) at 2 years in participants whose baseline HbA1cwas ≥ 7.5% (58 mmol/mol). Key secondary outcome – proportion of participants with HbA1c≤ 7.5% at 2 years. Other outcomes at 6, 12 and 24 months – moderate and severe hypoglycaemia; insulin dose; body weight; proteinuria; diabetic ketoacidosis; quality of life (QoL); fear of hypoglycaemia; treatment satisfaction; emotional well-being; qualitative interviews with participants and staff (2 weeks), and participants (6 months); and ICERs in trial and modelled estimates of cost-effectiveness.ResultsWe randomised 46 courses comprising 317 participants: 267 attended a Dose Adjustment For Normal Eating course (132 pump; 135 MDI); 260 were included in the intention-to-treat analysis, of which 235 (119 pump; 116 MDI) had baseline HbA1cof ≥ 7.5%. HbA1cand severe hypoglycaemia improved in both groups. The drop in HbA1c% at 2 years was 0.85 on pump and 0.42 on MDI. The mean difference (MD) in HbA1cchange at 2 years, at which the baseline HbA1cwas ≥ 7.5%, was –0.24% [95% confidence interval (CI) –0.53% to 0.05%] in favour of the pump (p = 0.098). The per-protocol analysis showed a MD in change of –0.36% (95% CI –0.64% to –0.07%) favouring pumps (p = 0.015). Pumps were not cost-effective in the base case and all of the sensitivity analyses. The pump group had greater improvement in diabetes-specific QoL diet restrictions, daily hassle plus treatment satisfaction, statistically significant at 12 and 24 months and supported by qualitative interviews.LimitationBlinding of pump therapy was not possible, although an objective primary outcome was used.ConclusionAdding pump therapy to structured training in flexible insulin therapy did not significantly enhance glycaemic control or psychosocial outcomes in adults with T1DM.Research priorityTo understand why few patients achieve a HbA1cof Trial registrationCurrent Controlled Trials ISRCTN61215213.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 20. See the NIHR Journals Library website for further project information.