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Colorectal cancer (CRC) has one of the highest cancer incidences and mortality rates. In stage III, postoperative chemotherapy benefits

During 1921 to 1922, a team effort by Banting, Macleod, Collip and Best isolated and purified insulin and demonstrated its life-giving properties, giving rise to the birth of insulin therapy. In the early years (1922-1950), priorities revolved around the manufacture of insulin to meet demand, improving purity to avoid allergic reactions, establishing insulin standards and increasing its duration of action to avoid multiple daily injections. Shortly after the emergence of insulin, Joslin and Allen advocated the need to achieve and maintain good glycaemic control to realize its full potential. Although this view was opposed by some during a dark period in the history of insulin, it was subsequently endorsed some 60 years later endorsed by the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study. Major scientific advances by the Nobel Laureates Sanger, Hodgkin, Yalow and Gilbert and also by Steiner have revolutionized the understanding of diabetes and facilitated major advances in insulin therapy. The more recent advent of recombinant technology over the last 40 years has provided the potential for unlimited source of insulin, and the ability to generate various insulin 'analogues', in an attempt to better replicate normal insulin secretory patterns. The emerging biosimilars now provide the opportunity to improve availability at a lower cost.

Aims The two predominant pathophysiological defects resulting in glucose intolerance are beta-cell dysfunction and insulin insensitivity. This study aimed to re-examine beta-cell function and insulin sensitivity across a continuum from normal glucose tolerance (NGT) to early type 2 diabetes (T2DM) employing highly specific insulin, C-peptide and intact proinsulin assays. Materials and methods A total of 104 persons with NGT, 85 with impaired glucose tolerance (IGT) and 554 with newly diagnosed T2DM were investigated. Following an overnight fast, all underwent a 4-h standardised mixed meal tolerance test (MTT), and on a second day, a sub-group underwent a frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT) over a 3-h period. The participants were stratified according to fasting glucose and BMI for analysis. Results The MTT revealed that increasing FPG was accompanied by progressively elevated and delayed postprandial glucose peaks. In parallel, following an initial compensatory increase in fasting and postprandial insulin responses there followed a progressive demise in overall beta-cell secretory capacity. FSIVGTT demonstrated a major reduction in the early insulin response to IV glucose in persons with IGT accompanied by a dramatic fall in insulin sensitivity. Beyond pre-diabetes, ever-increasing fasting and postprandial hyperglycaemia resulted predominantly from a progressively decreasing beta-cell secretory function. Conclusion This study utilising improved assay technology re-affirms that beta-cell dysfunction is evident throughout the spectrum of glucose intolerance, whereas the predominant fall in insulin sensitivity occurs early in its evolution.

This study was designed to examine the effectiveness of an evidence-based parenting program—Triple P Positive Parenting Program—in shelter settings for families experiencing homelessness. The intervention has not previously been evaluated in a shelter setting, where there is a critical need for evidence-based parenting programs. Using a within-group pre- and post-intervention with 3-month follow-up design, 39 mothers residing in a shelter with a child ages 2–6 years participated. Results of this preliminary study showed positive effects of Triple P Discussion Groups. There were significant improvements in mother-reported parenting practices and child behavior across time, but no change in child maltreatment risk as measured by the Brief Child Abuse Potential Inventory. Mothers rated satisfaction with the program high immediately after the group and again three weeks later. Results showed Triple P Discussion Groups are acceptable and have some positive effects for this vulnerable population in need of parenting support. We discuss implications of findings, limitations of the study (including a 33% attrition rate), and recommendations for further study.

The first insulin preparation injected in humans in 1922 was short-acting, extracted from animal pancreas, contaminated by impurities. Ever since the insulin extracted from animal pancreas has been continuously purified, until an unlimited synthesis of regular human insulin (RHI) became possible in the '80s using the recombinant-DNA (rDNA) technique. The rDNA technique then led to the designer insulins (analogs) in the early '90s. Rapid-acting insulin analogs were developed to accelerate the slow subcutaneous (sc) absorption of RHI, thus lowering the 2-h post-prandial plasma glucose (PP-PG) and risk for late hypoglycemia as comparing with RHI. The first rapid-acting analog was lispro (in 1996), soon followed by aspart and glulisine. Rapid-acting analogs are more convenient than RHI: they improve early PP-PG, and 24-h PG and A1C as long as basal insulin is also optimized; they lower the risk of late PP hypoglycemia and they allow a shorter time-interval between injection and meal. Today rapid-acting analogs are the gold standard prandial insulins. Recently, even faster analogs have become available (faster aspart, ultra-rapid lispro) or are being studied (Biochaperone lispro), making additional gains in lowering PP-PG. Rapid-acting analogs are recommended in all those with type 1 and type 2 diabetes who need prandial insulin replacement.

Background Liver cancer (Hepatocellular carcinoma; HCC) prevalence is increasing and with poor clinical outcome expected it means greater understanding of HCC aetiology is urgently required. This study explored a deep learning solution to detect biologically important features that distinguish prognostic subgroups. A novel architecture of an Artificial Neural Network (ANN) trained with a customised objective function (LRSC) was developed. The ANN should discover new data representations, to detect patient subgroups that are biologically homogenous (clustering loss) and similar in survival (survival loss) while removing noise from the data (reconstruction loss). The model was applied to TCGA-HCC multi-omics data and benchmarked against baseline models that only use a reconstruction objective function (BCE, MSE) for learning. With the baseline models, the new features are then filtered based on survival information and used for clustering patients. Different variants of the customised objective function, incorporating only reconstruction and clustering losses (LRC); and reconstruction and survival losses (LRS) were also evaluated. Robust features consistently detected were compared between models and validated in TCGA and LIRI-JP HCC cohorts. Results The combined loss (LRSC) discovered highly significant prognostic subgroups (P-value = 1.55E−77) with more accurate sample assignment (Silhouette scores: 0.59–0.7) compared to baseline models (0.18–0.3). All LRSC bottleneck features (N = 100) were significant for survival, compared to only 11–21 for baseline models. Prognostic subgroups were not explained by disease grade or risk factors. Instead LRSC identified robust features including 377 mRNAs, many of which were novel (61.27%) compared to those identified by the other losses. Some 75 mRNAs were prognostic in TCGA, while 29 were prognostic in LIRI-JP also. LRSC also identified 15 robust miRNAs including two novel (hsa-let-7g; hsa-mir-550a-1) and 328 methylation features with 71% being prognostic. Gene-enrichment and Functional Annotation Analysis identified seven pathways differentiating prognostic clusters. Conclusions Combining cluster and survival metrics with the reconstruction objective function facilitated superior prognostic subgroup identification. The hybrid model identified more homogeneous clusters that consequently were more biologically meaningful. The novel and prognostic robust features extracted provide additional information to improve our understanding of a complex disease to help reveal its aetiology. Moreover, the gene features identified may have clinical applications as therapeutic targets.

Background: Medical image segmentation is a well-studied subject within the field of image processing. The goal of this research is to create an AI retinal screening grading system that is both accurate and fast. We introduce a new segmentation network which achieves state-of-the-art results on semantic segmentation of color fundus photographs. By applying the net-work to identify anatomical markers of diabetic retinopathy (DR) and diabetic macular edema (DME), we collect sufficient information to classify patients by grades R0 and R1 or above, M0 and M1. Methods: The AI grading system was trained on screening data to evaluate the presence of DR and DME. The core algorithm of the system is a deep learning network that segments relevant anatomical features in a retinal image. Patients were graded according to the standard NHS Diabetic Eye Screening Program feature-based grading protocol. Results: The algorithm performance was evaluated with a series of 6,981 patient retinal images from routine diabetic eye screenings. It correctly predicted 98.9% of retinopathy events and 95.5% of maculopathy events. Non-disease events prediction rate was 68.6% for retinopathy and 81.2% for maculopathy. Conclusion: This novel deep learning model was trained and tested on patient data from annual diabetic retinopathy screenings can classify with high accuracy the DR and DME status of a person with diabetes. The system can be easily reconfigured according to any grading protocol, without running a long AI training procedure. The incorporation of the AI grading system can increase the graders’ productivity and improve the final outcome accuracy of the screening process.

Introduction Nusinersen antisense oligonucleotide infusions have been shown to be effective in the treatment spinal muscular atrophy. The majority of the evidence has been collected in young type 1 and type 2 patients, and evidence of efficacy in adult patients is limited. Case report A 48-year-old woman with spinal muscular atrophy type 3 who has received the loading dose and 8 maintenance infusions over an 8-month period. Grip and pinch strength, measured by hand-held dynamometry measured at baseline and in 6 to 12 months interval improved over a 24-month period. She also reported multiple other subjective improvements in function. Conclusions This is the first published case of nusinersen in a middle-aged adult with spinal muscular atrophy. Sustained clinically meaningful improvement may be possible with nusinersen initiation in mid adulthood.

Aim To examine the relationship between baseline fasting C-peptide (FCP) and outcomes in insulin-naive people with type 2 diabetes initiating basal insulin glargine 100 U/mL (Gla-100). Materials and methods Post hoc pooled analysis of nine randomized, treat-to-target trials in patients with type 2 diabetes inadequately controlled on oral antihyperglycaemic drugs initiating once-daily Gla-100. Participants (n = 2165) were stratified at baseline according to FCP (≤0.40, >0.40-1.20, >1.20-2.00, >2.00 nmol/L). Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 24 weeks. Results At baseline low FCP levels were associated with longer known diabetes duration, lower body mass index and higher fasting plasma glucose (FPG). Following Gla-100 introduction, the mean HbA1c reduction at week 24 was similar in all four FCP groups, albeit fewer people in the lowest FCP group achieved HbA1c 0.40 nmol/L. By contrast, FPG reduction and proportion reaching FPG ≤5.6 mmol/L were greatest in the lowest FCP group, diminishing at higher FCP levels. Gla-100 dose at week 24 was lowest in the ≤0.40 nmol/L FCP group and highest in the >1.20 nmol/L FCP group. Incidence and event rate of overall, nocturnal and severe hypoglycaemia were higher at week 24 in groups with lower FCP levels. In multivariable regression analysis baseline FCP, concomitant sulphonylurea use and endpoint HbA1c were strong predictors of hypoglycaemia. Conclusions FCP levels identified patients with type 2 diabetes experiencing different responses to basal insulin Gla-100. A low FCP identifies a markedly insulin-deficient, insulin-sensitive subgroup/phenotype with an enhanced risk of hypoglycaemia, which requires a low initial basal insulin dose, cautious titration and earlier addition of prandial glucose-lowering therapy.

Context.— There is a wide disconnect between patients and the pathologists who make their diagnoses. Recent literature highlights successful programs in which patients meet with pathologists to review their pathology reports and see their tissue under a microscope. We do not know how many patients are interested in such a service, nor do we understand what drives interested patients to want to meet with their pathologist and what specific value it may provide. Objective.— To quantify patient interest in a patient-pathologist consultation program and qualitatively assess motivations for patient interest or disinterest. Design.— Subjects were recruited from an academic cancer center and a local community cancer support group to respond to a survey about their interest in a patient-pathologist consultation program. Both online forms and paper surveys were available. The online survey was promoted via social media. Results.— There was a high level of patient interest, with 75% of respondents indicating they were definitely interested in a patient-pathologist consultation program. Key themes of interest were enhanced understanding of the diagnosis and disease, an opportunity to demystify the diagnostic process, and the perception that additional knowledge would empower the patient. Conclusions.— In a select group of cancer patients, there is a very high level of interest in a patient-pathologist consultation program. Pathologists, clinicians, and hospital leadership should work together to pilot these programs in diverse settings. Additional quantitative work to scale interventions for the interested population and qualitative work to design effective, patient-centered consultation programs and to assess value are needed.

Prediction models for population-based screening need, for global usage, to be resource-driven, involving predictors that are affordably resourced. Here, we report the development and validation of three resource-driven risk models to identify people with type 2 diabetes (T2DM) at risk of stage 3 CKD defined by a decline in estimated glomerular filtration rate (eGFR) to below 60 mL/min/1.73m2. The observational study cohort used for model development consisted of data from a primary care dataset of 20,510 multi-ethnic individuals with T2DM from London, UK (2007–2018). Discrimination and calibration of the resulting prediction models developed using cox regression were assessed using the c-statistic and calibration slope, respectively. Models were internally validated using tenfold cross-validation and externally validated on 13,346 primary care individuals from Wales, UK. The simplest model was simplified into a risk score to enable implementation in community-based medicine. The derived full model included demographic, laboratory parameters, medication-use, cardiovascular disease history (CVD) and sight threatening retinopathy status (STDR). Two less resource-intense models were developed by excluding CVD and STDR in the second model and HbA1c and HDL in the third model. All three 5-year risk models had good internal discrimination and calibration (optimism adjusted C-statistics were each 0.85 and calibration slopes 0.999–1.002). In Wales, models achieved excellent discrimination(c-statistics ranged 0.82–0.83). Calibration slopes at 5-years suggested models over-predicted risks, however were successfully updated to accommodate reduced incidence of stage 3 CKD in Wales, which improved their alignment with the observed rates in Wales (E/O ratios near to 1). The risk score demonstrated similar model performance compared to direct evaluation of the cox model. These resource-driven risk prediction models may enable universal screening for Stage 3 CKD to enable targeted early optimisation of risk factors for CKD.

Background: Medical image segmentation is a well-studied subject within the field of image processing. The goal of this research is to create an AI retinal screening grading system that is both accurate and fast. We introduce a new segmentation network which achieves state-of-the-art results on semantic segmentation of colour fundus photographs. By applying the network to identify anatomical markers of diabetic retinopathy (DR) and diabetic macular edema (DME) including: micro-aneurysms, haemorrhages, etc., we collect sufficient information to classify patients into R0 (no DR) and R1 or above (DR), as well as M0 (no DME) and M1 (DME). Methods: The AI grading system was trained on public and private screening data to evaluate the presence of DR and DME. The system’s core algorithm is a novel deep learning segmentation network (W-net) that locates and segments relevant anatomical features in a retinal image. Both eyes of the patients are graded individually, based on the detected features and classified according to the standard feature-based grading protocol used in the NHS Diabetic Eye Screening Programme. Results: The algorithm performance was evaluated with a series of patient retinal images from routine diabetic eye screenings and achieved state-of-the-art results. It correctly predicted 98% of retinopathy events (95% confidence interval [CI], 97.1-98.8) and 68.9% of maculopathy events (95% CI, 58.1-79.7). Non-disease events prediction rate was 68.6% for retinopathy and 81.3% for maculopathy. Conclusion: This novel deep learning segmentation model trained on a colour fundus photograph data set and tested on patient data from annual diabetic retinopathy screenings can detect and classify with high accuracy the DR and DME status of a person with diabetes. The system can be easily reconfigured according to any grading protocol, without starting a long AI training procedure. The incorporation of the AI grading system can increase the graders’ productivity and improve the final outcome of the screening process. Disclosure O. Katz: Employee; Self; NECAM, Research Support; Self; Northgate Public Services. D. Presil: Employee; Self; NECAM, Research Support; Self; Northgate Public Services. L. Cohen: Employee; Self; NECAM, Research Support; Self; Northgate Public Services. R. Nachmani: Employee; Self; NECAM, Research Support; Self; Northgate Public Services. N. Kirshner: Employee; Self; NEC, Research Support; Self; Northgate Public Service. D. R. Owens: Advisory Panel; Self; 360 Consulting. T. H. Lev: Employee; Self; NECAM (NEC Corporation of America), Research Support; Self; Northgate Public Services. A. Hadad: Consultant; Self; Necam.

Introduction\udStudies of prevalence and the demographic profile of type 1 diabetes are challenging because of the relative rarity of the condition, however, these outcomes can be determined using routine healthcare data repositories. Understanding the epidemiology of type 1 diabetes allows for targeted interventions and care of this life-affecting condition.\ud\ud\udObjectives\udTo describe the prevalence, incidence and demographics of persons with type 1 diabetes diagnosed in Wales, UK, using the Secure Anonymised Information Linkage (SAIL) Databank.\ud\ud\udMethods\udData derived from primary and secondary care throughout Wales available in the SAIL Databank were used to identify people with type 1 diabetes to determine the prevalence and incidence of type 1 diabetes over a 10 year period (2008–18) and describe the demographic and clinical characteristics of this population by age, socioeconomic deprivation and settlement type. The seasonal variation in incidence rates was also examined.\ud\ud\udResults\udThe prevalence of type 1 diabetes in 2018 was 0.32% in the whole population, being greater in men compared to women (0.35% vs 0.28% respectively); highest in those aged 15-29 years (0.52%) and living in the most socioeconomically deprived areas (0.38%). The incidence of type 1 diabetes over 10 years was 14.0 cases/100,000 people/year for the whole population of Wales. It was highest in children aged 0-14 years (33.6 cases/100,000 people/year) and areas of high socioeconomic deprivation (16.8 cases/100,000 people/year) and least in those aged 45-60 years (6.5 cases/100,000 people/year) and in areas of low socioeconomic deprivation (11.63 cases/100,000 people/year). A seasonal trend in the diagnoses of type 1 diabetes was observed with higher incidence in winter months.\ud\ud\udConclusion\udThis nation-wide retrospective epidemiological study using routine data revealed that the incidence of type 1 diabetes in Wales was greatest in those aged 0-14 years with a higher incidence and prevalence in the most deprived areas. These findings illustrate the need for health-related policies targeted at high deprivation areas to include type 1 diabetes in their remit.

« Variability in glucose homoeostasis » is a better description than « glycaemic variability » as it encompasses two categories of dysglycaemic disorders: i) the short-term daily glucose fluctuations and ii) long-term weekly, monthly or quarterly changes in either HbA1c, fasting or postprandial plasma glucose. Presently, the relationship between the “variability in glucose homoeostasis” and diabetes complications has never been fully clarified because studies are either observational or limited to retrospective analysis of trials not primarily designed to address this issue. Despite the absence of definitive evidence from randomized controlled trials (RCTs), it is most likely that acute and long-term glucose homoeostasis “cycling”, akin to weight and blood pressure “cycling” in obese and hypertensive individuals, are additional risk factors for diabetes complications in the presence of sustained ambient hyperglycaemia. As hypoglycaemic events are strongly associated with short- and long-term glucose variability, two relevant messages can be formulated. Firstly, due consideration should be given to avoid within-day glucose fluctuations in excess of 36% (coefficient of variation) at least for minimizing the inconvenience and dangers associated with hypoglycaemia. Secondly, it seems appropriate to consider that variability in glucose homoeostasis is not only associated with cardiovascular events but is also a causative risk factor via hypoglycaemic episodes as intermediary step. Untangling the” Gordian Knot”, to provide confirmation about the impact of variability in glucose homoeostasis and diabetes complications remains a daunting prospect.

AIMS To understand factors associated with repeat non-attendance at screening for diabetes-related retinopathy. METHODS Retrospective observational study using anonymised data from Diabetic Eye Screening Wales for people with a full history of screening invitations and attendances was linked with primary and secondary care records held in the Secure Anonymised Information Linkage Databank. Repeat non-attendance was defined as no record of attendance during any 36-month period despite three cycles of annual screening invitations. The associations between repeat non-attendance and potential risk factors were examined using multivariable logistic regression analysis, stratified according to type 1 and type 2 diabetes. RESULTS A total of 18% with type 1 diabetes (1146/6513) and 8% with type 2 diabetes (12,475/156,525) were repeat non-attenders. Participants attending their very first appointment were least likely to become repeat non-attenders [odds ratio (95% confidence interval)]: type 1 diabetes: 0.12 (0.09, 0.17) and type 2 diabetes: 0.08 (0.07, 0.09). For both types of diabetes, those of a younger age, living in areas of higher deprivation and subject to multiple house moves were at greater risk of becoming repeat non-attenders. CONCLUSION/INTERPRETATION A more tailored approach is needed for the younger population, those living in areas of higher deprivation and/or undergoing multiple residential relocation and to ensure attendance at their initial appointment to minimise future repeat non-attendance.

Aims/hypothesis Few studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes. Methods Data were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593). Results Data from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p p Conclusions/interpretation Younger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality.

Background: Esophageal adenocarcinoma is a molecularly heterogeneous disease that is rising rapidly in incidence and has a poor prognosis. Current methods of endoscopic surveillance in patients with Barrett’s esophagus (BE) using white light illumination are not sensitive to pre-malignant lesions that are flat in appearance and patchy in distribution. We aim to demonstrate specific binding by a peptide heterodimer to Barrett’s neoplasia in human subjects. Methods: Peptide monomers specific for EGFR and ErbB2 were arranged in a heterodimer configuration and labeled with IRDye800. The near-infrared (NIR)-labeled heterodimer was synthesized using current good manufacturing practices (cGMP) methods and performed pharmacology/toxicology study in animals using good laboratory practices (GLP). The NIR contrast agent was topically administered in the distal esophagus of patients with history of neoplastic BE undergoing endoscopic therapy or surveillance. Fluorescence images were collected using a flexible fiber accessory passed through the instrument channel of an upper endoscope. Fluorescence images were collected from n = 31 BE patients, and a deep learning model was used to segment the target (T) and background (B) regions to calculate the T/B ratio. Findings: Between August 2018 and November 2020, 25 human subjects were enrolled for safety study and 31 patients for either evaluation or therapy of Barrett’s neoplasia were recruited for imaging study. No adverse events attributed to the heterodimer were found. The mean T/B ratio in patients for HGD and EAC were significantly greater than that for BE with low grade dysplasia, without dysplasia, or squamous mucosa. At a T/B ratio of 1.5, 94.1% sensitivity and 92.6% specificity for detection of Barrett’s neoplasia was achieved with an AUC = 0.95. The presence of Barrett’s neoplasia was validated by pathological assessment of resected specimens. Interpretation: This “first-in-human” clinical study demonstrates feasibility to detect early Barrett’s neoplasia using a NIR-labeled peptide heterodimer. Trial Registration: This study was registered online at ClinicalTrials.gov (NCT03643068) Funding National Institutes of Health. Declaration of Interest: Authors (JC, TDW) are inventors on patents filed by the University of Michigan on the peptide heterodimer used in this study. Author (EJS) is an inventor on patents filed by the University of Washington on the multimodal scanning fiber endoscope (mmSFE) used in this study. The other authors disclose no conflicts. Ethical Approval: All study protocols were reviewed and approved by the Institutional Review Board (IRB) at Michigan Medicine

International audience; Therapeutic efficiency of Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs) is generally assessed from Randomized Controlled Trials (RCTs) by comparing primary or secondary outcomes in persons with a specific disease, having satisfied predefined criteria, and then randomly allocated to either active therapy or a placebo. These types of interventional studies are commonly referred to as “mega-trials” [1] due to the very large population sizes. After randomization, the eligible participants are equally distributed into the comparator groups and undertake a follow-up period of several months or years. The deleterious or beneficial effects of the tested therapy are then assessed at end-point by recording and comparing the occurrence of all-cause deaths or specific cardiovascular outcomes. To enhance the strength of the statistical analysis, the clinical outcomes are frequently aggregated into composite end-points such as “Major Adverse Cardiovascular Events” (MACE) that may not reflect the information provided by the statistical analysis of each event considered separately. The present commentary discusses the results obtained in recent RCTs [2], [3], [4], [5], [6] that were conducted with GLP-1 RAs in type 2 diabetes. Prior to review the data, the main statistical procedures used in the interventional trials are briefly summarized.

Objectives: Peripheral artery disease is a major cardiovascular disease affecting more than 200 million people globally and up to 4 times more frequent in the diabetic population. It can lead to lower extremity amputations or revascularisation and is associated with an increased risk of myocardial infarction, stroke and early mortality. This novel cross-sectional study aimed to explore the feasibility and acceptability of incorporating diabetic foot screening at routine diabetic retinopathy screening appointments. Methods: Participants underwent foot screening during the interval between pupil dilatation and retinal photography as part of the eye screening procedure. Lower limb arterial assessment included ankle brachial index, pulse volume waveform and protective light touch sensation. Results: Of 364 participants invited, 88% (n = 321) met the inclusion criteria. About 26.4% (n = 86) had asymptomatic peripheral artery disease and 3% (n = 10) had peripheral sensory neuropathy. Binary logistical regression analysis identified age (p Conclusion: Incorporating foot examination during eye screening appointments is feasible and was well received by participants and staff alike. Undiagnosed early peripheral artery disease was evident in a third of the study population emphasising the benefit of introducing foot surveillance into eye screening appointments for the early identification of lower limb arterial disease and peripheral sensory neuropathy.

Giant pandas (Ailuropoda melanoleuca) were historically hunted using dogs and are currently threatened by free-roaming dogs and their associated diseases. To better understand the spatial magnitude of this threat, we used a GIS approach to investigate edge effects of dogs on giant panda habitat. We first examined two nature reserves with contrasting free-roaming dog populations: Liziping, with many dogs (~0.44/km2), and Daxiangling, with few dogs (~0.14/km2). Spatial analysis indicated that giant pandas at Liziping (but not Daxiangling) showed a shift in habitat use away from populated areas consistent with a risk response to the foray distance of free-roaming dogs (10.9 km path-distance). Most giant panda locations (86%) from the 2014 census in Liziping were clustered around remote “dog-free zones.” Expanding this analysis across the entire giant panda range revealed that 40% of panda habitat is within the foray distance of dogs. Our assessment will inform dog control programs including monitoring, education, veterinary care, and other measures. We recommend that reserves designated for the release of translocated pandas receive priority consideration for dog control efforts. Only by understanding and managing complex interactions between humans, domestic animals, and wild animals can we sustain natural systems in a world increasingly dominated by humans.

Aim To examine the impact of structured self‐monitoring of blood glucose, with or without TeleCare support, on glycaemic control in people with sub‐optimally controlled Type 2 diabetes. Methods We conducted a 12‐month, multicentre, randomized controlled trial in people with established (>1 year) Type 2 diabetes not on insulin therapy, with sub‐optimal glycaemic control [HbA1c ≥58 to ≤119 mmol/mol (≥7.5% to ≤13%)]. A total of 446 participants were randomized to a control group (n =151) receiving usual diabetes care, a group using structured self‐monitoring of blood glucose alone (n =147) or a group using structured self‐monitoring of blood glucose with additional monthly ‘TeleCare’ support (n =148). The primary outcome was HbA1c at 12 months. Results A total of 323 participants (72%) completed the study; 116 (77%) in the control group, 99 (67%) in the self‐monitoring of blood glucose alone group and 108 (73%) in the self‐monitoring of blood glucose plus TeleCare group. Compared to baseline, the mean HbA1c was lower in all groups at 12 months, with reductions of 3.3 mmol/mol (95% CI –5.71 to –0.78) or 0.3% (95% CI –0.52 to –0.07; P=0.01) in the control group, 11.4 mmol/mol (95% CI –14.11 to –8.76) or 1.1% (–1.29 to –0.81; P, What's new? This 12‐month randomized controlled trial examined the impact of structured self‐monitoring of blood glucose (SMBG), with and without TeleCare support, on glycaemic control in people with sub‐optimally controlled Type 2 diabetes.Results showed that this standardized, structured SMBG intervention, with or without additional TeleCare, provided statistically and clinically significant improvements in glycaemic control.Structured SMBG should be offered as part of the self‐management process for all people with sub‐optimally controlled Type 2 diabetes, even when not treated with insulin. Unstructured SMBG (other than for safety purposes) should be regarded as a waste of valuable time and resources.

Highlights • SBRT for CRC results in excellent local control rates for nodal metastases. • Median PFS for NM was 19 months versus 9 months for VM. • Nodal site was significant prognostic factor on multivariate analysis for PFS/OS. • We hypothesise an immunoediting basis for the improved outcomes of NM., Background Stereotactic ablative radiotherapy (SBRT) is a radical option for oligometastatic colorectal cancer (CRC) patients, but most data relate to visceral metastases. Methods A prospective, multi-centre database of CRC patients treated with SBRT was interrogated. Inclusion criteria were ECOG PS 0–2, ≤3 sites of disease, a disease free interval of >6 months unless synchronous liver metastases. Primary endpoints were local control (LC), progression free survival (PFS) and overall survival (OS). Results 163 patients (172 metastases) were analysed. The median FU was 16 months (IQR 12.2–22.85). The LC at 1 year was 83.8% (CI 76.4%−91.9%) with a PFS of 55% (CI 47%−64.7%) respectively. LC at 1 year was 90% (CI 83%−99%) for nodal metastases (NM), 75% (63%−90%) for visceral metastases (VM). NM had improved median PFS (9 vs 19 months) [HR 0.6, CI 0.38–0.94, p = 0.032] and median OS (32 months vs not reached) [HR 0.28, CI 0.18–0.7, p = 0.0062] than VM, regardless of whether the NM were located inside or outside the pelvis. On multivariate analysis, NM and ECOG PS 0 were significant good prognostic factors. An exploratory analysis suggests KRAS WT is also a good prognostic factor. Conclusion Nodal site is an important prognostic determinant of SBRT that should incorporated into patient selection. We hypothesise this may have an immunoediting basis.

AIMS To identify factors associated with achievement of glycated haemoglobin A1c (HbA1c) target at 24 weeks after commencing basal insulin therapy in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS Post-hoc pooled analysis of 16 randomized, treat-to-target trials involving individuals with T2DM inadequately controlled with oral anti-hyperglycaemic drugs (n = 3415) initiated on once-daily insulin glargine 100 U/mL (Gla-100). Clinical outcomes were assessed by HbA1c response at 24 weeks and individuals were classified as "good responders" with HbA1c

Immune checkpoint inhibition targeted against cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has shown clinically significant survival benefit when used to treat multiple types of advanced cancer. These drugs have gained approval by the US Food and Drug Administration and their indications continue to increase. Checkpoint inhibitor therapy is associated with a unique side-effect profile characterized as immune-related adverse events (irAEs), which can result in significant morbidity and rarely mortality. Hepatotoxicity from checkpoint inhibitors is a less common irAE and often mild, while its incidence and severity vary based on the class and dose of checkpoint inhibitor, monotherapy versus combination therapy, and the type of cancer. Histological assessment of suspected irAEs is nonspecific and can show a variety of features. Hepatic irAEs can require discontinuation of checkpoint inhibitor therapy and treatment with immunosuppressive agents.

Objectives We sought to characterize a histologic pattern of mid- and deep-zone gastritis, distinct from the typical pattern of Helicobacter pylori or autoimmune gastritis and to see if it had any clinicopathologic association(s). Methods We analyzed inflammatory patterns and composition, excluded autoimmune gastritis using immunohistochemistry, and reviewed the medical record for demographics, medical/surgical history, presenting symptoms, endoscopic findings, and medications for 28 cases. Results All cases had inflammation in the middle and/or deep mucosal zones with sparing of the superficial/pit compartment. Subfeatures included corpus or antral predominance, pangastric involvement, prominence of a subset(s) of inflammatory cells, and degree of epithelial injury. Of 28 patients, 13 had autoimmune disease(s), autoantibodies, or both. There was no other unifying clinical feature. Conclusions This unique pattern of gastritis should be distinguished from other entities such as H pylori and autoimmune gastritis. At least a subset may be an autoimmune condition different from classic autoimmune gastritis.

BackgroundAll patients undergoing tympanomastoid surgery should be assessed post-operatively for a ‘dead ear’; however, tuning forks are frequently inaccessible.ObjectiveTo demonstrate that smartphone-based vibration applications provide equivalent accuracy to tuning forks when performing Weber's test.MethodsData were collected on lay participants with no underlying hearing loss. Earplugs were used to simulate conductive hearing loss. Both the right and left ears were tested with the iBrateMe vibration application on an iPhone and using a 512 Hz tuning fork.ResultsOccluding the left ear, the tuning fork lateralised to the left in 18 out of 20 cases. In 20 out of 20 cases, sound lateralised to the left with the iPhone (chi-square test, p = 0.147). Occluding the right ear, the tuning fork lateralised to the right in 19 out of 20 cases. In 19 out of 20 cases, sound lateralised to the right with the iPhone (chi-square test, p > 0.999).ConclusionSmartphone-based vibration applications represent a viable, more accessible alternative to tuning forks when assessing for conductive hearing loss. They can therefore be utilised on the ward round, in patients following tympanomastoid surgery, for example.

Locally recurrent rectal cancer results in significant symptoms and is associated with prognosis of less than 1 year unless radical resection can be offered. Unfortunately, radical resection rates are low and therefore strategies to palliate symptoms and to maximise downstaging are of significant interest. As the majority of those presenting with locally recurrent rectal cancer will have received previous irradiation for their primary tumour, re-irradiation may offer benefit in this setting. The literature to date is considered in both palliative patients and those with potentially operable disease. Palliative patients gain significant symptomatic relief from standard dose fractionations of up to 30 Gy. In potentially operable patients, the evidence is discussed in the context of key questions; including indications for treatment, dose and fractionation, radiotherapy technique, margins and constraints. Finally, we highlight some additional areas of interest for consideration in future research and development.

After years of intensive investigation, the definition of glycaemic variability remains unclear and the term variability in glucose homoeostasis might be more appropriate covering both short and long-term glycaemic variability. For the latter, we remain in the search of an accurate definition and related targets. Recent work leads us to consider that the within-subject variability of HbA1c calculated from consecutive determinations of HbA1c at regular time-intervals could be the most relevant index for assessing the long-term variability with a threshold value of 5% (%CV = SD of HbA1c/mean HbA1c) to separate stability from lability of HbA1c. Presently, no one can deny that short- and long-term glucose variability should be maintained within their lower ranges to limit the incidence of hypoglycaemia. Usually, therapeutic strategies aimed at reducing post-meal glucose excursions, i.e. the major contributor to daily glucose fluctuations, exert a beneficial effect on the short-term glucose variability. This explains the effectiveness of adjunct therapies with either GLP- receptor agonists or SGLT inhibitors in type 2 diabetes. In type 1 diabetes, the application of a CGM device alone reduces the short-term glycaemic variability. In contrast, sophisticated insulin delivery does not necessarily lead to such reductions despite marked downward shifts of 24-hour glycaemic profiles. Such contrasting observations raise the question as to whether the prolonged wear of CGM devices is or not the major causative factor for improvement in glucose variability among intensively insulin-treated persons with type 1 diabetes.

The gastrointestinal tract is the most common extranodal site of involvement by lymphoma, with B-cell tumors outnumbering T-cell tumors by a wide margin. Diffuse large B-cell lymphoma is the most common lymphoid neoplasm involving the gastrointestinal tract; but a variety of other B- and T-cell neoplasms occur in the gastrointestinal organs, often with characteristic associations and/or manifestations. Although the diagnosis of gastrointestinal lymphomas can sometimes seem daunting to general pathologists, a knowledge of the most commonly encountered entities, in combination with a reasoned and pragmatic approach to the diagnostic workup, makes it possible to approach most cases with confidence.

Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular (CV) comorbidities, with CV disease being the most common cause of death in adults with T2DM. Although glucocentric therapies may improve glycaemic control (as determined by glycated haemoglobin levels), evidence suggests that this approach alone has limited beneficial effects on CV outcomes relative to improvements in lipid and blood pressure control. This may be explained in part by the fact that current antidiabetic treatment regimens primarily address overall glycaemia and/or fasting plasma glucose, but not the postprandial plasma glucose (PPG) excursions that have a fundamental causative role in increasing CV risk. This literature review evaluates the relationship between PPG and the risk of CV disease, discusses the treatment of T2DM with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and examines the associated CV outcomes. The literature analysis suggests that exaggerated PPG excursions are a risk factor for CV disease because of their adverse pathophysiologic effects on the vasculature, resulting in increased all-cause and CV-related mortality. Although GLP-1 RAs are well established in the current T2DM treatment paradigm, a subgroup of these compounds has a particularly pronounced, persistent and short-lived effect on gastric emptying and, hence, lower PPG substantially. However, current long-term data on CV outcomes with GLP-1 RAs are contradictory, with both beneficial and adverse effects having been reported. This review explores the opportunity to direct treatment towards controlling PPG excursions, thereby improving not only overall glycaemic control but also CV outcomes.

Most algorithms for type 2 diabetes mellitus (T2DM) do not recommend treatment escalation until glycated haemoglobin (HbA1c) fails to reach the recommended target of 7% (53 mmol/mol) within approximately 3 months on any treatment regimen ("treat to failure"). Clinical inertia and/or poor adherence to therapy contribute to patients not reaching glycaemic targets when managed according to this paradigm. Clinical inertia exists across the entire spectrum of anti-diabetes therapies, although it is most pronounced when initiating and optimizing insulin therapy. Possible reasons include needle aversion, fear of hypoglycaemia, excessive weight gain and/or the need for increased self-monitoring of blood glucose. Studies have suggested, however, that early intensive insulin therapy in newly diagnosed, symptomatic patients with T2DM with HbA1c >9% (75 mmol/mol) can preserve beta-cell function, thereby modulating the disease process. Furthermore, postprandial plasma glucose is a key component of residual dysglycaemia, evident especially when HbA1c remains above target despite fasting normoglycaemia. Therefore, to achieve near normoglycaemia, additional treatment with prandial insulin or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) is often required. Long- or short-acting GLP-1 RAs offer effective alternatives to basal or prandial insulin in patients inadequately controlled with other therapies or basal insulin alone, respectively. This review highlights the limitations of current algorithms, and proposes an alternative based on the early introduction of insulin therapy and the rationale for the sequential or fixed combination of GLP-1 RAs with insulin ("treat-to-success" paradigm).

Introduction The incidence of thyroid cancer has increased worldwide, whether a real or apparent increase is debated. Literature from the USA suggests greater diagnostic scrutiny, environmental and genetic factors may all play a part. This increase will result in a greater number of referrals for surgical assessment. This study examined the trend in incidence of thyroid cancer in England and Wales. Materials and Methods A retrospective study, using the HES database over the period 2000-2010. Data were extracted of all newly diagnosed thyroid cancers in England and Wales and the age at diagnosis. Data were examined for the change in incidence of thyroid cancer diagnosis dependent on the age group of the patient using the linear regression model. Results 45411 patients were identified. In England the incidence of thyroid cancer rose from 5.7/100,000 of the population in 2000 to 9.9/100,000 in 2010 and in Wales it rose from 3.5/100,000 in 2000 to 7.5/100,000. There was a statistical increase (P≤0.02) (t-stat >2) in the diagnosis of thyroid cancers across all age groups with exception of the 0-14 age group (P>0.5). Conclusion There has been a statistical increase in the incidence of thyroid cancer. This is likely to impact on hospitals and cancer service resources. An increase in surgical demand and the coinciding ageing population highlights the importance of further investigation into the etiology, use of imaging, patient demographics, histology and overall mortality of this patient group.

Biosynthetic human insulin and insulin analogues are the mainstay of insulin therapy for both type 1 and type 2 diabetes although access to human insulin at affordable prices remains a global issue. The world is experiencing an exponential rise in the prevalence of diabetes presenting an urgent need to establish effective diabetes therapy in countries burdened by inadequate health care budgets, malnutrition and infectious diseases. Recombinant human insulin has replaced animal insulins and animal-based semisynthetic human insulin thereby available in sufficient quantities and at affordable prices able to provide global access to insulin therapy. In many patients, analog insulins can offer additional clinical benefit, although at a considerably higher price thus severely restricting availability in low income countries. The approval process for recombinant human insulins (i.e. biosimilars) and analogue insulins is highly variable in the developing countries in contrast to Europe and in North America, where it is well established within a strict regulatory framework. This review aims to discuss the future access to human insulin therapy in a global context with an ever increasing burden of diabetes and significant economic implications.

B Rubbo, S Best, RA Hirst. Arch Dis Child. 2020;105(8):724–729 To provide detailed characterization of children with primary ciliary dyskinesia (PCD) from the National Health Service in England and compare lung function to children with cystic fibrosis (CF). All children ( n = 333) with PCD who had an annual visit at the nationally commissioned PCD centers in England during 2015 were included. Lung function was compared with 2970 children with CF from England’s National CF registry. Visit data were evaluated for multiple factors, including height, weight, BMI, spirometry, audiometry, airway microbiology samples, and antibiotic use (prophylactic and exacerbations). Global Lung Initiative (GLI) equations were used to estimate z -scores for forced expiratory volume in one second (FEV1) and forced …

OBJECTIVE: To determine the risk factors for having diabetic retinopathy (DR) in children and young people (CYP) with type 1 diabetes (T1DM) at first screening. METHODS: Records from the Diabetes Eye Screening Wales (DESW) service for people in Wales, UK, with T1DM diagnosed under age 18 years were combined with other electronic health record (EHR) data in the Secure Anonymised Information Linkage (SAIL) Databank. Data close to the screening date were collected, and risk factors derived from multivariate, multinomial logistic regression modelling. RESULTS: Data from 4172 persons, with median (lower quartile, upper quartile) age 16.3 (13.0, 22.3) years and duration of diabetes 6.6 (2.3, 12.3) years were analysed. 62.6% (n = 2613) had no DR, 26.7% (n = 1112) background DR, and 10.7% (n = 447) had referable DR (RDR). No RDR was observed under 19 years of age. Factors associated with an increased risk of DR were diabetes duration, elevated HbA(1c), and diastolic blood pressure. People diagnosed with T1DM at 12 years or older had an additional risk for each year they had diabetes compared to those diagnosed before age 12 controlling for the diabetes duration (odds ratios 1.23 and 1.34, respectively). CONCLUSIONS: This study found that 37.4% of the study cohort had DR at first screening, the risk being greater the longer the duration of diabetes or higher the HbA(1c) and diastolic blood pressure. In addition, people diagnosed at 12 years of age or over were more likely to have DR with each additional year with diabetes.

The prevention of type 2 diabetes mellitus (T2DM) is a target priority for the WHO and the United Nations and is a key priority in the 2018 Berlin Declaration, which is a global call for early actions related to T2DM. Health-care policies advocate that individuals at high risk of developing T2DM undertake lifestyle modification, irrespective of whether the prediabetes phenotype is defined by hyperglycaemia in the postprandial state (impaired glucose tolerance) and/or fasting state (impaired fasting glucose) or by intermediate HbA1c levels. However, current evidence indicates that diabetes prevention programmes based on lifestyle change have not been successful in preventing T2DM in individuals with isolated impaired fasting glucose. We propose that further research is needed to identify effective lifestyle interventions for individuals with isolated impaired fasting glucose. Furthermore, we call for the identification of innovative approaches that better identify people with impaired glucose tolerance, who benefit from the currently available lifestyle-based diabetes prevention programmes.

Due to the progressive nature of type 2 diabetes (T2DM), initiation of insulin therapy is very likely in the disease continuum. This article aims at highlighting the current situation with regard to insulin therapy in people with T2DM in Europe and at presenting the associated unmet need. Challenges for both people with T2DM and healthcare professionals include clinical inertia also derived from fear of hypoglycaemia, weight gain and injections as well as increased need for a comprehensive diabetes management. We compare national and international guidelines and recommendations for the initiation and intensification of insulin therapy with the real-world situation in six European countries, demonstrating that glycaemic targets are only met in a minority of people with T2DM on insulin therapy. Furthermore, this work evaluates currently recorded numbers of people with T2DM treated with insulin in Europe, the proportion not achieving the stated glycaemic targets and thus in need to enhance insulin therapy e.g. by a change in means of insulin delivery including, but not limited to, insulin pens, wearable mealtime insulin delivery patches, patch pumps, and conventional insulin pumps with continuous subcutaneous insulin infusion.

Background and Aims There is inconsistent evidence supporting the self-monitoring of blood glucose (SMBG) in people with non-insulin treated type 2 diabetes (T2D). Structured SMBG protocols have a greater impact on glycaemic control than unstructured SMBG and may improve measures of glycaemic variability (GV), though few previous studies have reported on specific GV outcomes. Our aim was to determine the impact of structured SMBG on simple measures of GV in people with T2D. Methods Participants undertook structured SMBG over 12 months, with HbA1c recorded at baseline and at 3-monthly follow-up. For each participant, the mean blood glucose (MBG), fasting blood glucose (FBG), standard deviation BG (SD-BG), coefficient of variation of BG (CV-BG), mean absolute glucose change (MAG) and HbA1c were determined for each 3-month period. Responders were participants with an improvement in HbA1c of ≥5 mmol/mol (0.5%) over 12 months. Results Data from two hundred and thirty-one participants were included for analysis. Participants had a baseline median [interquartile range] HbA1c 68.0 [61.5–75.5] mmol/mol (8.4%). Participants demonstrated significant improvements in the MBG (−1.25 mmol/L), FBG (−0.97 mmol/L), SD-BG (−0.44 mmol/L), CV-BG (−1.43%), MAG (−0.97 mmol/L), and HbA1c (−7.0 mmol/mol) (all p Conclusions Structured SMBG improved all the observed measures of GV. These results support the use of structured SMBG in people with non-insulin treated T2D.

International audience; Recognizing the role of dysglycaemia, 'ambient' hyperglycaemia, 'metabolic memory' and glycaemic variability as risk factors for macrovascular diseases is mandatory for effective diabetes management. Chronic hyperglycaemia, also referred to as 'ambient hyperglycaemia', was only fully acknowledged as a risk factor for adverse cardiovascular events when the beneficial effects of intensive glucose-lowering strategies were consolidated in the extended follow-up (> 10 years) of patients included in the United Kingdom Prospective Diabetes Study (UKPDS) and Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study. These studies led to the concept of the glucose-lowering 'legacy effect' (metabolic memory), which depends on the duration and magnitude of glucose-lowering, and is not a 'forever' phenomenon, as demonstrated in the 15-year follow-up of the Veterans Affairs Diabetes Trial (VADT). The relatively weak evidence for linking long- and short-term glycaemic variability to vascular complications in patients with diabetes is mainly due to a reliance on observational and retrospective studies, and the lack of randomized interventional trials. However, hypoglycaemia may play an intermediary role in accentuating the link between glycaemic variability and vascular events.

Objective Examine the health and economic impact of extending screening intervals in people with Type 2 diabetes (T2DM) and Type 1 diabetes (T1DM) without diabetes-related retinopathy (DR). Setting Diabetic Eye Screening Wales (DESW). Study design Retrospective observational study with cost-utility analysis (CUA) and Decremental Cost-Effectiveness Ratios (DCER) study. Intervention Biennial screening versus usual care (annual screening). Inputs Anonymised data from DESW were linked to primary care data for people with two prior screening events with no DR. Transition probabilities for progression to DR were estimated based on a subset of 26,812 and 1232 people with T2DM and T1DM, respectively. DCER above £20,000 per QALY was considered cost-effective. Results The base case analysis DCER results of £71,243 and £23,446 per QALY for T2DM and T1DM respectively at a 3.5% discount rate and £56,822 and £14,221 respectively when discounted at 1.5%. Diabetes management represented by the mean HbA1c was 7.5% for those with T2DM and 8.7% for T1DM. Sensitivity analysis Extending screening to biennial based on HbA1c, being the strongest predictor of progression of DR, at three levels of HbA1c 6.5%, 8.0% and 9.5% lost one QALY saving the NHS £106,075; £58,653 and £31,626 respectively for T2DM and £94,696, £37,646 and £11,089 respectively for T1DM. In addition, extending screening to biennial based on the duration of diabetes > 6 years for T2DM per QALY lost, saving the NHS £54,106 and for 6-12 and > 12 years for T1DM saving £83,856, £23,446 and £13,340 respectively. Conclusions Base case and sensitivity analyses indicate biennial screening to be cost-effective for T2DM irrespective of HbA1c and duration of diabetes. However, the uncertainty around the DCER indicates that annual screening should be maintained for those with T1DM especially when the HbA1c exceeds 80 mmol/mol (9.5%) and duration of diabetes is greater than 12 years.

The class of rapid‐acting insulin analogues were introduced more than 20 years ago to control postprandial plasma glucose (PPG) excursions better than unmodified regular human insulin. Insulins, lispro, aspart and glulisine all achieved an earlier onset of action, greater peak effect and shorter duration of action resulting in lower PPG levels and a reduced risk of late postprandial hypoglycaemia. However, the subcutaneous absorption rate of these analogues still fails to match the physiological profile of insulin in the systemic circulation following a meal. Recent reformulations of aspart and lispro have generated a second generation of more rapid‐acting insulin analogue candidates, including fast‐acting aspart (faster aspart), ultra‐rapid lispro and BioChaperone Lispro. These modifications have the potential to mimic physiological prandial insulin secretion better with an even earlier onset of action with improved PPG control, shorter duration of effect and reduced risk of hypoglycaemia. Recent phase 3 trials in type 1 and type 2 diabetes show that faster aspart and ultra‐rapid lispro compared with conventional aspart and lispro, achieved fewer PPG excursions with a small increase in post‐meal hypoglycaemia but similar or marginally superior glycated haemoglobin levels, and suggest the need for parallel optimization of basal insulin replacement. Phase 1 trials for BioChaperone Lispro are equally encouraging with phase 3 trials yet to be initiated. Comparative analysis of the clinical and pharmacological evidence for these new prandial insulin candidates in the treatment of type 1 and type 2 diabetes is the main focus of this review.

International audience; Since the approval of the first continuous glucose-monitoring (CGM) device [1], CGM has been increasingly introduced to people with type 1 diabetes and to a much lesser extent those with insulin-requiring type 2 diabetes [2], [3], [4], [5]. Numerous studies have since demonstrated that the use of unblinded real-time or flash glucose monitoring facilitates the adjustment of insulin doses thus improving glycaemic control [6], [7], [8], [9]. Also in pregnant women with type 1 diabetes CGM users experienced better glycaemic control when compared with non-users in the CONCEPTT trial [10]. Several factors contribute to the expanded utilization of CGM in persons with diabetes including the improved accuracy of the latest generation of CGM devices [4], [11], [12] and the introduction of factory-calibrated devices apparently not requiring additional self-calibration, which has enhanced the quality of life of many users.

Aims The purpose of this study is to assess the prevalence of diabetic retinopathy (DR) world-wide from articles published since 2015 where the assessment of the presence and severity of DR was based on retinal images. Methods A total of 4 databases were searched for the MESH terms diabetic retinopathy and prevalence. Of 112 publications 32 studies were included and individual data pooled for analysis. The presence of any DR or diabetic macular edema (DME) was recorded and severity as mild, moderate or severe non-proliferative DR (NPDR), proliferative DR (PDR) and DME and/or clinically significant macular edema (CSME). The level of severity of DR reported refer to persons with diabetes and not individual eyes. Results The global prevalence of DR and DME, for the period 2015 to 2019 were 27.0% for any DR comprising of 25.2%, NPDR, 1.4% PDR and 4.6% DME. The lowest prevalence was in Europe at 20.6% and South East Asia at 12.5% and highest in Africa at 33.8%, Middle East and North Africa 33.8%, and the Western Pacific region at 36.2%. Conclusions This study illustrated difficulties in deriving a meaningful global prevalence rate for DR and DME due to the lack of uniformity in defining the study populations, methodological differences, retinal image capture and grading criteria. Therefore, international consensus is required using a minimal data set for future studies.

OBJECTIVE To evaluate the respective contributions of short-term glycemic variability and mean daily glucose (MDG) concentration to the risk of hypoglycemia in type 1 diabetes. RESEARCH DESIGN AND METHODS People with type 1 diabetes (n = 100) investigated at the University Hospital of Montpellier (France) underwent continuous glucose monitoring (CGM) on two consecutive days, providing a total of 200 24-h glycemic profiles. The following parameters were computed: MDG concentration, within-day glycemic variability (coefficient of variation for glucose [%CV]), and risk of hypoglycemia (presented as the percentage of time spent below three glycemic thresholds: 3.9, 3.45, and 3.0 mmol/L). RESULTS MDG was significantly higher, and %CV significantly lower (both P < 0.001), when comparing the 24-h glycemic profiles according to whether no time or a certain duration of time was spent below the thresholds. Univariate regression analyses showed that MDG and %CV were the two explanatory variables that entered the model with the outcome variable (time spent below the thresholds). The classification and regression tree procedure indicated that the predominant predictor for hypoglycemia was %CV when the threshold was 3.0 mmol/L. In people with mean glucose ≤7.8 mmol/L, the time spent below 3.0 mmol/L was shortest (P < 0.001) when %CV was below 34%. CONCLUSIONS In type 1 diabetes, short-term glycemic variability relative to mean glucose (i.e., %CV) explains more hypoglycemia than does mean glucose alone when the glucose threshold is 3.0 mmol/L. Minimizing the risk of hypoglycemia requires a %CV below 34%.

ObjectiveTo describe the behavioural and psychiatric problems found in nursing home psychiatric referrals in the Dublin South city area.MethodsWe undertook two consecutive surveys of nursing home referrals to the St James’s Hospital psychiatry of old age service over a 2-year period. During the second survey a new clinical nurse specialist was specifically appointed to manage the seven nursing homes included in the study.ResultsThe most common reason for referral during survey one was uncooperative/aggressive behaviour (22%). For survey two, patients were most commonly referred for low mood (31%) or agitation (29%). During survey one, the majority of patients assessed were diagnosed with behavioural and psychological symptoms of dementia (41%). This was also a prevalent diagnosis during survey two, affecting 27% of those referred. Only 7% of patients were considered to be delirious during survey one. This rose to 31% the following year making it the most common diagnosis during survey two. Over the 2-year study period, 7% of referred patients were diagnosed with depression. In terms of prescribing practices, the discontinuation rate of antipsychotic mediation following psychiatric input was 13% in survey one. By survey two, this had risen to 47%.ConclusionsDelirium is often undetected and untreated in nursing homes. Residents presenting with psychiatric symptoms should undergo routine bloods and urinalysis prior to psychiatric referral. Dedicated input from trained psychiatric nursing staff can lead to both an improvement in the recognition of delirium and reduced prescribing rates of antipsychotic medication.