The biological carbon pump in CMIP6 models: 21st century trends and uncertainties.

The biological carbon pump (BCP) stores ∼1,700 Pg C from the atmosphere in the ocean interior, but the magnitude and direction of future changes in carbon sequestration by the BCP are uncertain. We quantify global trends in export production, sinking organic carbon fluxes, and sequestered carbon in the latest Coupled Model Intercomparison Project Phase 6 (CMIP6) future projections, finding a consistent 19 to 48 Pg C increase in carbon sequestration over the 21st century for the SSP3-7.0 scenario, equivalent to 5 to 17% of the total increase of carbon in the ocean by 2100. This is in contrast to a global decrease in export production of -0.15 to -1.44 Pg C y-1. However, there is significant uncertainty in the modeled future fluxes of organic carbon to the deep ocean associated with a range of different processes resolved across models. We demonstrate that organic carbon fluxes at 1,000 m are a good predictor of long-term carbon sequestration and suggest this is an important metric of the BCP that should be prioritized in future model studies.

Decoding sounds depicting hand-object interactions in primary somatosensory cortex.

Neurons, even in the earliest sensory regions of cortex, are subject to a great deal of contextual influences from both within and across modality connections. Recent work has shown that primary sensory areas can respond to and, in some cases, discriminate stimuli that are not of their target modality: for example, primary somatosensory cortex (SI) discriminates visual images of graspable objects. In the present work, we investigated whether SI would discriminate sounds depicting hand-object interactions (e.g. bouncing a ball). In a rapid event-related functional magnetic resonance imaging experiment, participants listened attentively to sounds from 3 categories: hand-object interactions, and control categories of pure tones and animal vocalizations, while performing a one-back repetition detection task. Multivoxel pattern analysis revealed significant decoding of hand-object interaction sounds within SI, but not for either control category. Crucially, in the hand-sensitive voxels defined from an independent tactile localizer, decoding accuracies were significantly higher for hand-object interactions compared to pure tones in left SI. Our findings indicate that simply hearing sounds depicting familiar hand-object interactions elicit different patterns of activity in SI, despite the complete absence of tactile stimulation. These results highlight the rich contextual information that can be transmitted across sensory modalities even to primary sensory areas.

Changes in continuous glucose monitoring metrics and predictors of improvement 12 months after conversion from Freestyle Libre to Freestyle Libre 2.

AIMS: We sought to assess whether conversion from Freestyle Libre to Freestyle Libre 2 (with low and high glucose alert functions) was associated with improved glucose metrics. RESEARCH DESIGN AND METHODS: A prospective observational study to assess changes in CGM metrics in 672 adults with type 1 diabetes when converting to Freestyle Libre 2. Secondary outcomes included predictors of reduction in time below range (TBR) and increase in time in range (TIR). RESULTS: TBR fell by a median of 1.0% (IQR -2.7 to 0.3, p < 0.001) after 12 months and TIR decreased by 1.0% (-8.7 to 6.0, p = 0.004). TIR did not fall in people using high glucose alerts (p = 0.353). Average duration of low glucose events (<3.9 mmoL/L) fell by 10 min (-46 to 18, p < 0.001). Significant improvements in TIR (p = 0.029) and time above 13.9 mM (p = 0.002) were observed in those using high glucose alerts. Alert threshold settings were not associated with glycaemic response; however, low alert use was independently associated with a fall in TBR of ≥0.5% (HR 1.9 [95% CI 1.2-3.1], p = 0.009) and high alert use was independently associated with a rise in TIR of ≥5% (HR 1.6 [95% CI 1.0-2.5], p = 0.043) at 12 months. CONCLUSIONS: Conversion to Freestyle Libre 2 was associated with significant improvements in low glucose metrics. Alert function users were more likely to see improvements across all CGM metrics. Challenges remain in encouraging alert use, helping users set optimal alert thresholds and optimizing response to alerts.

UK's Association of British Clinical Diabetologist's Diabetes Technology Network (ABCD-DTN): Best practice guide for hybrid closed-loop therapy.

This best practice guide is written with the aim of providing an overview of current hybrid closed-loop (HCL) systems in use within the United Kingdom's (UK) National Health Service (NHS) and to provide education and advice for their management on both an individual and clinical service level. The environment of diabetes technology, and particularly HCL systems, is rapidly evolving. The past decade has seen unprecedented advances in the development of HCL systems. These systems improve glycaemic outcomes and reduce the burden of treatment for people with type 1 diabetes (pwT1D). It is anticipated that access to these systems will increase in England as a result of updates in National Institute of Health and Care Excellence (NICE) guidance providing broader support for the use of real-time continuous glucose monitoring (CGM) for pwT1D. NICE is currently undertaking multiple-technology appraisal into HCL systems. Based on experience from centres involved in supporting advanced technologies as well as from the recent NHS England HCL pilot, this guide is intended to provide healthcare professionals with UK expert consensus on the best practice for initiation, optimisation and ongoing management of HCL therapy.

Non-invasive imaging of functional pancreatic islet beta-cell mass in people with type 1 diabetes mellitus.

AIMS: To investigate whether manganese-enhanced magnetic resonance imaging can assess functional pancreatic beta-cell mass in people with type 1 diabetes mellitus. METHODS: In a prospective case-control study, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. RESULTS: Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma C-peptide concentrations respectively. Pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r = 0.73, p < 0.001) but not in healthy volunteers (r = -0.054, p = 0.880). There were no statistically significant correlations between manganese uptake and age, body-mass index, or glycated haemoglobin. There was strong intra-observer (mean difference: 0.31 (limits of agreement -1.42 to 2.05) mL/100 g of tissue/min; intra-class correlation, ICC = 0.99), inter-observer (-1.23 (-5.74 to 3.27) mL/100 g of tissue/min; ICC = 0.85) and scan-rescan (-0.72 (-2.9 to 1.6) mL/100 g of tissue/min; ICC = 0.96) agreement for pancreatic manganese uptake. CONCLUSIONS: Manganese-enhanced magnetic resonance imaging provides a potential reproducible non-invasive measure of functional beta-cell mass in people with type 1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoring disease progression and assessing novel immunomodulatory interventions.

Hand-Selective Visual Regions Represent How to Grasp 3D Tools: Brain Decoding during Real Actions.

Most neuroimaging experiments that investigate how tools and their actions are represented in the brain use visual paradigms where tools or hands are displayed as 2D images and no real movements are performed. These studies discovered selective visual responses in occipitotemporal and parietal cortices for viewing pictures of hands or tools, which are assumed to reflect action processing, but this has rarely been directly investigated. Here, we examined the responses of independently visually defined category-selective brain areas when participants grasped 3D tools (N = 20; 9 females). Using real-action fMRI and multivoxel pattern analysis, we found that grasp typicality representations (i.e., whether a tool is grasped appropriately for use) were decodable from hand-selective areas in occipitotemporal and parietal cortices, but not from tool-, object-, or body-selective areas, even if partially overlapping. Importantly, these effects were exclusive for actions with tools, but not for biomechanically matched actions with control nontools. In addition, grasp typicality decoding was significantly higher in hand than tool-selective parietal regions. Notably, grasp typicality representations were automatically evoked even when there was no requirement for tool use and participants were naive to object category (tool vs nontools). Finding a specificity for typical tool grasping in hand-selective, rather than tool-selective, regions challenges the long-standing assumption that activation for viewing tool images reflects sensorimotor processing linked to tool manipulation. Instead, our results show that typicality representations for tool grasping are automatically evoked in visual regions specialized for representing the human hand, the primary tool of the brain for interacting with the world.

Flash monitor initiation is associated with improvements in HbA1c levels and DKA rates among people with type 1 diabetes in Scotland: a retrospective nationwide observational study.

AIMS/HYPOTHESIS: We assessed the real-world effect of flash monitor (FM) usage on HbA1c levels and diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH) rates among people with type 1 diabetes in Scotland and across sociodemographic strata within this population. METHODS: This study was retrospective, observational and registry based. Using the national diabetes registry, 14,682 individuals using an FM at any point between 2014 and mid-2020 were identified. Within-person change from baseline in HbA1c following FM initiation was modelled using linear mixed models accounting for within-person pre-exposure trajectory. DKA and SHH events were captured through linkage to hospital admission and mortality data. The difference in DKA and SHH rates between FM-exposed and -unexposed person-time was assessed among users, using generalised linear mixed models with a Poisson likelihood. In a sensitivity analysis, we tested whether changes in these outcomes were seen in an age-, sex- and baseline HbA1c-matched sample of non-users over the same time period. RESULTS: Prevalence of ever-FM use was 45.9% by mid-2020, with large variations by age and socioeconomic status: 64.3% among children aged <13 years vs 32.7% among those aged ≥65 years; and 54.4% vs 36.2% in the least-deprived vs most-deprived quintile. Overall, the median (IQR) within-person change in HbA1c in the year following FM initiation was -2.5 (-9.0, 2.5) mmol/mol (-0.2 [-0.8, 0.2]%). The change varied widely by pre-usage HbA1c: -15.5 (-31.0, -4.0) mmol/mol (-1.4 [-2.8, -0.4]%) in those with HbA1c > 84 mmol/mol [9.8%] and 1.0 (-2.0, 5.5) mmol/mol (0.1 [-0.2, 0.5]%) in those with HbA1c < 54 mmol/mol (7.1%); the corresponding estimated fold change (95% CI) was 0.77 (0.76, 0.78) and 1.08 (1.07, 1.09). Significant reductions in HbA1c were found in all age bands, sexes and socioeconomic strata, and regardless of prior/current pump use, completion of a diabetes education programme or early FM adoption. Variation between the strata of these factors beyond that driven by differing HbA1c at baseline was slight. No change in HbA1c in matched non-users was observed in the same time period (median [IQR] within-person change = 0.5 [-5.0, 5.5] mmol/mol [0.0 (-0.5, 0.5)%]). DKA rates decreased after FM initiation overall and in all strata apart from the adolescents. Estimated overall reduction in DKA event rates (rate ratio) was 0.59 [95% credible interval (CrI) 0.53, 0.64]) after FM vs before FM initiation, accounting for pre-exposure trend. Finally, among those at higher risk for SHH, estimated reduction in event rates was rate ratio 0.25 (95%CrI 0.20, 0.32) after FM vs before FM initiation. CONCLUSIONS/INTERPRETATION: FM initiation is associated with clinically important reductions in HbA1c and striking reduction in DKA rate. Increasing uptake among the socioeconomically disadvantaged offers considerable potential for tightening the current socioeconomic disparities in glycaemia-related outcomes.

Postradioiodine Graves' management: The PRAGMA study.

OBJECTIVE: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post-RI and compare effectiveness of common management strategies. DESIGN: Retrospective, multicentre and observational study. PATIENTS: Adult patients with Graves' disease treated with RI with 12 months' follow-up. MEASUREMENTS: Euthyroidism was defined as both serum thyrotropin (thyroid-stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4. RESULTS: Of 812 patients studied post-RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post-RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%-28.7%). No negative outcomes (new-onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres. CONCLUSIONS: Dysthyroidism in the 12 months post-RI was common. Differences between post-RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.

Efficacy and safety of cotadutide, a dual glucagon-like peptide-1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease.

AIM: To assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease. MATERIALS AND METHODS: In this phase 2a study (NCT03550378), patients with body mass index 25-45 kg/m2 , estimated glomerular filtration rate 30-59 ml/min/1.73 m2 and type 2 diabetes [glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)] controlled with insulin and/or oral therapy combination, were randomized 1:1 to once-daily subcutaneous cotadutide (50-300 µg) or placebo for 32 days. The primary endpoint was plasma glucose concentration assessed using a mixed-meal tolerance test. RESULTS: Participants receiving cotadutide (n = 21) had significant reductions in the mixed-meal tolerance test area under the glucose concentration-time curve (-26.71% vs. +3.68%, p < .001), more time in target glucose range on continuous glucose monitoring (+14.79% vs. -21.23%, p = .001) and significant reductions in absolute bodyweight (-3.41 kg vs. -0.13 kg, p < .001) versus placebo (n = 20). In patients with baseline micro- or macroalbuminuria (n = 18), urinary albumin-to-creatinine ratios decreased by 51% at day 32 with cotadutide versus placebo (p = .0504). No statistically significant difference was observed in mean change in estimated glomerular filtration rate between treatments. Mild/moderate adverse events occurred in 71.4% of participants receiving cotadutide and 35.0% receiving placebo. CONCLUSIONS: We established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albumin-to-creatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longer-term clinical trials.

Occupational posttraumatic stress disorder and workplace violence in workers' compensation claims.

Acts of violence are the fifth leading cause of nonfatal occupational injuries in the United States. Experiencing a traumatic event at work can have serious mental health consequences, including the development of posttraumatic stress disorder (PTSD). This study aimed to quantify the prevalence of PTSD caused by workplace violence (WPV) in a statewide workers' compensation system and compare the outcomes and treatment of WPV cases versus those caused by other traumatic events. Using a retrospective cohort study design, workers who reported PTSD as the primary reason for a workers' compensation claim and had no coexisting physical injuries were found in California during 2009-2018. A total of 3,772 PTSD cases were identified, 48.9% of which were attributed to WPV. Demographic risk factors associated with WPV PTSD included lower income, younger age, female gender, and employment in retail or finance, p < .001-p = .007. For individuals who returned to work, claims due to WPV resulted in longer medically approved time away from work than non-WPV causes (Mdn = 132.5 days vs. Mdn = 91 days, respectively), p < .001. Three of the top 10 most frequently prescribed medications were administered against evidence-based guidelines. This study found that many treatments prescribed to PTSD patients are based on insufficient evidence, and the provision of existing empirically supported treatments is needed, particularly in generalized populations. The findings support the need for additional recognition of the cause of workplace PTSD to facilitate appropriate referrals to WPV or PTSD specialists to support return-to-work efforts.

Continuous subcutaneous insulin infusion therapy is associated with reduced retinopathy progression compared with multiple daily injections of insulin.

AIMS/HYPOTHESIS: We aimed to compare diabetic retinopathy outcomes in people with type 1 diabetes following introduction of continuous subcutaneous insulin infusion (CSII) therapy with outcomes in people receiving continuing therapy with multiple daily insulin injections (MDI). METHODS: This is a retrospective cohort study using the Scottish Care Information - Diabetes database for retinal screening outcomes and HbA1c changes in 204 adults commenced on CSII therapy between 2013 and 2016, and 211 adults eligible for CSII during the same period but who continued on MDI therapy. Diabetic retinopathy progression (time to minimum one-grade worsening in diabetic retinopathy from baseline grading) was plotted for CSII and MDI cohorts using Kaplan-Meier curves, and outcomes were compared using multivariate Cox regression analysis adjusting for age, sex, baseline HbA1c, blood pressure, cholesterol, smoking status and socioeconomic quintile. Impact of baseline HbA1c and change in HbA1c on diabetic retinopathy progression was assessed within CSII and MDI cohorts. RESULTS: CSII participants were significantly younger, were from less socially deprived areas, and had lower HbA1c and higher diastolic BP at baseline. There was a larger reduction in HbA1c at 1 year in those on CSII vs MDI (-6 mmol/mol [-0.6%] vs -2 mmol/mol [-0.2%], p < 0.01). Diabetic retinopathy progression occurred in a smaller proportion of adults following commencement of CSII vs continued MDI therapy over mean 2.3 year follow-up (26.5% vs 18.6%, p = 0.0097). High baseline HbA1c (75 mmol/mol [9%]) was associated with diabetic retinopathy progression in the MDI group (p = 0.0049) but not the CSII group (p = 0.93). Change in HbA1c at follow-up, irrespective of baseline glycaemic status, did not significantly affect diabetic retinopathy progression in either group. CONCLUSIONS/INTERPRETATION: CSII was associated with reduced diabetic retinopathy progression compared with continued MDI therapy, and may be protective against diabetic retinopathy progression for those with high baseline HbA1c. Progression of diabetic retinopathy over 3 years was not associated with a change in HbA1c.

Marked improvements in glycaemic outcomes following insulin pump therapy initiation in people with type 1 diabetes: a nationwide observational study in Scotland.

AIMS/HYPOTHESIS: Our aim was to assess the use of continuous subcutaneous insulin infusion (CSII) in people with type 1 diabetes in Scotland and its association with glycaemic control, as measured by HbA1c levels, frequency of diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH), overall and stratified by baseline HbA1c. METHODS: We included 4684 individuals with type 1 diabetes from the national Scottish register, who commenced CSII between 2004 and 2019. We presented crude within-person differences from baseline HbA1c over time since initiation, crude DKA and SHH event-rates pre-/post-CSII exposure. We then used mixed models to assess the significance of CSII exposure, taking into account: (1) the diffuse nature of the intervention (i.e. structured education often precedes initiation); (2) repeated within-person measurements; and (3) background time-trends occurring pre-intervention. RESULTS: HbA1c decreased after CSII initiation, with a median within-person change of -5.5 mmol/mol (IQR -12.0, 0.0) (-0.5% [IQR -1.1, 0.0]). Within-person changes were most substantial in those with the highest baseline HbA1c, with median -21.0 mmol/mol (-30.0, -11.0) (-1.9% [-2.7, -1.0]) change in those with a baseline >84 mmol/mol (9.8%) within a year of exposure, that was sustained: -19.0 mmol/mol (-27.6, -6.5) (-1.7% [-2.5, -0.6]) at ≥5 years. Statistical significance and magnitude of change were supported by the mixed models results. The crude DKA event-rate was significantly lower in post-CSII person-time compared with pre-CSII person-time: 49.6 events (95% CI 46.3, 53.1) per 1000 person-years vs 67.9 (64.1, 71.9); rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.61 (95% credible interval [CrI] 0.47, 0.77; posterior probability of reduction pp = 1.00). The crude overall SHH event-rate in post-CSII vs pre-CSII person-time was also lower: 17.8 events (95% CI 15.8, 19.9) per 1000 person-years post-exposure vs 25.8 (23.5, 28.3) pre-exposure; rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.67 (95% CrI 0.45, 1.01; pp = 0.97). CONCLUSIONS/INTERPRETATION: CSII therapy was associated with marked falls in HbA1c especially in those with high baseline HbA1c. CSII was independently associated with reduced DKA and SHH rates. CSII appears to be an effective option for intensive insulin therapy in people with diabetes for improving suboptimal glycaemic control.

Effectiveness of parathyroid hormone (PTH) analogues on fracture healing: a meta-analysis.

This meta-analysis evaluated the evidence for the use of parathyroid hormone (PTH) analogues to improve fracture healing. Eligible studies were prospective randomised controlled trials of adults with acute fractures treated with a PTH analogue. PTH improved functional outcomes but did not affect fracture healing rate or reduce pain. PURPOSE: This meta-analysis evaluated the evidence of parathyroid hormone (PTH) analogues in fracture healing. The use of PTH analogues to prevent osteoporotic fractures is well investigated, and studies are emerging on extended indications. One such indication receiving increasing attention is the effect of PTH in fracture healing; however, the overall degree of efficacy remains inconclusive. METHODS: A systematic electronic database search of MEDLINE, EMBASE and the Cochrane Library was conducted for relevant articles in August 2019 with no date restrictions. Randomised controlled trials of adults with acute fractures treated with a PTH analogue were included. PTH was compared with a comparator intervention, placebo or no treatment. RESULTS: PTH analogue treatment improved functional outcomes in a range of fracture types but did not affect the fracture healing rate or reduce pain. Most trials included in this review were in elderly patients with osteoporosis. There was no evidence that PTH treatment caused harm or impeded fracture healing. CONCLUSIONS: Meta-analysis of published data supports the use of PTH analogues to improve functional outcomes but not fracture healing rate or pain for different fracture types. The evidence for PTH analogue use in fracture healing is less clear in younger, non-osteoporotic patient populations. Trial design was heterogeneous and of limited quality, justifying further original trials.

Sedentary behaviour and bone health in older adults: a systematic review.

Older adults spend more than 8 h/day in sedentary behaviours. Detrimental effects of sedentary behaviour (SB) on health are established, yet little is known about SB and bone health (bone mineral density; BMD) in older adults. The purpose of this review is to examine associations of SB with BMD in older adults. Five electronic databases were searched: Web of Science (Core Collection); PubMed; EMBASE; Sports Medicine and Education and PsycInfo. Inclusion criteria were healthy older adults mean age ≥ 65 years; measured SB and measured BMD using dual-energy X-ray absorptiometry. Quality was assessed using National Institute of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. After excluding duplicates 17813 papers were assessed; 17757 were excluded on title/abstract, 49 at full text, resulting in two prospective and five cross-sectional observational studies reviewed. Four were rated 'good' and three were rated 'fair' using the quality assessment criteria. Findings varied across the studies and differed by gender. In women, four studies reported significant positive associations of SB with BMD at different sites, and two found significant negative associations. Five studies which examined both men and women, men reported negative or no associations of SB with femoral neck, pelvic, whole body, spine or leg BMD. Whilst these findings suggest differences between men and women in the associations of SB with BMD, they may be due to the varying anatomical sections examined for BMD, the different methods used to measure SB, the varied quality of the studies included and the limited number of published findings.

Socioeconomic deprivation, technology use, C-peptide, smoking and other predictors of glycaemic control in adults with type 1 diabetes.

AIMS: Intensive glycaemic control is associated with substantial health benefits in people with type 1 diabetes. We sought to examine clinical and demographic factors associated with meeting glycaemic targets in type 1 diabetes. METHODS: We conducted a cross-sectional analysis of 4594 individuals with type 1 diabetes. The primary outcome of the study was assessing factors associated with meeting HbA1c targets. Secondary endpoints included factors associated with continuous subcutaneous insulin infusion (CSII) use and persistent C-peptide secretion. RESULTS: Socioeconomic deprivation was strongly associated with a lower likelihood of achieving an HbA1c <58 mmol/mol (7.5%) (20% in the most deprived quintile vs. 40% in the least deprived, p < 0.001). In multivariate analysis, absence of smoking history (OR 3.06, p < 0.001), flash monitoring (OR 1.49, p < 0.001), CSII (1.43, p = 0.022) and longer diabetes duration (OR 1.02 per year, p = 0.004) were independently associated with achieving HbA1c <58 mmol/mol (7.5%), whereas increasing age (OR 0.99 per year, p = 0.004) and C-peptide <50 pM (OR 0.58, p < 0.001) were associated with a lower likelihood of meeting this target. Low C-peptide (<50 pM) was less likely in men (OR 0.55, p < 0.001) and never smokers (0.44, p < 0.001) in multivariate analysis. CONCLUSIONS: Lower levels of deprivation, non-smoking, higher C-peptide, technology use, lower BMI and male gender were all associated with a higher likelihood of meeting HbA1c targets. Access to proven diabetes treatments is lower in the most deprived individuals. Urgent efforts are required to provide treatments which are effective across the socioeconomic gradient.

Impact of routine clinic measurement of serum C-peptide in people with a clinician-diagnosis of type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to determine the impact of the routine use of serum C-peptide in an out-patient clinic setting on individuals with a clinician-diagnosis of type 1 diabetes. METHODS: In this single-centre study, individuals with type 1 diabetes of at least 3 years duration were offered random serum C-peptide testing at routine clinic review. A C-peptide ≥200 pmol/L prompted further evaluation of the individual using a diagnostic algorithm that included measurement of islet cell antibodies and genetic testing. Where appropriate, a trial of anti-diabetic co-therapies was considered. RESULTS: Serum C-peptide testing was performed in 859 individuals (90% of the eligible cohort), of whom 114 (13.2%) had C-peptide ≥200 pmol/L. The cause of diabetes was reclassified in 58 individuals (6.8% of the tested cohort). The majority of reclassifications were to type 2 diabetes (44 individuals; 5.1%), with a smaller proportion of monogenic diabetes (14 individuals; 1.6%). Overall, 13 individuals (1.5%) successfully discontinued insulin, while a further 16 individuals (1.9%) had improved glycaemic control following the addition of co-therapies. The estimated total cost of the testing programme was £23,262 (~€26,053), that is, £27 (~€30) per individual tested. In current terms, the cost of prior insulin therapy in the individuals with monogenic diabetes who successfully stopped insulin was approximately £57,000 (~€64,000). CONCLUSIONS/INTERPRETATION: Serum C-peptide testing can easily be incorporated into an out-patient clinic setting and could be a cost-effective intervention. C-peptide testing should be strongly considered in individuals with a clinician-diagnosis of type 1 diabetes of at least 3 years duration.

Preserved C-peptide secretion is associated with fewer low-glucose events and lower glucose variability on flash glucose monitoring in adults with type 1 diabetes.

AIMS/HYPOTHESIS: We aimed to assess whether persistence of C-peptide secretion is associated with less glucose variability and fewer low-glucose events in adults with type 1 diabetes who use flash monitoring. METHODS: We performed a cross-sectional study of 290 adults attending a university teaching hospital diabetes clinic, with type 1 diabetes, who use flash monitoring and in whom a random plasma C-peptide was available in the past 2 years. Variables relating to flash monitoring were compared between individuals with low C-peptide (<10 pmol/l) and those with persistent C-peptide (either 10-200 pmol/l or 10-50 pmol/l). In addition, the relationship between self-reported hypoglycaemia and C-peptide was assessed (n = 167). Data are median (interquartile range). RESULTS: Individuals with preserved C-peptide secretion (10-200 pmol/l) had shorter duration of diabetes (15 [9-24] vs 25 [15-34] years, p < 0.001) and older age at diagnosis (23 [14-28] vs 15 [9-25] years, p < 0.001), although current age did not differ in this cohort. Preserved C-peptide was associated with lower time with glucose <3.9 mmol/l (3% [2-6%] vs 5% [3-9%], p < 0.001), fewer low-glucose events per 2 week period (7 [4-10] vs 10 [5-16], p < 0.001), lower SD of glucose (3.8 [3.4-4.2] vs 4.1 [3.5-4.7] mmol/l, p = 0.017) and lower CV of glucose (38.0 [35.0-41.6] vs 41.8 [36.5-45.8], p < 0.001). These differences were also present in those with C-peptide 10-50 pmol/l and associations were independent of diabetes duration and estimated HbA1c in logistic regression analysis. Preserved C-peptide was also associated with lower rates of self-reported asymptomatic hypoglycaemia (8.0% vs 22.8% in the past month, p = 0.028). CONCLUSIONS/INTERPRETATION: Preserved C-peptide secretion is associated with fewer low-glucose events and lower glucose variability on flash monitoring. This suggests that individuals with preserved C-peptide may more safely achieve intensive glycaemic targets.

Developmental changes in the processing of faces as revealed by EEG decoding.

Rapidly and accurately processing information from faces is a critical human function that is known to improve with developmental age. Understanding the underlying drivers of this improvement remains a contentious question, with debate continuing as to the presence of early vs. late maturation of face-processing mechanisms. Recent behavioural evidence suggests an important 'hallmark' of expert face processing - the face inversion effect - is present in very young children, yet neural support for this remains unclear. To address this, we conducted a detailed investigation of the neural dynamics of face processing in children spanning a range of ages (6-11 years) and adults. Uniquely, we applied multivariate pattern analysis (MVPA) to the electroencephalogram signal (EEG) to test for the presence of a distinct neural profile associated with canonical upright faces when compared both to other objects (houses) and to inverted faces. Results revealed robust discrimination profiles, at the individual level, of differentiated neural activity associated with broad face categorization and further with its expert processing, as indexed by the face inversion effect, from the youngest ages tested. This result is consistent with an early functional maturation of broad face processing mechanisms. Yet, clear quantitative differences between the response profile of children and adults is suggestive of age-related refinement of this system with developing face and general expertise. Standard ERP analysis also provides some support for qualitative differences in the neural response to inverted faces in children in contrast to adults. This neural profile is in line with recent behavioural studies that have reported impressively expert early face abilities during childhood, while also providing novel evidence of the ongoing neural specialisation between child and adulthood.

The influence of antidepressant and psychotherapy treatment adherence on future work leaves for patients with major depressive disorder.

BACKGROUND: Depression is the greatest contributor to worldwide disability. The purpose of this study was to understand the influence of antidepressant and psychotherapy treatment adherence on future work leaves for patients with major depressive disorder. METHODS: Patients with a newly diagnosed major depressive disorder (n = 26,256) were identified in IBM® Watson™ MarketScan® medical and disability claims databases. Antidepressant and psychotherapy adherence metrics were evaluated in the acute phase of treatment, defined as the 114 days following the depression diagnosis. Multiple variable Cox proportional hazards regression models evaluated the influence of antidepressant and/or psychotherapy adherence on future injury or illness work leaves. RESULTS: The majority of work leaves in the 2-year follow-up period occurred in the acute phase of treatment (71.2%). Among patients without a work leave in the acute phase and who received antidepressants and/or psychotherapy (n = 19,994), those who were adherent to antidepressant or psychotherapy treatment in the acute phase had a 16% (HR = 0.84, 95% CI = 0.77-0.91) reduced risk of a future work leave compared to treatment non-adherent patients. Patients who were non-adherent or adherent to antidepressant treatment had a 22% (HR = 1.22, 95% CI = 1.11-1.35) and 13% (HR = 1.13, 95% CI = 1.01-1.27) greater risk of a future work leave, respectively, than patients not receiving antidepressant treatment. Conversely, patients who were non-adherent or adherent to psychotherapy treatment had a 9% (HR = 0.91, 95% CI = 0.81-1.02) and 28% (HR = 0.72, 95% CI = 0.64-0.82) reduced risk of a future work leave, respectively, than patients not receiving psychotherapy treatment. CONCLUSIONS: This analysis suggests that treatment adherence may reduce the likelihood of a future work leave for patients with newly diagnosed major depressive disorder. Psychotherapy appears more effective than antidepressants in reducing the risk of a future work leave.

Marked improvement in HbA1c following commencement of flash glucose monitoring in people with type 1 diabetes.

AIMS/HYPOTHESIS: Minimal evidence supports the efficacy of flash monitoring in lowering HbA1c. We sought to assess the impact of introducing flash monitoring in our centre. METHODS: We undertook a prospective observational study to assess change in HbA1c in 900 individuals with type 1 diabetes following flash monitoring (comparator group of 518 with no flash monitoring). Secondary outcomes included changes in hypoglycaemia, quality of life, flash monitoring data and hospital admissions. RESULTS: Those with baseline HbA1c ≥58 mmol/mol (7.5%) achieved a median -7 mmol/mol (interquartile range [IQR] -13 to -1) (0.6% [-1.2 to -0.1]%) change in HbA1c (p < 0.001). The percentage achieving HbA1c <58 mmol/mol rose from 34.2% to 50.9% (p < 0.001). Median follow-up was 245 days (IQR 182 to 330). Individuals not using flash monitoring experienced no change in HbA1c across a similar timescale (p = 0.508). Higher HbA1c (p < 0.001), younger age at diagnosis (p = 0.003) and lower social deprivation (p = 0.024) were independently associated with an HbA1c fall of ≥5 mmol/mol (0.5%). More symptomatic (OR 1.9, p < 0.001) and asymptomatic (OR 1.4, p < 0.001) hypoglycaemia was reported after flash monitoring. Following flash monitoring, regimen-related and emotional components of the diabetes distress scale improved although the proportion with elevated anxiety (OR 1.2, p = 0.028) and depression (OR 2.0, p < 0.001) scores increased. Blood glucose test strip use fell from 3.8 to 0.6 per day (p < 0.001). Diabetic ketoacidosis admissions fell significantly following flash monitoring (p = 0.043). CONCLUSIONS/INTERPRETATION: Flash monitoring is associated with significant improvements in HbA1c and fewer diabetic ketoacidosis admissions. Higher rates of hypoglycaemia may relate to greater recognition of hitherto unrecognised events. Impact upon quality of life parameters was mixed but overall treatment satisfaction was overwhelmingly positive.