Branching topology of the human embryo transcriptome revealed by Entropy Sort Feature Weighting.

Analysis of single cell transcriptomics (scRNA-seq) data is typically performed after subsetting to highly variable genes (HVGs). Here, we show that Entropy Sorting provides an alternative mathematical framework for feature selection. On synthetic datasets, continuous Entropy Sort Feature Weighting (cESFW) outperforms HVG selection in distinguishing cell-state-specific genes. We apply cESFW to six merged scRNA-seq datasets spanning human early embryo development. Without smoothing or augmenting the raw counts matrices, cESFW generates a high-resolution embedding displaying coherent developmental progression from eight-cell to post-implantation stages and delineating 15 distinct cell states. The embedding highlights sequential lineage decisions during blastocyst development, while unsupervised clustering identifies branch point populations obscured in previous analyses. The first branching region, where morula cells become specified for inner cell mass or trophectoderm, includes cells previously asserted to lack a developmental trajectory. We quantify the relatedness of different pluripotent stem cell cultures to distinct embryo cell types and identify marker genes of naïve and primed pluripotency. Finally, by revealing genes with dynamic lineage-specific expression, we provide markers for staging progression from morula to blastocyst.

On the surprising effectiveness of a simple matrix exponential derivative approximation, with application to global SARS-CoV-2.

The continuous-time Markov chain (CTMC) is the mathematical workhorse of evolutionary biology. Learning CTMC model parameters using modern, gradient-based methods requires the derivative of the matrix exponential evaluated at the CTMC's infinitesimal generator (rate) matrix. Motivated by the derivative's extreme computational complexity as a function of state space cardinality, recent work demonstrates the surprising effectiveness of a naive, first-order approximation for a host of problems in computational biology. In response to this empirical success, we obtain rigorous deterministic and probabilistic bounds for the error accrued by the naive approximation and establish a "blessing of dimensionality" result that is universal for a large class of rate matrices with random entries. Finally, we apply the first-order approximation within surrogate-trajectory Hamiltonian Monte Carlo for the analysis of the early spread of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across 44 geographic regions that comprise a state space of unprecedented dimensionality for unstructured (flexible) CTMC models within evolutionary biology.

Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y. In this study, we made a knock-in (KI) mouse line with a very low expression of G90D-Rho (equal in amount to ~0.1% of normal rhodopsin, WT-Rho, in WT rods), with the remaining WT-Rho replaced by REY-Rho, a mutant with a very low efficiency of activating transducin due to a charge reversal of the highly conserved ERY motif to REY. We observed two kinds of constitutive noise: one being spontaneous isomerization (R*) of G90D-Rho at a molecular rate (R* s-1) 175-fold higher than WT-Rho and the other being G90D-Rho-generated dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s-1 from WT-Rho. Neither noise type originated from G90D-Opsin because exogenous 11-cis-retinal had no effect. Extrapolating the above observations at low (0.1%) expression of G90D-Rho to normal disease exhibited by a KI mouse model with RhoG90D/WTand RhoG90D/G90D genotypes predicts the disease condition very well quantitatively. Overall, the continuous noise from G90D-Rho therefore predominates, constituting the major equivalent background light causing rod desensitization in CSNB.

Direct Electron Transfer-Type Oxidoreductases for Biomedical Applications.

Among the various types of enzyme-based biosensors, sensors utilizing enzymes capable of direct electron transfer (DET) are recognized as the most ideal. However, only a limited number of redox enzymes are capable of DET with electrodes, that is, dehydrogenases harboring a subunit or domain that functions specifically to accept electrons from the redox cofactor of the catalytic site and transfer the electrons to the external electron acceptor. Such subunits or domains act as built-in mediators for electron transfer between enzymes and electrodes; consequently, such enzymes enable direct electron transfer to electrodes and are designated as DET-type enzymes. DET-type enzymes fall into several categories, including redox cofactors of catalytic reactions, built-in mediators for DET with electrodes and by their protein hierarchic structures, DET-type oxidoreductases with oligomeric structures harboring electron transfer subunits, and monomeric DET-type oxidoreductases harboring electron transfer domains. In this review, we cover the science of DET-type oxidoreductases and their biomedical applications. First, we introduce the structural biology and current understanding of DET-type enzyme reactions. Next, we describe recent technological developments based on DET-type enzymes for biomedical applications, such as biosensors and biochemical energy harvesting for self-powered medical devices. Finally, after discussing how to further engineer and create DET-type enzymes, we address the future prospects for DET-type enzymes in biomedical engineering.

Switching off: disruptive TMS reveals distinct contributions of the posterior middle temporal gyrus and angular gyrus to bilingual speech production.

The role of the left temporoparietal cortex in speech production has been extensively studied during native language processing, proving crucial in controlled lexico-semantic retrieval under varying cognitive demands. Yet, its role in bilinguals, fluent in both native and second languages, remains poorly understood. Here, we employed continuous theta burst stimulation to disrupt neural activity in the left posterior middle-temporal gyrus (pMTG) and angular gyrus (AG) while Italian-Friulian bilinguals performed a cued picture-naming task. The task involved between-language (naming objects in Italian or Friulian) and within-language blocks (naming objects ["knife"] or associated actions ["cut"] in a single language) in which participants could either maintain (non-switch) or change (switch) instructions based on cues. During within-language blocks, cTBS over the pMTG entailed faster naming for high-demanding switch trials, while cTBS to the AG elicited slower latencies in low-demanding non-switch trials. No cTBS effects were observed in the between-language block. Our findings suggest a causal involvement of the left pMTG and AG in lexico-semantic processing across languages, with distinct contributions to controlled vs. "automatic" retrieval, respectively. However, they do not support the existence of shared control mechanisms within and between language(s) production. Altogether, these results inform neurobiological models of semantic control in bilinguals.

Continuous Strain Regulation of Palladium-Gold at the Atomic Level.

Revealing the effect of surface structure changes on the electrocatalytic performance is beneficial to the development of highly efficient catalysts. However, precise regulation of the catalyst surface at the atomic level remains challenging. Here, we present a continuous strain regulation of palladium (Pd) on gold (Au) via a mechanically controllable surface strain (MCSS) setup. It is found that the structural changes induced by the strain setup can accelerate electron transfer at the solid-liquid interface, thus achieving a significantly improved performance toward hydrogen evolution reaction (HER). In situ X-ray diffraction (XRD) experiments further confirm that the enhanced activity is attributed to the increased interplanar spacing resulting from the applied strain. Theoretical calculations reveal that the tensile strain modulates the electronic structure of the Pd active sites and facilitates the desorption of the hydrogen intermediates. This work provides an effective approach for revealing the relationships between the electrocatalyst surface structure and catalytic activity.

Physiological Microenvironment Dependent Self-Cross-Linking of Multifunctional Nanohybrid for Prolonged Antibacterial Therapy via Synergistic Chemodynamic-Photothermal-Biological Processes.

Herein, a multifunctional nanohybrid (PL@HPFTM nanoparticles) was fabricated to perform the integration of chemodynamic therapy, photothermal therapy, and biological therapy over the long term at a designed location for continuous antibacterial applications. The PL@HPFTM nanoparticles consisted of a polydopamine/hemoglobin/Fe2+ nanocomplex with comodification of tetrazole/alkene groups on the surface as well as coloading of antimicrobial peptides and luminol in the core. During therapy, the PL@HPFTM nanoparticles would selectively cross-link to surrounding bacteria via tetrazole/alkene cycloaddition under chemiluminescence produced by the reaction between luminol and overexpressed H2O2 at the infected area. The resulting PL@HPFTM network not only significantly damaged bacteria by Fe2+-catalyzed ROS production, effective photothermal conversion, and sustained release of antimicrobial peptides but dramatically enhanced the retention time of these therapeutic agents for prolonged antibacterial therapy. Both in vitro and in vivo results have shown that our PL@HPFTM nanoparticles have much higher bactericidal efficiency and remarkably longer periods of validity than free antibacterial nanoparticles.

Incorporating functional annotation with bilevel continuous shrinkage for polygenic risk prediction.

BACKGROUND: Genetic variants can contribute differently to trait heritability by their functional categories, and recent studies have shown that incorporating functional annotation can improve the predictive performance of polygenic risk scores (PRSs). In addition, when only a small proportion of variants are causal variants, PRS methods that employ a Bayesian framework with shrinkage can account for such sparsity. It is possible that the annotation group level effect is also sparse. However, the number of PRS methods that incorporate both annotation information and shrinkage on effect sizes is limited. We propose a PRS method, PRSbils, which utilizes the functional annotation information with a bilevel continuous shrinkage prior to accommodate the varying genetic architectures both on the variant-specific level and on the functional annotation level. RESULTS: We conducted simulation studies and investigated the predictive performance in settings with different genetic architectures. Results indicated that when there was a relatively large variability of group-wise heritability contribution, the gain in prediction performance from the proposed method was on average 8.0% higher AUC compared to the benchmark method PRS-CS. The proposed method also yielded higher predictive performance compared to PRS-CS in settings with different overlapping patterns of annotation groups and obtained on average 6.4% higher AUC. We applied PRSbils to binary and quantitative traits in three real world data sources (the UK Biobank, the Michigan Genomics Initiative (MGI), and the Korean Genome and Epidemiology Study (KoGES)), and two sources of annotations: ANNOVAR, and pathway information from the Kyoto Encyclopedia of Genes and Genomes (KEGG), and demonstrated that the proposed method holds the potential for improving predictive performance by incorporating functional annotations. CONCLUSIONS: By utilizing a bilevel shrinkage framework, PRSbils enables the incorporation of both overlapping and non-overlapping annotations into PRS construction to improve the performance of genetic risk prediction. The software is available at https://github.com/styvon/PRSbils .

Threshold of hyperglycaemia associated with mortality in critically ill patients: a multicentre, prospective, observational study using continuous glucose monitoring.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) provides comprehensive information on the exposure to dysglycaemia. This study aimed to investigate the threshold of hyperglycaemia related to mortality risk in critically ill patients using CGM technology. METHODS: A total of 293 adult critically ill patients admitted to intensive care units of five medical centres were prospectively included between May 2020 and November 2021. Participants wore intermittently scanned CGM for a median of 12.0 days. The relationships between different predefined time above ranges (TARs), with the thresholds of hyperglycaemia ranging from 7.8 to 13.9 mmol/l (140-250 mg/dl), and in-hospital mortality risk were assessed by multivariate Cox proportional regression analysis. Time in ranges (TIRs) of 3.9 mmol/l (70 mg/dl) to the predefined hyperglycaemic thresholds were also assessed. RESULTS: Overall, 66 (22.5%) in-hospital deaths were identified. Only TARs with a threshold of 10.5 mmol/l (190 mg/dl) or above were significantly associated with the risk of in-hospital mortality, after adjustment for covariates. Furthermore, as the thresholds for TAR increased from 10.5 mmol/l to 13.9 mmol/l (190 mg/dl to 250 mg/dl), the hazards of in-hospital mortality increased incrementally with every 10% increase in TARs. Similar results were observed concerning the associations between TIRs with various upper thresholds and in-hospital mortality risk. For per absolute 10% decrease in TIR 3.9-10.5 mmol/l (70-190 mg/dl), the risk of in-hospital mortality was increased by 12.1% (HR 1.121 [95% CI 1.003, 1.253]). CONCLUSIONS/INTERPRETATION: A glucose level exceeding 10.5 mmol/l (190 mg/dl) was significantly associated with higher risk of in-hospital mortality in critically ill patients.

Accuracy of continuous glucose monitoring in the hospital setting: an observational study.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) improves glycaemic outcomes in the outpatient setting; however, there are limited data regarding CGM accuracy in hospital. METHODS: We conducted a prospective, observational study comparing CGM data from blinded Dexcom G6 Pro sensors with reference point of care and laboratory glucose measurements during participants' hospitalisations. Key accuracy metrics included the proportion of CGM values within ±20% of reference glucose values >5.6 mmol/l or within ±1.1 mmol/l of reference glucose values ≤5.6 mmol/l (%20/20), the mean and median absolute relative difference between CGM and reference value (MARD and median ARD, respectively) and Clarke error grid analysis (CEGA). A retrospective calibration scheme was used to determine whether calibration improved sensor accuracy. Multivariable regression models and subgroup analyses were used to determine the impact of clinical characteristics on accuracy assessments. RESULTS: A total of 326 adults hospitalised on 19 medical or surgical non-intensive care hospital floors were enrolled, providing 6648 matched glucose pairs. The %20/20 was 59.5%, the MARD was 19.2% and the median ARD was 16.8%. CEGA showed that 98.2% of values were in zone A (clinically accurate) and zone B (benign). Subgroups with lower accuracy metrics included those with severe anaemia, renal dysfunction and oedema. Application of a once-daily morning calibration schedule improved accuracy (MARD 11.4%). CONCLUSIONS/INTERPRETATION: The CGM accuracy when used in hospital may be lower than that reported in the outpatient setting, but this may be improved with appropriate patient selection and daily calibration. Further research is needed to understand the role of CGM in inpatient settings.

Cost-utility analysis of Dexcom G6 real-time continuous glucose monitoring versus FreeStyle Libre 1 intermittently scanned continuous glucose monitoring in adults with type 1 diabetes in Belgium.

AIMS/HYPOTHESIS: The aim of this study was to assess the long-term cost-effectiveness of Dexcom G6 real-time continuous glucose monitoring (rtCGM) with alert functionality compared with FreeStyle Libre 1 intermittently scanned continuous glucose monitoring (isCGM) without alerts in adults with type 1 diabetes in Belgium. METHODS: The IQVIA CORE Diabetes Model was used to estimate cost-effectiveness. Input data for the simulated baseline cohort were sourced from the randomised ALERTT1 trial (ClinicalTrials.gov. REGISTRATION NO: NCT03772600). The age of the participants was 42.9 ± 14.1 years (mean ± SD), and the baseline HbA1c was 57.8 ± 9.5 mmol/mol (7.4 ± 0.9%). Participants using rtCGM showed a reduction in HbA1c of 3.6 mmol/mol (0.36 percentage points) based on the 6-month mean between-group difference. In the base case, both rtCGM and isCGM were priced at €3.92/day (excluding value-added tax [VAT]) according to the Belgian reimbursement system. The analysis was performed from a Belgian healthcare payer perspective over a lifetime time horizon. Health outcomes were expressed as quality-adjusted life years. Probabilistic and one-way sensitivity analyses were used to account for parameter uncertainty. RESULTS: In the base case, rtCGM dominated isCGM, resulting in lower diabetes-related complication costs and better health outcomes. The associated main drivers favouring rtCGM were lower HbA1c, fewer severe hypoglycaemic events and reduced fear of hypoglycaemia. The results were robust under a wide range of one-way sensitivity analyses. In models where the price of rtCGM is €5.11/day (a price increase of 30.4%) or €12.34/day (a price increase of 214.8%), rtCGM was cost-neutral or reached an incremental cost-effectiveness ratio of €40,000 per quality-adjusted life year, respectively. CONCLUSIONS/INTERPRETATION: When priced similarly, Dexcom G6 rtCGM with alert functionality has both economic and clinical benefits compared with FreeStyle Libre 1 isCGM without alerts in adults with type 1 diabetes in Belgium, and appears to be a cost-effective glucose monitoring modality. Trial registration ClinicalTrials.gov NCT03772600.

The use of technology in type 2 diabetes and prediabetes: a narrative review.

The increasing incidence of type 2 diabetes, which represents 90% of diabetes cases globally, is a major public health concern. Improved glucose management reduces the risk of vascular complications and mortality; however, only a small proportion of the type 2 diabetes population have blood glucose levels within the recommended treatment targets. In recent years, diabetes technologies have revolutionised the care of people with type 1 diabetes, and it is becoming increasingly evident that people with type 2 diabetes can also benefit from these advances. In this review, we describe the current knowledge regarding the role of technologies for people living with type 2 diabetes and the evidence supporting their use in clinical practice. We conclude that continuous glucose monitoring systems deliver glycaemic benefits for individuals with type 2 diabetes, whether treated with insulin or non-insulin therapy; further data are required to evaluate the role of these systems in those with prediabetes (defined as impaired glucose tolerance and/or impaired fasting glucose and/or HbA1c levels between 39 mmol/mol [5.7%] and 47 mmol/mol [6.4%]). The use of insulin pumps seems to be safe and effective in people with type 2 diabetes, especially in those with an HbA1c significantly above target. Initial results from studies exploring the impact of closed-loop systems in type 2 diabetes are promising. We discuss directions for future research to fully understand the potential benefits of integrating evidence-based technology into care for people living with type 2 diabetes and prediabetes.

Continuous glucose monitoring in adults with type 2 diabetes: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) is increasingly used in the treatment of type 2 diabetes, but the effects on glycaemic control are unclear. The aim of this systematic review and meta-analysis is to provide a comprehensive overview of the effect of CGM on glycaemic control in adults with type 2 diabetes. METHODS: We performed a systematic review using Embase, MEDLINE, Web of Science, Scopus and ClinicalTrials.gov from inception until 2 May 2023. We included RCTs investigating real-time CGM (rtCGM) or intermittently scanned CGM (isCGM) compared with self-monitoring of blood glucose (SMBG) in adults with type 2 diabetes. Studies with an intervention duration <6 weeks or investigating professional CGM, a combination of CGM and additional glucose-lowering treatment strategies or GlucoWatch were not eligible. Change in HbA1c and the CGM metrics time in range (TIR), time below range (TBR), time above range (TAR) and glycaemic variability were extracted. We evaluated the risk of bias using the Cochrane risk-of-bias tool version 2. Data were synthesised by performing a meta-analysis. We also explored the effects of CGM on severe hypoglycaemia and micro- and macrovascular complications. RESULTS: We found 12 RCTs comprising 1248 participants, with eight investigating rtCGM and four isCGM. Compared with SMBG, CGM use (rtCGM or isCGM) led to a mean difference (MD) in HbA1c of -3.43 mmol/mol (-0.31%; 95% CI -4.75, -2.11, p<0.00001, I2=15%; moderate certainty). This effect was comparable in studies that included individuals using insulin with or without oral agents (MD -3.27 mmol/mol [-0.30%]; 95% CI -6.22, -0.31, p=0.03, I2=55%), and individuals using oral agents only (MD -3.22 mmol/mol [-0.29%]; 95% CI -5.39, -1.05, p=0.004, I2=0%). Use of rtCGM showed a trend towards a larger effect (MD -3.95 mmol/mol [-0.36%]; 95% CI -5.46 to -2.44, p<0.00001, I2=0%) than use of isCGM (MD -1.79 mmol/mol [-0.16%]; 95% CI -5.28, 1.69, p=0.31, I2=64%). CGM was also associated with an increase in TIR (+6.36%; 95% CI +2.48, +10.24, p=0.001, I2=9%) and a decrease in TBR (-0.66%; 95% CI -1.21, -0.12, p=0.02, I2=45%), TAR (-5.86%; 95% CI -10.88, -0.84, p=0.02, I2=37%) and glycaemic variability (-1.47%; 95% CI -2.94, -0.01, p=0.05, I2=0%). Three studies reported one or more events of severe hypoglycaemia and macrovascular complications. In comparison with SMBG, CGM use led to a non-statistically significant difference in the incidence of severe hypoglycaemia (RR 0.66, 95% CI 0.15, 3.00, p=0.57, I2=0%) and macrovascular complications (RR 1.54, 95% CI 0.42, 5.72, p=0.52, I2=29%). No trials reported data on microvascular complications. CONCLUSIONS/INTERPRETATION: CGM use compared with SMBG is associated with improvements in glycaemic control in adults with type 2 diabetes. However, all studies were open label. In addition, outcome data on incident severe hypoglycaemia and incident microvascular and macrovascular complications were scarce. REGISTRATION: This systematic review was registered on PROSPERO (ID CRD42023418005).

Glycaemia risk index uncovers distinct glycaemic variability patterns associated with remission status in type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this work was to define a unique remission status using glycaemia risk index (GRI) and other continuous glucose monitoring (CGM) metrics in individuals with type 1 diabetes for improved phenotyping. METHODS: A group of 140 individuals with type 1 diabetes were recruited for a cross-sectional study. The participants were categorised into four groups based on their remission status, which was defined as insulin-dose-adjusted A1c (IDAA1c) <9 or C-peptide ≥300 pmol/l: new-onset (n=24); mid-remission (n=44); post-remission (n=44); and non-remission (individuals who did not experience remission, n=28). Participants in the remission phase were referred to as 'remitters', while those who were not in the remission phase were referred to as 'non-remitters', the latter group including new-onset, post-remission and non-remission participants. Clinical variables such as HbA1c, C-peptide and insulin daily dose, as well as IDAA1C and CGM data, were collected. The patterns of CGM metrics were analysed for each group using generalised estimating equations to investigate the glycaemic variability patterns associated with remission status. Then, unsupervised hierarchical clustering was used to place the participants into subgroups based on GRI and other CGM core metrics. RESULTS: The glycaemic variability patterns associated with remission status were found to be distinct based on the circadian CGM metrics. Remitters showed improved control of blood glucose levels over 14 days within the range of 3.9-10 mmol/l, and lower GRI compared with non-remitters (p<0.001). Moreover, GRI strongly correlated with IDAA1C (r=0.62; p<0.001) and was sufficient to distinguish remitters from non-remitters. Further, four subgroups demonstrating distinct patterns of glycaemic variability associated with different remission status were identified by clustering on CGM metrics: remitters with low risk of dysglycaemia; non-remitters with high risk of hypoglycaemia; non-remitters with high risk of hyperglycaemia; and non-remitters with moderate risk of dysglycaemia. CONCLUSIONS/INTERPRETATION: GRI, an integrative index, together with other traditional CGM metrics, helps to identify different glycaemic variability patterns; this might provide specifically tailored monitoring and management strategies for individuals in the various subclusters.

Continuous glucose monitoring with structured education in adults with type 2 diabetes managed by multiple daily insulin injections: a multicentre randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to compare the effectiveness of stand-alone intermittently scanned continuous glucose monitoring (isCGM) with or without a structured education programme and blood glucose monitoring (BGM) in adults with type 2 diabetes on multiple daily insulin injections (MDI). METHODS: In this 24 week randomised open-label multicentre trial, adults with type 2 diabetes on intensive insulin therapy with HbA1c levels of 58-108 mmol/mol (7.5-12.0%) were randomly assigned in a 1:1:1 ratio to isCGM with a structured education programme on adjusting insulin dose and timing according to graphical patterns in CGM (intervention group), isCGM with conventional education (control group 1) or BGM with conventional education (control group 2). Block randomisation was conducted by an independent statistician. Due to the nature of the intervention, blinding of participants and investigators was not possible. The primary outcome was change in HbA1c from baseline at 24 weeks, assessed using ANCOVA with the baseline value as a covariate. RESULTS: A total of 159 individuals were randomised (n=53 for each group); 148 were included in the full analysis set, with 52 in the intervention group, 49 in control group 1 and 47 in control group 2. The mean (± SD) HbA1c level at baseline was 68.19±10.94 mmol/mol (8.39±1.00%). The least squares mean change (± SEM) from baseline HbA1c at 24 weeks was -10.96±1.35 mmol/mol (-1.00±0.12%) in the intervention group, -6.87±1.39 mmol/mol (-0.63±0.13%) in control group 1 (p=0.0367 vs intervention group) and -6.32±1.42 mmol/mol (-0.58±0.13%) in control group 2 (p=0.0193 vs intervention group). Adverse events occurred in 28.85% (15/52) of individuals in the intervention group, 26.42% (14/53) in control group 1 and 48.08% (25/52) in control group 2. CONCLUSIONS/INTERPRETATION: Stand-alone isCGM offers a greater reduction in HbA1c in adults with type 2 diabetes on MDI when education on the interpretation of graphical patterns in CGM is provided. TRIAL REGISTRATION: ClinicalTrials.gov NCT04926623. FUNDING: This study was supported by Daewoong Pharmaceutical Co., Ltd.

Discordance between mean glucose and time in range in relation to HbA1c in individuals with type 1 diabetes: results from the GOLD and SILVER trials.

AIMS/HYPOTHESIS: Previous studies have shown that individuals with similar mean glucose levels (MG) or percentage of time in range (TIR) may have different HbA1c values. The aim of this study was to further elucidate how MG and TIR are associated with HbA1c. METHODS: Data from the randomised clinical GOLD trial (n=144) and the follow-up SILVER trial (n=98) of adults with type 1 diabetes followed for 2.5 years were analysed. A total of 596 paired HbA1c/continuous glucose monitoring measurements were included. Linear mixed-effects models were used to account for intra-individual correlations in repeated-measures data. RESULTS: In the GOLD trial, the mean age of the participants (± SD) was 44±13 years, 63 (44%) were female, and the mean HbA1c (± SD) was 72±9.8 mmol/mol (8.7±0.9%). When correlating MG with HbA1c, MG explained 63% of the variation in HbA1c (r=0.79, p<0.001). The variation in HbA1c explained by MG increased to 88% (r=0.94, p value for improvement of fit <0.001) when accounting for person-to-person variation in the MG-HbA1c relationship. Time below range (TBR; <3.9 mmol/l), time above range (TAR) level 2 (>13.9 mmol/l) and glycaemic variability had little or no effect on the association. For a given MG and TIR, the HbA1c of 10% of individuals deviated by >8 mmol/mol (0.8%) from their estimated HbA1c based on the overall association between MG and TIR with HbA1c. TBR and TAR level 2 significantly influenced the association between TIR and HbA1c. At a given TIR, each 1% increase in TBR was related to a 0.6 mmol/mol lower HbA1c (95% CI 0.4, 0.9; p<0.001), and each 2% increase in TAR level 2 was related to a 0.4 mmol/mol higher HbA1c (95% CI 0.1, 0.6; p=0.003). However, neither TIR, TBR nor TAR level 2 were significantly associated with HbA1c when accounting for MG. CONCLUSIONS/INTERPRETATION: Inter-individual variations exist between MG and HbA1c, as well as between TIR and HbA1c, with clinically important deviations in relatively large groups of individuals with type 1 diabetes. These results may provide important information to both healthcare providers and individuals with diabetes in terms of prognosis and when making diabetes management decisions.

Diabetes technology in people with diabetes and advanced chronic kidney disease.

Diabetes is the leading cause and a common comorbidity of advanced chronic kidney disease. Glycaemic management in this population is challenging and characterised by frequent excursions of hypoglycaemia and hyperglycaemia. Current glucose monitoring tools, such as HbA1c, fructosamine and glycated albumin, have biases in this population and provide information only on mean glucose exposure. Revolutionary developments in glucose sensing and insulin delivery technology have occurred in the last decade. Newer factory-calibrated continuous glucose monitors provide real-time glucose data, with predictive alarms, allowing improved assessment of glucose excursions and preventive measures, particularly during and between dialysis sessions. Furthermore, integration of continuous glucose monitors and their predictive alerts with automated insulin delivery systems enables insulin administration to be decreased or stopped proactively, leading to improved glycaemic management and diminishing glycaemic fluctuations. While awaiting regulatory approval, emerging studies, expert real-world experience and clinical guidelines support the use of diabetes technology devices in people with diabetes and advanced chronic kidney disease.

Perceived glucose levels matter more than CGM-based data in predicting diabetes distress in type 1 or type 2 diabetes: a precision mental health approach using n-of-1 analyses.

AIMS/HYPOTHESIS: Diabetes distress is one of the most frequent mental health issues identified in people with type 1 and type 2 diabetes. Little is known about the role of glucose control as a potential contributor to diabetes distress and whether the subjective perception of glucose control or the objective glycaemic parameters are more important for the experience. With the emergence of continuous glucose monitoring (CGM), this is a relevant question as glucose values are now visible in real-time. We employed a precision monitoring approach to analyse the independent associations of perceived and measured glucose control with diabetes distress on a daily basis. By using n-of-1 analyses, we aimed to identify individual contributors to diabetes distress per person and analyse the associations of these individual contributors with mental health at a 3 month follow-up. METHODS: In this prospective, observational study, perceived (hypoglycaemia/hyperglycaemia/glucose variability burden) and measured glucose control (time in hypoglycaemia and hyperglycaemia, CV) were assessed daily for 17 days using an ecological momentary assessment (EMA) approach with a special EMA app and CGM, respectively. Mixed-effect regression analysis was performed, with daily diabetes distress as the dependent variable and daily perceived and CGM-measured metrics of glucose control as random factors. Individual regression coefficients of daily distress with perceived and CGM-measured metrics were correlated with levels of psychosocial well-being at a 3 month follow-up. RESULTS: Data from 379 participants were analysed (50.9% type 1 diabetes; 49.6% female). Perceived glucose variability (t=14.360; p<0.0001) and perceived hyperglycaemia (t=13.637; p<0.0001) were the strongest predictors of daily diabetes distress, while CGM-based glucose variability was not significantly associated (t=1.070; p=0.285). There was great heterogeneity between individuals in the associations of perceived and measured glucose parameters with diabetes distress. Individuals with a stronger association between perceived glucose control and daily distress had more depressive symptoms (ß=0.32), diabetes distress (ß=0.39) and hypoglycaemia fear (ß=0.34) at follow-up (all p<0.001). Individuals with a stronger association between CGM-measured glucose control and daily distress had higher levels of psychosocial well-being at follow-up (depressive symptoms: ß=-0.31; diabetes distress: ß=-0.33; hypoglycaemia fear: ß=-0.27; all p<0.001) but also higher HbA1c (ß=0.12; p<0.05). CONCLUSIONS/INTERPRETATION: Overall, subjective perceptions of glucose seem to be more influential on diabetes distress than objective CGM parameters of glycaemic control. N-of-1 analyses showed that CGM-measured and perceived glucose control had differential associations with diabetes distress and psychosocial well-being 3 months later. The results highlight the need to understand the individual drivers of diabetes distress to develop personalised interventions within a precision mental health approach.

Glycaemic patterns during breastfeeding with postpartum use of closed-loop insulin delivery in women with type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to describe the relationship between breastfeeding episodes and maternal glucose levels, and to assess whether this differs with closed-loop vs open-loop (sensor-augmented pump) insulin therapy. METHODS: Infant-feeding diaries were collected at 6 weeks, 12 weeks and 24 weeks postpartum in a trial of postpartum closed-loop use in 18 women with type 1 diabetes. Continuous glucose monitoring (CGM) data were used to identify maternal glucose patterns within the 3 h of breastfeeding episodes. Generalised mixed models adjusted for breastfeeding episodes in the same woman, repeat breastfeeding episodes, carbohydrate intake, infant age at time of feeding and early pregnancy HbA1c. This was a secondary analysis of data collected during a randomised trial (ClinicalTrials.gov registration no. NCT04420728). RESULTS: CGM glucose remained above 3.9 mmol/l in the 3 h post-breastfeeding for 93% (397/427) of breastfeeding episodes. There was an overall decrease in glucose at nighttime within 3 h of breastfeeding (1.1 mmol l-1 h-1 decrease on average; p=0.009). A decrease in nighttime glucose was observed with open-loop therapy (1.2 ± 0.5 mmol/l) but was blunted with closed-loop therapy (0.4 ± 0.3 mmol/l; p<0.01, open-loop vs closed-loop). CONCLUSIONS/INTERPRETATION: There is a small decrease in glucose after nighttime breastfeeding that usually does not result in maternal hypoglycaemia; this appears to be blunted with the use of closed-loop therapy.

Use of diabetes technology in children.

Children with type 1 diabetes and their caregivers face numerous challenges navigating the unpredictability of this complex disease. Although the burden of managing diabetes remains significant, new technology has eased some of the load and allowed children with type 1 diabetes to achieve tighter glycaemic management without fear of excess hypoglycaemia. Continuous glucose monitor use alone improves outcomes and is considered standard of care for paediatric type 1 diabetes management. Similarly, automated insulin delivery (AID) systems have proven to be safe and effective for children as young as 2 years of age. AID use improves not only blood glucose levels but also quality of life for children with type 1 diabetes and their caregivers and should be strongly considered for all youth with type 1 diabetes if available and affordable. Here, we review key data on the use of diabetes technology in the paediatric population and discuss management issues unique to children and adolescents.