Tight Range Research Articles

Twelve-Month Real-World Use of an Advanced Hybrid Closed-Loop System Versus Previous Therapy in a Dutch Center For Specialized Type 1 Diabetes Care.

Complexity of glucose regulation in persons with type 1 diabetes (PWDs) necessitates increased automation of insulin delivery (AID). This study aimed to analyze real-world data over 12 months from PWDs who started using the MiniMed 780G (MM780G) advanced hybrid closed-loop (aHCL) AID system at the Diabeter clinic, focusing on glucometrics and clinical outcomes. Persons with type 1 diabetes switching to the MM780G system were included. Clinical data (e.g. HbA1c, previous modality) was collected from Diabeter's electronic health records and glucometrics (time in range [TIR], time in tight range [TITR], time above range [TAR], time below range [TBR], glucose management indicator [GMI]) from CareLink Personal for a 12-month post-initiation period of the MM780G system. Outcomes were age-stratified, and the MM780G system was compared with previous use of older systems (MM640G and MM670G). Longitudinal changes in glucometrics were also evaluated. A total of 481 PWDs were included, with 219 having prior pump/sensor system data and 334 having monthly longitudinal data. After MM780G initiation, HbA1c decreased from 7.6 to 7.1% (P < .0001) and the percentage of PWDs with HbA1c <7% increased from 30% to 50%. Glucose management indicator and TIR remained stable with mean GMI of 6.9% and TIR >70% over 12 months. Age-stratified analysis showed consistent improvements of glycemic control across all age groups, with older participants achieving better outcomes. Participants using recommended system settings achieved better glycemic outcomes, reaching TIR up to 77% and TTIR up to 55%. Use of MM780G system results in significant and sustained glycemic improvements, consistent across age groups and irrespective of previous treatment modalities.

Novel Protocol for the Use of Advanced Hybrid Closed-Loop System in Adolescents Engaged in Contact Sports.

Managing exercise remains challenging for adolescent athletes with type 1 diabetes (T1D), especially in contact sports. Even the use of hybrid closed loops can cause problems due to the need to disconnect the pump during some training or competitions. This study evaluated the efficacy of a novel protocol for the use of an Advanced Hybrid Closed-Loop System in adolescent football players with T1D during a sports camp. Eleven boys aged 14.9 years (25-75th percentile: 14-15.5), with a diabetes duration of 5.7 years (5.2-7) and regular training schedules in junior football leagues, participated in the study. They started AHCL (MiniMed780G, Medtronic) therapy a month before a week-long sports camp and were observed during the sports camp and the preceding week. Daily camp activities included two 1.5-hour training sessions. Protocol included a 90-minute temporary target of 150 mg/dL before and insulin pump disconnection during training. Physical activity was tracked using wGT3X-BT Actigraph monitors. The camp provided conditions of demanding physical activity (6.6[6-6.9] hours/day of moderate-to-vigorous intensity). After starting AHCL, the average participant time spent in the target glucose range (70-180mg/dL) was 79.34±8.46%, and no significant change was observed during the camp (mean difference +0.79±8.24%, p=0.7581). Median glucose levels dropped by 10.91±12.08mg/dL (p=0.0134), and time in the tight target range increased by 11.41±11.60% (p=0.0008) without increasing the time below range (&lt;70mg/dL) or glycemic variability. During the camp, daily insulin dose and basal/bolus ratio remained comparable with baseline, but the relative amount of automated bolus insulin decreased by 14.24±4.65% (p&lt;0.0001). The predefined regimen, including a temporary target before and disconnection of AHCL during football training, was safe and may provide satisfactory glucose control in active adolescents with T1D. This protocol could be adapted for use in other intensive contact sports.

7507 Early Detection of Hyperglycemia Using CGM Despite Reduced Dosing of Teprotumumab

Abstract Disclosure: L. Needleman: None. S.H. Kim: None. A.L. Kossler: None. C. Dosiou: None. Background: In a previous longitudinal observation study, we showed that patients with prediabetes increased HbA1c by a mean of 0.7% and 30% progressed to type 2 diabetes after treatment with teprotumumab for 3 months, or after 4 infusions [1]. However, temporal effects of hyperglycemia and the impact of lower doses of teprotumumab on hyperglycemia are unknown. Clinical case: An 86-year-old woman was diagnosed with Graves’ disease after evaluation for palpitations showed undetectable TSH, free T4 2.31 ng/dL (ref. 0.8-1.8 ng/dL), total T3 252 ng/dL (ref. 76-181 ng/dL), and elevated TSI (5.0, ref. &amp;lt;1.3). Thyroxine levels normalized four weeks after starting methimazole. Nine weeks after the initial presentation she developed diplopia and bilateral proptosis. She was diagnosed with active moderate-to-severe thyroid eye disease (CAS 4/7) and was started on teprotumumab 10 mg/kg intravenously every three weeks. The dose was not increased to 20 mg/kg due to concern for adverse effects given the patient’s age and underlying hearing impairment. At baseline, she had prediabetes based on a HbA1c of 6.0%. Additional risk factors for type 2 diabetes included older age and Asian race [1]. Continuous glucose monitoring (CGM, Dexcom G7) before starting teprotumumab showed 71% time in tight range (TITR, 70-140 mg/dL) with average fasting glucose of 115 mg/dL. Prior to starting teprotumumab, she received counseling for lifestyle modification including carbohydrate moderation. Ten days following her first teprotumumab dose, her TITR reduced to 66%. After three doses of teprotumumab, her proptosis improved by 2 mm, CAS decreased to 1/7, and diplopia resolved. However, the TITR was 59% and average fasting glucose increased to 128 mg/dL. HbA1c also increased to 7.4% and the patient was started on metformin. Conclusion: In this case, teprotumumab increased glucose as early as after the first infusion. Glucose tolerance continued to worsen with subsequent doses, with development of type 2 diabetes, even with reduced dosage of teprotumumab. This case demonstrates that monitoring for teprotumumab-related hyperglycemia can be optimized with use of CGM and that lower doses of teprotumumab do not eliminate the risk of worsening glucose tolerance. Whether hyperglycemia would have been more severe with full dose teprotumumab remains uncertain. Reference: [1] Amarikwa L, Mohamed A, Kim SH, Kossler AL, Dosiou C. Teprotumumab-Related Hyperglycemia. J Clin Endocrinol Metab. 2023 Mar 10;108(4):858-864. Presentation: 6/3/2024

Continuous glucose monitoring-based metrics and the duration of hypoglycaemia events with once-weekly insulin icodec versus once-daily insulin glargine U100 in insulin-naive type 2 diabetes: an exploratory analysis of ONWARDS 1

Continuous glucose monitoring (CGM) can provide a comprehensive assessment of glycaemic control. This exploratory analysis of the ONWARDS 1 trial assessed CGM-based metrics and CGM-derived hypoglycaemia duration in insulin-naive individuals with type 2 diabetes treated with subcutaneous once-weekly insulin icodec (icodec) versus once-daily insulin glargine U100 (glargine U100). ONWARDS 1 was a 78-week (52-week main treatment phase and a 26-week treatment extension phase plus a 5-week follow-up), randomised, open-label, treat-to-target, phase 3a trial done at 143 sites (outpatient clinics and hospital departments) across 12 countries. Adults (aged ≥18 years) with type 2 diabetes (HbA1c: 7·0-11·0%) who had not previously received insulin were randomly assigned (1:1) via an interactive web-response system to once-weekly icodec or once-daily glargine U100. Double-masked CGM data were collected during treatment initiation (weeks 0-4), midtrial (weeks 22-26), end of main phase (weeks 48-52), end of extension phase (weeks 74-78), and follow-up (weeks 78-83). Secondary and exploratory outcomes were CGM-based metrics, including the mean percentages of time in glycaemic range (TIR; sensor glucose 3·9-10·0 mmol/L [70-180 mg/dL]), time in tight range (TITR; 3·9-7·8 mmol/L [70-140 mg/dL]), time above range (TAR; >10·0 mmol/L [>180 mg/dL]), and time below range (TBR; <3·9 mmol/L [<70 mg/dL] and <3·0 mmol/L [<54 mg/dL]), and CGM-derived hypoglycaemic episode durations (episodes defined by sensor glucose <3·9 mmol/L [<70 mg/dL for ≥15 consecutive minutes]). Analyses were done in the full analysis set (all randomly assigned participants). The ONWARDS 1 trial is registered with ClinicalTrials.gov, NCT04460885, and is complete. Participants were enrolled and randomly assigned in ONWARDS 1 between Nov 25, 2020, and Dec 1, 2022 (n=492 in each treatment group). During treatment initiation, we observed no statistically significant differences in the mean percentages of TIR, TITR, TAR, and TBR with icodec versus glargine U100. During the midtrial, end of main phase, and end of extension phase periods, the mean percentages of TIR and TITR were statistically significantly greater and the mean percentages of TAR statistically significantly lower with icodec versus glargine U100. The mean percentages of TIR met the internationally recommended CGM target (>70%) with icodec but not with glargine U100 during the three periods. TBR (<3·9 mmol/L [<70 mg/dL] and <3·0 mmol/L [<54 mg/dL]) was low and below recommended targets (<4% and <1%, respectively) across all study periods in both treatment groups, with no statistically significant differences between treatment groups for the lower threshold (<3·0 mmol/L [<54 mg/dL]). During the follow-up period, mean percentages of TIR, TITR, TAR, and TBR did not statistically significantly differ with icodec versus glargine U100. The duration of overall hypoglycaemic episodes was similar between treatment groups throughout the trial (median duration ≤35 min). These CGM data support the long-term efficacy and safety of icodec versus glargine U100 during treatment and indicated no increase in the duration of individual hypoglycaemic episodes with icodec versus glargine U100 in insulin-naive individuals with type 2 diabetes. Novo Nordisk.

Relationship of Physical Factors to the Occurrence of Injuries in Young Gymnasts.

There is a large population of young athletes who participate in gymnastics, and the prevention of injury in junior athletes is considered important. However, few studies have prospectively investigated the relationship between physical factors and the occurrence of injury. To investigate the physical characteristics that are factors in the injury occurrence in elementary and junior high school gymnasts. Prospective observational study. A total of 36 healthy young gymnasts (at national competition level) were enrolled in the study. Once a week for 23 weeks, injuries were prospectively investigated using self-report questionnaires under the supervision of a research staff. Joint range of motion (hip, ankle, shoulder, and wrist), tightness (Thomas test, Ely test, straight leg raise [SLR], triceps surae, combined abduction test [CAT], horizontal flexion test [HFT]), and muscle elasticity (multifidus) were assessed to compare differences in physical function between injured and non-injured participants. Injuries occurred most commonly in the wrist (42.1%), lower back (30.2%), and foot (9.5%) among males, whereas heel (22.2%), knee (16.0%), and lower back (12.8%) were the most common injury sites among females. Wrist injuries in male athletes showed decreased shoulder joint range of motion, and lower back injuries showed decreased hip and shoulder joint range of motion. Lower back injuries in female athletes showed decreased hip extension mobility. Heel and knee joint injuries in females also showed increased range of motion and decreased tightness. The results of this study indicate that the factors related to flexibility differ according to injury location. Further studies are required to clarify the physical factors that influence injury occurrence by examining the effects of the gymnasts' muscle strength, age, individual factors, and left-right differences. 3.

12-Month Time in Tight Range Improvement with Advanced Hybrid-Closed Loop System in Adults with Type1 Diabetes.

Time in tight range (TITR) is an emerging and valuable metric for assessing normoglycemia. The latest advancement in automated insulin delivery (AID) systems, the advanced hybrid closed-loop (AHCL) systems, are particularly noteworthy for managing type1 diabetes (T1D) and enhancing glycemic control. In a real-world clinical setting, we carried out a retrospective evaluation of TITR in 42 adult subjects with T1D using the AHCL Minimed™ 780G system over a 12-month period. Within just 14days of activating the automatic mode, the AHCL Minimed™ 780G system showed rapid improvement in TITR, and in the other continuous glucose monitoring (CGM) metrics. This improvement persisted over 12months, achieving the proposed 45-50% range for effective glycemic control. The AHCL Minimed™ 780G system significantly enhances TITR, demonstrating continuous improvement throughout a 12-month follow-up period.

Children and adolescent with suboptimal control of type 1 diabetes improve during the first 2 years on automated insulin delivery system.

This study investigates the influence of the automated insulin delivery system (AID) on glycaemic control in children and adolescents with type 1 diabetes (T1D) who do not reach optimal glycaemic control with traditional treatment options. All the patients aged 7 to 16 years with T1D who initiated the AID system between 24 October 2020 and 5 January 2022 in the Helsinki University Hospital and had haemoglobin A1C (HbA1c) levels above 53 mmol/mol/7.0% (N = 79) were included. Time in tight range (TITR), time in range (TIR), HbA1c, mean sensor glucose (SG) value, time below range (TBR) and SG coefficient of variance (CV) were measured at 0, 3, 12 and 24 months. The changes in the outcome measures between the time points were included in the analyses, and statistically significant level was p-value <0.01. After the initiation of AID, glycaemic control improved, and the effect lasted throughout the study period. Between 0 and 3 months, TITR and TIR increased (mean 11.7% [10.6], mean 18.1% [standard deviation [SD] 13.7], p < 0.001), whereas HbA1c and mean SG values decreased significantly (-8.3 mmol/mol [8.7]/-2.9% [2.9], p < 0.001, -1.8 mmol/L [1.7], p < 0.001). These effects were sustainable and were still visible at 12 and 24 months. Glycaemic control in patients not reaching treatment goals improved significantly after the initiation of the AID system, and the favourable effect lasted throughout the follow-up. AID treatment could be an option for also those paediatric patients with T1D who do not have good skills in diabetes management.

Temporary Target versus Suspended Insulin Infusion in Patients with Type 1 Diabetes Using the MiniMed 780G Advanced Closed-Loop Hybrid System During Aerobic Exercise. Randomized crossover clinical trial.

To compare the safety and continuous glucose monitoring (CGM) metrics during aerobic exercise (AE) of using temporary target (TT) versus (vs.) suspension of insulin infusion (SII) in adults with type 1 diabetes (T1D) using advanced hybrid closed-loop systems. Randomized crossover clinical trial. Two moderate-intensity AE sessions were performed, one with TT and one with SII. Hypoglycemic events and CGM metrics were analyzed during the immediate (baseline and 59 minutes), early (60 minutes to 6 hours), and late (6 to 36 hours) post-exercise phases. 33 patients were analyzed (44.6±13.8 years, 52% male, time in range (%TIR 70-180 mg/dL) 79.4 ± 12%, time below range (%TBR) <70 and <54 mg/dL was 1.8±1.7% and 0.5±0.9%, respectively). Differences were found between TT vs. SII use in the early phase for %TIR 70-180 mg/dL (83.0 vs. 65.3,p=0.005), time in tight range (%TITR 70-140mg/dL) (56.3 vs. 41.5,p=0.04) and time above range (%TAR>180mg/dL) (15.3 vs. 31.8,p=0.01). No significant differences were found in the CGM metrics during the different phases of physical activity. When evaluating the diurnal period, %TIR was higher for TT use (82.1 vs. 73.1,p=0.02) and %TAR was higher for SII (15.0 vs. 22.96,p=0.04), with no difference in the number of hypoglycemic events or changes in time below range (%TBR) <70 and <54 mg/dL. The use of TT compared to SII is equally safe in the immediate, early and late phases of AE. However, the use of TT allows a better glycemic profile to be achieved in the early phase of exercise.

Impact of triple transmembrane regulator therapy on glucose metabolism in cystic fibrosis related diabetes during clinical practice

AimsTo evaluate the impact of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on Cystic Fibrosis Related Diabetes (CFRD) glycemic control and insulin treatment in patients with CFRD during clinical practice. MethodsWe carried out a retrospective observational study of 23 adult patients with CFRD who started treatment with ETI. They had, at least, one F508del mutation. Data were collected before ETI initiation and 3, 6, and 12 months after. ResultsGlycemic control measured by HbA1c significantly improved by 0.3 % (0.1–0.5) after 3 months of ETI therapy (p = 0.004) and kept this improvement during follow-up (p < 0.001). The proportion of patients needing multiple daily injections of insulin was reduced by 16 % (p = 0.023). Total daily insulin dose dropped by 0.12 (0.05–0.18) UI/kg/day (p < 0.001). Data derived from Flash Continuous Glucose Monitoring (CGM) for patients treated with insulin stayed unchanged after insulin reduction, except for a significant 8 % (0.3–15.6) increase in the Time In Tight Range (TITR) between 70 and 140 mg/dL (p = 0.043). ConclusionETI therapy impacted CFRD in clinical practice reducing insulin needs and improving glycemic control measured by HbA1c and CGM. The improvements can be observed from the first 3 months of treatment.

'We're taught green is good': Perspectives on time in range and time in tight range from youth with type 1 diabetes, and parents of youth with type 1 diabetes.

Continuous glucose monitoring (CGM) systems are standard of care for youth with type 1 diabetes with the goal of spending >70% time in range (TIR; 70-180 mg/dL, 3.9-10 mmol/L). We aimed to understand paediatric CGM user experiences with TIR metrics considering recent discussion of shifting to time in tight range (TITR; >50% time between 70 and 140 mg/dL, 3.9 and 7.8 mmol/L). Semi-structured interviews and focus groups with adolescents with type 1 diabetes and parents of youth with type 1 diabetes focused on experiences with TIR goals and reactions to TITR. Groups and interviews were audio-recorded, transcribed and analysed using content analysis. Thirty participants (N = 19 parents: age 43.6 ± 5.3 years, 79% female, 47% non-Hispanic White, 20 ± 5 months since child's diagnosis; N = 11 adolescents: age 15.3 ± 2 years, 55% female, 55% non-Hispanic White, 16 ± 3 months since diagnosis) attended. Participants had varying levels of understanding of TIR. Some developed personally preferred glucose ranges. Parents often aimed to surpass 70% TIR. Many described feelings of stress and disappointment when they did not meet a TIR goal. Concerns about TITR included increased stress and burden; risk of hypoglycaemia; and family conflict. Some participants said TITR would not change their daily lives; others said it would improve their diabetes management. Families requested care team support and a clear scientific rationale for TITR. The wealth of CGM data creates frequent opportunities for assessing diabetes management and carries implications for management burden. Input from people with type 1 diabetes and their families will be critical in considering a shift in glycaemic goals and targets.

Exploring the Continuous Glucose Monitoring in Pediatric Diabetes: Current Practices, Innovative Metrics, and Future Implications.

Continuous glucose monitoring (CGM) systems, including real-time CGM and intermittently scanned CGM, have revolutionized diabetes management, particularly in children and adolescents with type 1 diabetes (T1D). These systems provide detailed insights into glucose variability and detect asymptomatic and nocturnal hypoglycemia, addressing limitations of traditional self-monitoring blood glucose methods. CGM devices measure interstitial glucose concentrations constantly, enabling proactive therapeutic decisions and optimization of glycemic control through stored data analysis. CGM metrics such as time in range, time below range, and coefficient of variation are crucial for managing T1D, with emerging metrics like time in tight range and glycemia risk index showing potential for enhanced glycemic assessment. Recent advancements suggest the utility of CGM systems in monitoring the early stages of T1D and individuals with obesity complicated by pre-diabetes, highlighting its therapeutic versatility. This review discusses the current CGM systems for T1D during the pediatric age, established and emerging metrics, and future applications, emphasizing the critical role of CGM devices in improving glycemic control and clinical outcomes in children and adolescents with diabetes.

Evaluation of time in tight range and the glycaemia risk index in adults with type 1 diabetes using an advanced hybrid closed loop system: A 1-year real-world assessment.

To assess the long-term glycaemic outcomes, with additional metrics, in adults with type 1 diabetes (T1D) using the Tandem t:slim X2 with Control-IQ technology advanced hybrid closed-loop (AHCL) system. This was a single-centre, retrospective study involving 56 T1D patients who transitioned to the Tandem t:slim X2 with Control-IQ system. The primary and secondary endpoints consisted of variations in time in tight range (TiTR; 70-140 mg/dL) and the glycaemia risk index (GRI), respectively. Additional standardized continuous glucose monitoring (CGM) metrics, mean sensor glucose, coefficient of variation, the glucose management indicator (GMI), HbA1c and insulin daily dose, were also evaluated. Variables were measured at baseline and at 15 days, 3 months, 6 months and 1 year after Tandem t:slim X2 Control-IQ initiation. Glucose outcomes are expressed as mean (standard deviation). Use of Tandem t:slim X2 with Control-IQ over 1 year was associated with an increase in mean TiTR, from 38.11% (17.05%) to 43.10% (13.20%) (P = .059), and with a decline in the GRI, from 41.03 (25.48) to 28.55 (16.27) (P = .008). CGM metrics, including time in range and time above range, showed consistent improvements. Mean sensor glucose, the GMI and HbA1c decreased significantly over time. After an initial increase, insulin daily dose remained stable throughout the 12 months. The results highlight the sustained effectiveness of Tandem t:slim X2 with Control-IQ in improving glycaemic outcomes over 1 year and support the use of this technology for the management of T1D.

Distortions of the Hubble diagram: Line-of-sight signatures of local galaxy clusters

The Universe expansion rate is modulated around local inhomogeneities due to their gravitational potential. Velocity waves are then observed around galaxy clusters in the Hubble diagram. This paper studies them in a ∼738 Mpc-wide, 20483-particle cosmological simulation of our cosmic environment (a.k.a. CLONE: Constrained LOcal &amp; Nesting Environment Simulation). For the first time, the simulation shows that velocity waves that arise in the lines of sight of the most massive dark matter halos agree with those observed in local galaxy velocity catalogs in the lines of sight of Coma and several other local (Abell) clusters. For the best-constrained clusters such as Virgo and Centaurus – that is, those closest to us – secondary waves caused by galaxy groups, further into the non-linear regime, also stand out. This match was not utterly expected given that before being evolved into a fully non-linear z = 0 state, assuming ΛCDM, CLONE initial conditions are constrained solely with linear theory, the power spectrum, and highly uncertain and sparse local peculiar velocities. Additionally, Gaussian fits to velocity wave envelopes show that wave properties are tightly tangled with cluster masses. This link is complex, though, and involves the environment and formation history of the clusters. A proposed metric, measuring the distance between the observed and several re-centred simulated lines of sight, waves included, is shown to be capable of providing a tight mass range estimate for massive local clusters. Using machine learning techniques to grasp more thoroughly the complex wave-mass relation, velocity waves could in the near future be used to provide additional and independent mass estimates from galaxy dynamics within large cluster radii.

Long-Term Improvements in Glycemic Control with Dexcom CGM Use in Adults with Noninsulin-Treated Type 2 Diabetes.

Aims: The objective of this real-world, observational study was to evaluate change in continuing glucose monitoring (CGM) metrics for 1 year after CGM initiation in adults with noninsulin-treated type 2 diabetes (T2D). Methods: Data were analyzed from Dexcom G6 and G7 users who self-reported: T2D, ≥18 years, gender, no insulin use, and had a baseline percent time in range (TIR) 70-180 mg/dL of ≤70%. Outcomes were change in CGM metrics from baseline to 6 and 12 months overall and for younger (<65 years) and older (≥65 years) cohorts. Additional analyses explored the relationship between use of the high alert feature and change in TIR and time in tight range (TITR) 70-140 mg/dL. Results: CGM users (n = 3,840) were mean (SD) 52.5 (11.2) years, 47.9% female, mean TIR was 41.7% (21.4%), and 12.4% of participants were ≥65 years. Significant improvement in all CGM metrics not meeting target values at baseline was observed at 6 months, with continued improvement at 12 months. Mean baseline TIR increased by 17.3% (32.1%) from 41.7% (21.4%) to 59.0% (28.9%), and mean glucose management indicator decreased by 0.5% (1.2%) from 8.1% (0.9%) to 7.6% (1.1%) (both P < 0.001). Participants who maintained or customized the high alert default setting of 250 mg/dL had a greater increase in TIR and TITR compared with participants who disabled the alert. Days of CGM use over 12 months were high in 84.7% (15.9%). Conclusion: In this large, real-world study of adults with suboptimally controlled T2D not using insulin, Dexcom CGM use was associated with meaningful improvements in glycemic control over 12 months. Use of the high alert system feature was positively associated with glycemic outcomes. High use of CGM over 12 months suggests benefits related to consistent CGM use in this population.

1920-LB: Strong Correlation between More Readings in Tight Range and Greater Engagement with the OneTouch Reveal Diabetes App in a Real-World Dataset of 23,147 People with Type 1 Diabetes

1920-LB: Strong Correlation between More Readings in Tight Range and Greater Engagement with the OneTouch Reveal Diabetes App in a Real-World Dataset of 23,147 People with Type 1 Diabetes

Effects of Individualized Anemia Therapy on Hemoglobin Stability: A Randomized Controlled Pilot Trial in Patients on Hemodialysis.

Anemia is common among hemodialysis patients. Maintaining stable hemoglobin levels within predefined target levels can be challenging, particularly in patients with frequent hemoglobin fluctuations both above and below the desired targets. We conducted a multi-center, randomized, controlled trial comparing our anemia therapy assistance software against a standard population-based anemia treatment protocol. We hypothesized that personalized dosing of erythropoiesis stimulating agents (ESA) improves hemoglobin target attainment. Ninety-six patients undergoing hemodialysis and receiving methoxy polyethylene glycol-epoetin beta were randomized 1:1 to the intervention group (personalized ESA dose recommendations computed by the software) or the standard of care group for twenty-six weeks. The therapy assistance software combined a physiology-based mathematical model and a model predictive controller designed to stabilize hemoglobin levels within a tight target range (10 to 11 g/dl). The primary outcome measure was the percentage of hemoglobin measurements within the target. Secondary outcome measures included measures of hemoglobin variability and ESA utilization. The intervention group showed an improved median percentage of hemoglobin measurements within target at 47% (IQR 39 to 58), with a 10 percentage points median difference between the two groups (95% CI: 3 to 16; P=0.008). The odds ratio of being within the hemoglobin target in the standard of care group compared to the group receiving the personalized ESA recommendations was 0.68 (95% CI: 0.51 to 0.92). The variability of hemoglobin levels decreased in the intervention group, with the percentage of patients experiencing fluctuating hemoglobin levels being 45% vs 82% in the standard of care group. ESA usage was reduced by about 25% in the intervention group. Our results demonstrated an improved hemoglobin target attainment and variability by employing personalized ESA recommendations using the physiology-based anemia therapy assistance software.

Time In Tight Range in children and adolescents with type 1 diabetes: A cross-sectional observational single centre study evaluating efficacy of new advanced technologies.

Early and tight glycaemic control is crucial to prevent long-term complications of Type 1 Diabetes (T1D). The aim of our study was to compare glucose metrics, including Time In Tight Range (TITR), in a real-world setting. We performed a single-centre cross-sectional study in 534 children and adolescents with T1D. Participants were divided into four groups (multiple daily injections+real-time Continuous glucose monitoring (CGM), multiple daily injections+intermittently scanned CGM, sensor augmented pump (SAP), and Advanced Hybrid Closed-Loop (AHCL). Demographical and clinical data were collected and analysed. The group with AHCL showed significantly higher Time In Range (TIR) (71.31%±10.88) than SAP (57.82%±14.98; p<0.001), MDI+rtCGM (54.56%±17.04; p<0.001) and MDI+isCGM (52.17%±19.36; p<0.001) groups with a lower Time Above Range (p<0.001). The group with AHCL also showed lower Time Below Range than MDI+isCGM and SAP groups (p<0.01). The overall TITR was 37%±14 with 19% of participants who reached a TITR ≥50% with a mean TIR of 81%. AHCL had significantly higher TITR (45.46%±11.77) than SAP (36.25%±13.53; p<0.001), MDI+rtCGM (34.03%±13.89; p<0.001) and MDI+isCGM (33.37%±15.84; p<0.001) groups with a lower Coefficient of Variation (p<0.001). Our study indicates that AHCL ensures a better glycaemic control with an improvement in both TIR and TITR, along with a reduction in CV. Implementation of automated insulin delivery systems should be considered in the treatment of children and adolescents with T1D.

Utility of time in tight range (TITR) in evaluating metabolic control in pediatric and adult patients with type 1 diabetes in treatment with advanced hybrid closed-loop systems

PurposeTo analyze the time in tight range (TITR), and its relationship with other glucometric parameters in patients with type 1 diabetes (T1D) treated with advanced hybrid closed-loop (AHCL) systems.MethodsA prospective observational study was conducted on pediatric and adult patients with T1D undergoing treatment with AHCL systems for at least 3 months. Clinical variables and glucometric parameters before and after AHCL initiation were collected.ResultsA total of 117 patients were evaluated. Comparison of metabolic control after AHCL initiation showed significant improvements in HbA1c (6.9 ± 0.9 vs. 6.6 ± 0.5%, p < 0.001), time in range (TIR) (68.2 ± 11.5 vs. 82.5 ± 6.9%, p < 0.001), TITR (43.7 ± 10.8 vs. 57.3 ± 9.7%, p < 0.001), glucose management indicator (GMI) (6.9 ± 0.4 vs. 6.6 ± 0.3%, p < 0.001), time below range (TBR) 70–54 mg/dl (4.3 ± 4.5 vs. 2.0 ± 1.4%, p < 0.001), and time above range (TAR) > 180 mg/dl (36.0 ± 7.6 vs. 15.1 ± 6.4%, p < 0.001). Coefficient of variation (CV) also improved (36.3 ± 5.7 vs. 30.6 ± 3.7, p < 0.001), while time between 140–180 mg/dl remained unchanged. In total, 76.3% achieved TITR > 50% (100% pediatric). Correlation analysis between TITR and TIR and GRI showed a strong positive correlation, modified by glycemic variability.ConclusionsAHCL systems achieve significant improvements in metabolic control (TIR > 70% in 93.9% patients). The increase in TIR was not related to an increase in TIR 140–180 mg/dl. Despite being closely related to TIR, TITR allows for a more adequate discrimination of the achieved control level, especially in a population with good initial metabolic control. The correlation between TIR and TITR is directly influenced by the degree of glycemic variability.

The association of chronic complications with time in tight range and time in range in people with type 1 diabetes: a retrospective cross-sectional real-world study.

The aim of this study was to evaluate the association of chronic complications with time in tight range (TITR: 3.9-7.8 mmol/l) and time in range (TIR: 3.9-10.0 mmol/l) in people with type 1 diabetes. The prevalence of microvascular complications (diabetic retinopathy, diabetic nephropathy and diabetic peripheral neuropathy [DPN]) and macrovascular complications according to sensor-measured TITR/TIR was analysed cross-sectionally in 808 adults with type 1 diabetes. Binary logistic regression was used to evaluate the association between TITR/TIR and the presence of complications without adjustment, with adjustment for HbA1c, and with adjustment for HbA1c and other confounding factors (sex, age, diabetes duration, BMI, BP, lipid profile, smoking, and use of statins and renin-angiotensin-aldosterone system inhibitors). The mean TITR and TIR were 33.9 ± 12.8% and 52.5 ± 15.0%, respectively. Overall, 46.0% had any microvascular complication (34.5% diabetic retinopathy, 23.8% diabetic nephropathy, 16.0% DPN) and 16.3% suffered from any macrovascular complication. The prevalence of any microvascular complication, diabetic retinopathy, diabetic nephropathy and a cerebrovascular accident (CVA) decreased with increasing TITR/TIR quartiles (all ptrend<0.05). Each 10% increase in TITR was associated with a lower incidence of any microvascular complication (OR 0.762; 95% CI 0.679, 0.855; p<0.001), diabetic retinopathy (OR 0.757; 95% CI 0.670, 0.856; p<0.001), background diabetic retinopathy (OR 0.760; 95% CI 0.655, 0.882; p<0.001), severe diabetic retinopathy (OR 0.854; 95% CI 0.731, 0.998; p=0.048), diabetic nephropathy (OR 0.799; 95% CI 0.699, 0.915; p<0.001), DPN (OR 0.837; 95% CI 0.717, 0.977; p=0.026) and CVA (OR 0.651; 95% CI 0.470, 0.902; p=0.010). The independent association of TITR with any microvascular complication (OR 0.867; 95% CI 0.762, 0.988; p=0.032), diabetic retinopathy (OR 0.837; 95% CI 0.731, 0.959; p=0.010), background diabetic retinopathy (OR 0.831; 95% CI 0.705, 0.979; p=0.027) and CVA (OR 0.619; 95% CI 0.426, 0.899; p=0.012) persisted after adjustment for HbA1c. Similar results were obtained when controlling for HbA1c and other confounding factors. TITR and TIR are inversely associated with the presence of microvascular complications and CVA in people with type 1 diabetes. Although this study was not designed to establish a causal relationship, this analysis adds validity to the use of TITR and TIR as key measures in glycaemic management. ClinicalTrials.gov NCT02601729 and NCT02898714.

Supercoiled DNA percentage: A key in-process control of linear DNA template for mRNA drug substance manufacturing

The development of messenger RNA (mRNA) vaccines and therapeutics necessitates the production of high quality in-vitro-transcribed mRNA drug substance with specific critical quality attributes (CQAs), which are closely tied to the uniformity of linear DNA template. The supercoiled plasmid DNA is the precursor to the linear DNA template, and the supercoiled DNA percentage is commonly regarded as a key in-process control (IPC) during the manufacturing of linear DNA template. In this study, we investigate the influence of supercoiled DNA percentage on key mRNA CQAs, including purity, capping efficiency, double-stranded RNA (dsRNA), and distribution of polyA tail. Our findings reveal a significant impact of supercoiled DNA percentage on mRNA purity, and in vitro transcription yield. Notably, we observe that the impact on mRNA purity can be mitigated through Oligo-dT chromatography, alleviating the tight range of DNA supercoiled percentage to some extent. Overall, this study provides valuable insights into IPC strategies for DNA template CMC (Chemistry, Manufacturing, and Controls) and process development for mRNA drug substance.