Dendritic cell development-History, advances, and open questions.

Dendritic cells (DCs) are uniquely potent in orchestrating T cell immune response, thus they are indispensable immune sentinels. They originate from progenitors in the bone marrow through hematopoiesis, a highly regulated developmental process involving multiple cellular and molecular events. This review highlights studies of DC development-from the discovery of DCs as glass-adherent antigen presenting cells to the debate and resolution of their origin and lineage map. In particular, we summarize the roles of lineage-specific cytokines, the placement of distinct hematopoietic progenitors within the DC lineage and transcriptional programs governing DC development, which together have allowed us to diagram the current view of DC hematopoiesis. Important open questions and debates on the DC development and relevant models are also discussed.

Association between attendance at an American diabetes camp and improvements in glycaemic control and treatment satisfaction.

INTRODUCTION: Few studies have evaluated glycaemic control using continuous glucose monitoring (CGM) in individuals before and after attendance at a diabetes camp or by comparing control groups at home to control groups at camp. METHODS: Youth (6-17 years) with T1D and receiving insulin therapy were enrolled at a week-long diabetes camp. They participated in three clinic visits: at the start of a week at home, by initiating a Dexcom G6 CGM system; at the start of a week at camp, where the home week G6 was removed and a camp week G6 was inserted; and after camp, where the camp week G6 was removed. We administered Problem Areas in Diabetes (PAID) surveys at the second and third visits. Participants with <80% CGM data coverage or who did not complete all PAID surveys were excluded from analysis. We compared glycaemic control and PAID scores between the week at home and week at camp. RESULTS: Of 76 enrolled campers, 69 completed the study and 52 had results that qualified for analysis. The mean participant age was 12.5 ± 2.2 years. Camp was associated with significantly improved treatment satisfaction, time in desired glucose range and insulin sensitivity. Time in hyperglycaemia and basal insulin requirements decreased significantly. CONCLUSIONS: Diabetes camp is associated with significant improvements in diabetes treatment satisfaction and glycaemic control compared to home care.

Real-World Hypoglycemia Avoidance With a Predictive Low Glucose Alert Does Not Depend on Frequent Screen Views.

BACKGROUND: Frequent real-time continuous glucose monitoring (rtCGM) data viewing has been associated with reduced mean glucose and frequent scanning of an intermittently scanned continuous glucose monitoring (isCGM) system has been associated with reduced hypoglycemia for patients with diabetes. However, requiring patients to frequently interact with their glucose monitoring devices to detect actual or impending hypoglycemia is burdensome. We hypothesized that a predictive low glucose alert, which forecasts glucose ≤55 mg/dL within 20 minutes and is included in a new rtCGM system, could mitigate hypoglycemia without requiring frequent device interaction. METHODS: We analyzed estimated glucose values (EGVs) from an anonymized convenience sample of 15,000 patients who used Dexcom G6 (Dexcom, Inc, San Diego, CA, USA) and its mobile app for at least 30 days with or without the "Urgent Low Soon" alert (ULS) enabled. Screen view frequency was determined as the frequency with which the trend screen was accessed on the app. Multiple screen views within any 5-minute interval were counted as one. Hypoglycemia exposure for patients in the top and bottom quartiles of screen view frequency (>8.25 and <3.30 per day, respectively) was calculated as the percentage of EGVs below various thresholds. RESULTS: Over 93% of users enabled the ULS alert; its use was associated with significantly reduced hypoglycemia <55 and <70 mg/dL, independent of screen view frequency. CONCLUSION: Use of the G6 ULS alert may disencumber rtCGM users by promoting significant reductions in hypoglycemia without requiring frequent device interactions.

Performance of the Dexcom G6 Continuous Glucose Monitoring System in Pregnant Women with Diabetes.

Background: The aim of this study was to determine the performance of the Dexcom G6 continuous glucose monitoring (CGM) system across three sensor wear sites in pregnant women with diabetes in the second or third trimesters. Methods: Participants with type 1 (T1D), type 2 (T2D), or gestational (GDM) diabetes mellitus were enrolled at three sites. Each wore two G6 sensors on the abdomen, upper buttock, and/or posterior upper arm for 10 days and underwent a 6-h clinic session between days 3 and 7 of sensor wear, during which YSI reference blood glucose values were obtained every 30 min. No intentional glucose manipulations were performed. Accuracy metrics included the proportion of CGM values that were within ±20% of paired reference values >100 mg/dL or ±20 mg/dL of YSI values ≤100 mg/dL (hereafter referred to as %20/20), as well as the analogous %15/15, %30/30, and %40/40. The mean absolute relative difference (MARD) between CGM-YSI pairs was also calculated. Results: Thirty-two participants with T1D (n = 20), T2D (n = 3), or GDM (n = 9) were enrolled: 19 were in the second trimester and 13 were in the third trimester of pregnancy. Compared with the reference, 92.5% of CGM values were within ±20%/20 mg/dL. The overall MARD and that of sensors worn on the abdomen, upper buttock, and posterior upper arm was 10.3%, 11.5%, 11.2%, and 8.7%, respectively. There were no device-related adverse events. Skin reactions at the insertion sites were absent or minor. Conclusions: The Dexcom G6 CGM system is accurate and safe in pregnant women with diabetes.

Real-Time Sharing and Following of Continuous Glucose Monitoring Data in Youth.

BACKGROUND: Those caring for children and adolescents with diabetes often use glucose concentration and trending information in management decisions. Some continuous glucose monitoring (CGM) systems offer real-time sharing and monitoring capabilities through mobile apps carried by the person with diabetes and the caregiver(s), respectively. Few large studies have explored real-world associations between sharing and following, CGM utilization, and glycemic outcomes. METHODS: We performed a retrospective evaluation of device usage and glycemic control in 15,000 youth ranging in age from 2 to 18 years by analyzing anonymized data that had been uploaded with a mobile app that provides optional sharing. The presence or absence of a real-time monitor (a "Follower") was established on 15 June 2018. Each day with ≥ 1 uploaded glucose values was counted as a day of device usage. Between-group glucose comparisons were made with two-sided Welch's t tests. RESULTS: Overall, 94.8% of the population used the sharing feature and had at least one Follower. The mean numbers of Followers for patients aged 2-5, 6-12, and 13-18 years were 2.8, 2.8, and 2.4, respectively. In all three age categories, the presence of at least one Follower was associated with lower mean glucose values, more glucose values in the 70- to 180-mg/dL range, correspondingly fewer glucose values representing hypoglycemia and hyperglycemia, and significantly more device utilization. CONCLUSION: Real-time sharing and following of CGM data are associated with improved device utilization and glycemic parameters. The observed association suggests either more timely interventions or higher levels of engagement among the caregivers or the youth with diabetes. FUNDING: Dexcom, Inc.

Real-World Hypoglycemia Avoidance with a Continuous Glucose Monitoring System's Predictive Low Glucose Alert.

BACKGROUND: Programmable and fixed auditory and/or vibratory threshold alerts are essential features of real-time continuous glucose monitoring (rtCGM) systems that provide users time to intervene before the onset of clinical hypoglycemia or hyperglycemia. A sixth-generation rtCGM system from Dexcom, Inc. (G6) includes a new alert that is triggered when an algorithm predicts that an estimated glucose value ≤55 mg/dL will occur within 20 min, allowing users more time to act to avoid hypoglycemia. We examined whether this predictive low glucose alert provided added benefit to traditional low threshold alerts. METHODS: We analyzed glucose values from an anonymized sample of 1424 patients who transitioned to G6 from the preceding fifth-generation system (G5) with no predictive alert. Users with the low threshold alert setting of 70 or 80 mg/dL were evaluated separately. Receiver users, those who disabled the predictive low glucose alert, or those with <30 days of data immediately before or after the transition to G6 were excluded. RESULTS: Percent time <54, ≤55, <70, and >250 mg/dL fell significantly after the transition to G6, independent of low threshold alert setting. Time in range improved for G6 users with a low threshold alert setting of 70 mg/dL. CONCLUSIONS: Advance warning provided by predictive low glucose alerts may further reduce hypoglycemia among rtCGM-experienced users.

Performance of a Factory-Calibrated, Real-Time Continuous Glucose Monitoring System in Pediatric Participants With Type 1 Diabetes.

BACKGROUND: The perceived value and consistent use of continuous glucose monitoring (CGM) systems depends in part on their accuracy. We assessed the performance of a sixth-generation CGM system (Dexcom G6) in children and adolescents. METHODS: Forty-nine participants (6-17 years of age, mean ± SD of 13.5 ± 3.3 years), all with type 1 diabetes, enrolled and data were available from 37. Each participant wore 1 sensor for up to 10 days and was asked to undergo an in-clinic visit lasting 6-12 hours for frequent blood glucose (BG) sample testing on one of the sensor wear days. Estimated glucose values (EGVs) from the G6 system were compared with venous BG values measured with a laboratory reference instrument (YSI). RESULTS: The overall mean absolute relative difference (MARD) for 1387 EGV-YSI pairs was 7.7%, and the overall percentage of EGVs within 20% or 20 mg/dL of the YSI reference value (for YSI > or ⩽100 mg/dL, respectively, the "%20/20") was 96.2%. The %20/20 was 92.1% on Day 1 and 91.0% on Day 10 of sensor wear. For EGVs <70 mg/dL, 92.6% of the YSI values were within 20 mg/dL and for EGVs >250 mg/dL, 100% of the YSI values were within 20%. Differences between EGVs and YSI values in over 99.9% of the pairs posed no or only slight clinical risk as evaluated by surveillance error grid analysis. CONCLUSIONS: The accuracy of the G6 CGM system in pediatrics may encourage consistent use of the system and contribute to improved glycemic outcomes in this population.

Accuracy, Utilization, and Effectiveness Comparisons of Different Continuous Glucose Monitoring Systems.

BACKGROUND: Accuracy and feature sets of continuous glucose monitoring (CGM) systems may influence device utilization and outcomes. We compared clinical trial accuracy and real-world utilization and effectiveness of two different CGM systems. MATERIALS AND METHODS: Separately conducted accuracy studies of a fifth-generation and a sixth-generation CGM system involved 50 and 159 adults, respectively. For between-system performance comparisons, propensity score methods were utilized to balance cohort characteristics. Real-world outcomes were assessed in 10,000 anonymized patients who had switched from the fifth-generation to the sixth-generation system and had used connected mobile devices to upload data from both systems, allowing pairwise comparisons of device utilization and glucose concentration distributions. RESULTS: Propensity score-adjusted mean absolute relative differences for the fifth- and sixth-generation systems were 9.0% and 9.9%, and the percentages of values within ±20%/20 mg/dL were 93.1% and 92.5%, respectively. The sixth-generation system, but not the fifth-generation system, met accuracy criteria for interoperable CGM systems. Both systems had high real-world utilization rates (93.8% and 95.3% in the fifth- and sixth-generation systems, respectively). Use of the sixth-generation system was associated with fewer glucose values <55 mg/dL (<3.1 mmol/L) (0.7% vs. 1.1%, P < 0.001) and more values 70-180 mg/dL (3.9-10.0 mmol/L) (57.3% vs. 56.0%, P < 0.001) than the fifth-generation system. CONCLUSIONS: CGM performance outcomes can be compared through the propensity score analysis of clinical trial data and pairwise comparisons of real-world data. The systems compared here had nearly equivalent accuracy and utilization rates. Longer term biochemical and psychosocial benefits observed with the fifth-generation system are also expected with the sixth-generation system.

The Effect of Reduced Self-Monitored Blood Glucose Testing After Adoption of Continuous Glucose Monitoring on Hemoglobin A1c and Time in Range.

The effectiveness of real-time continuous glucose monitoring (rtCGM) in adults with diabetes treated with insulin injections was evaluated in the 24-week DIAMOND clinical trial comparing rtCGM users to a control group using self-monitored blood glucose (SMBG) testing ( Clinicaltrials.gov : NCT02282397). All participants were instructed to use SMBG results for diabetes management decisions; however, SMBG testing frequency varied within the rtCGM group. This brief report evaluated how SMBG frequency changes in the rtCGM group were correlated with glycemic outcomes in the same trial. Baseline and end-of-study hemoglobin A1c (HbA1c) levels, percentages of CGM values in the 70-180 mg/dL target range (time in range [TIR]), mean of daily differences (MODD), and glycemic coefficients of variation (CVs) were compared. The rtCGM group analyzed included 175 participants-99 with type 1 diabetes (T1D) and 76 with type 2 diabetes (T2D). When comparing participants whose SMBG testing frequency decreased by >1/day versus ≤1/day, mean change in HbA1c was similar (-0.9 ± 0.7 percentage points in both groups, P = 0.59), as was change in TIR (+3.9 ± 14.3 vs. +5.7 ± 13.7 percentage points, respectively, P = 0.39). Likewise, when comparing participants in the highest and lowest quartiles of SMBG frequency reduction (≥2.2 vs. ≤0.4 fewer tests/day, respectively), changes in HbA1c (-0.8 ± 0.6 vs. -0.9 ± 0.6 percentage points, respectively, P = 0.52) and TIR (+4.8 ± 13.2 vs. +5.6 ± 12.7 percentage points, respectively, P = 0.98) were similar. The mean (standard deviation [SD]) change in MODD was -8.3 mg/dL (14.8) and -5.5 mg/dL (14.7) for participants who reduced their SMBG frequency by >1 test/day and ≤1 test/day, respectively; the mean (SD) change in CV was -3.6% (5.0) and -1.6% (5.1) for participants who reduced their SMBG frequency by >1 test/day and ≤1 test/day, respectively. These findings suggest that individuals who decrease the frequency of SMBG testing can effectively base some of their diabetes-related treatment decisions on glucose concentrations, trend information, and alarms provided by their rtCGM systems.

Clonal analysis of human dendritic cell progenitor using a stromal cell culture.

Different dendritic cell (DC) subsets co-exist in humans and coordinate the immune response. Having a short life, DCs must be constantly replenished from their progenitors in the bone marrow through hematopoiesis. Identification of a DC-restricted progenitor in mouse has improved our understanding of how DC lineage diverges from myeloid and lymphoid lineages. However, identification of the DC-restricted progenitor in humans has not been possible because a system that simultaneously nurtures differentiation of human DCs, myeloid and lymphoid cells, is lacking. Here we report a cytokine and stromal cell culture that allows evaluation of CD34(+) progenitor potential to all three DC subsets as well as other myeloid and lymphoid cells, at a single cell level. Using this system, we show that human granulocyte-macrophage progenitors are heterogeneous and contain restricted progenitors to DCs.

Circulating precursors of human CD1c+ and CD141+ dendritic cells.

Two subsets of conventional dendritic cells (cDCs) with distinct cell surface markers and functions exist in mouse and human. The two subsets of cDCs are specialized antigen-presenting cells that initiate T cell immunity and tolerance. In the mouse, a migratory cDC precursor (pre-CDC) originates from defined progenitors in the bone marrow (BM). Small numbers of short-lived pre-CDCs travel through the blood and replace cDCs in the peripheral organs, maintaining homeostasis of the highly dynamic cDC pool. However, the identity and distribution of the immediate precursor to human cDCs has not been defined. Using a tissue culture system that supports the development of human DCs, we identify a migratory precursor (hpre-CDC) that exists in human cord blood, BM, blood, and peripheral lymphoid organs. hpre-CDCs differ from premonocytes that are restricted to the BM. In contrast to earlier progenitors with greater developmental potential, the hpre-CDC is restricted to producing CD1c(+) and CD141(+) Clec9a(+) cDCs. Studies in human volunteers demonstrate that hpre-CDCs are a dynamic population that increases in response to levels of circulating Flt3L.

Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow.

In mice, two restricted dendritic cell (DC) progenitors, macrophage/dendritic progenitors (MDPs) and common dendritic progenitors (CDPs), demonstrate increasing commitment to the DC lineage, as they sequentially lose granulocyte and monocyte potential, respectively. Identifying these progenitors has enabled us to understand the role of DCs and monocytes in immunity and tolerance in mice. In humans, however, restricted monocyte and DC progenitors remain unknown. Progress in studying human DC development has been hampered by lack of an in vitro culture system that recapitulates in vivo DC hematopoiesis. Here we report a culture system that supports development of CD34(+) hematopoietic stem cell progenitors into the three major human DC subsets, monocytes, granulocytes, and NK and B cells. Using this culture system, we defined the pathway for human DC development and revealed the sequential origin of human DCs from increasingly restricted progenitors: a human granulocyte-monocyte-DC progenitor (hGMDP) that develops into a human monocyte-dendritic progenitor (hMDP), which in turn develops into monocytes, and a human CDP (hCDP) that is restricted to produce the three major DC subsets. The phenotype of the DC progenitors partially overlaps with granulocyte-macrophage progenitors (GMPs). These progenitors reside in human cord blood and bone marrow but not in the blood or lymphoid tissues.