Advances in Insulin Infusion Set in the New Era of Automated Insulin Delivery: A Systematic Review.

INTRODUCTION: Automated insulin delivery (AID) has become a well-known research topic devoted to achieving better glycemic outcomes. AID systems consist primarily of three components: the continuous glucose monitoring system, the insulin delivery system, either tethered or patch pump, and the control system (algorithm). A key component in the tethered pump AID system is the insulin infusion set (IIS). This Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) study was conducted to evaluate the IIS evolution in the era of AID and to provide future perspectives of IIS clinical use. METHODS: Literature searches for articles published from January 2016 to July 2022 were performed in Embase/Medline and PubMed. Data were extracted following PRISMA guidelines. Primary meta-analysis outcomes were IIS wear duration, total daily dose of insulin, and IIS failure reasons/modes. RESULTS: We identified 387 publications, of which 15 eligible studies compared various IISs comprising over 1400 participants and >53 000 wears. Half of the studies published in 2022 were focused on extended IISs designed for wear durations of seven days or more. Three clinical trials have demonstrated the safe use of extended IISs to seven days of wear in individuals with type 1 diabetes, and two also demonstrated good glycemic control throughout the seven-day use. CONCLUSIONS: Research in insulin infusion technology has increased in the last six years, and extended IISs have demonstrated improved overall performance, particularly in duration of wear. Paths for future products are discussed with an emphasis on understanding the existing barriers related to both technical and nontechnical issues.

Development of the Extended Infusion Set and Its Mechanism of Action.

Continuous subcutaneous insulin infusion (CSII, or insulin pump) and continuous glucose monitoring (CGM) sensors have been increasingly used and associated with improved glycemic control by people with type 1 diabetes and insulin-requiring type 2 diabetes. Commonly used infusion sets in most CSII systems are limited to a wear time of 3 days. In contradistinction, CGM sensors are currently approved for seven and more days of wear. With the motivation to provide a 7-day infusion set that matches the CGM wear time and to improve patient experience, the recently CE-marked and FDA 510k-cleared Medtronic extended infusion set (EIS) was designed.s The EIS offers enhanced new features that include use for up to 7 days, improved convenience, comfort, and better quality of life for insulin pump users.

Evaluation of Extended Infusion Set Performance in Adults with Type 1 Diabetes: Infusion Set Survival Rate and Glycemic Outcomes from a Pivotal Trial.

Background: Standard insulin infusion sets (IISs) are to be replaced every 2 to 3 days to avoid complications and diabetic ketosis due to set failure. This pivotal trial evaluated the safety and performance of a new extended-wear infusion set (EIS) when used for 7 days by adults with type 1 diabetes (T1D). Methods: This single-arm, nonrandomized trial enrolled adults (18-80 years of age) with T1D, who used their own MiniMed™ 670G system with insulin lispro or insulin aspart and the EIS for up to 7 days, across 12 consecutive wears. Safety endpoints included incidence of serious adverse events (SAEs), serious adverse device effects (SADEs), unanticipated adverse device effects (UADEs), severe hypoglycemia (SevHypo), severe hyperglycemia (SevHyper), diabetic ketoacidosis (DKA), and skin infection. The EIS failure rate due to unexplained hyperglycemia (i.e., suspected occlusion), the overall EIS survival rate, glycemic control outcomes (i.e., A1C, mean sensor glucose and time spent in established glucose ranges), total daily insulin delivered, and satisfaction with the EIS were determined. Results: The intention to treat population (n = 259, 48% men, 45.0 ± 14.1 years) wore a total of 3041 EIS devices. No SADE, UADE, or DKA events was reported. Overall rates of SAEs, SevHypo, SevHyper, and skin infection were 3.8, 2.5, 104.1, and 20.1 events per 100 participant-years. The rate of EIS failure due to unexplained hyperglycemia at the end of day 7 was 0.1% (95% confidence interval [CI]: 0.03-0.51) and 0.4% (95% CI: 0.16-1.00) for insulin lispro and aspart use, respectively. Overall EIS survival rate at the end of day 7 was 77.8% (95% CI: 76.2-79.3), glycemic control did not change, and participants reported greater satisfaction with the EIS compared with standard IISs worn before the study (P < 0.001). Conclusions: This investigation demonstrates that the EIS, when worn for up to 7 days, was safe and rated with high satisfaction, without adversely affecting glycemic control in adults with T1D. Clinical Trial Registration number: NCT04113694 (https://clinicaltrials.gov/ct2/show/NCT04113694).

The improved survival rate and cost-effectiveness of a 7-day continuous subcutaneous insulin infusion set.

AIMS: The purpose of this article is to compare the insulin cost-savings of the Medtronic Extended Infusion Set (or EIS, a.k.a. Extended Wear Infusion Set) designed and labeled for up to 7-day use with rapid-acting insulins to the current standard of care, 2- to 3-day infusion sets. METHODS: There are three major improvements (reducing insulin waste, plastic waste, and adverse events) with the extended duration of infusion set wear. This analysis focuses on cost savings from reduced insulin wastage during set changes. Studies published on insulin infusion set survival and EIS clinical trial data (NCT04113694) were used to estimate device lifetime performance using a Markov chain Monte Carlo model, including the assessment of adverse effects and device failure. Total costs associated with infusion set change or failure were systematically found in published literature or estimated based on physical usage, and the direct impact on insulin costs was calculated. RESULTS: Based on the model and clinical data, EIS users can expect to change their infusion sets about 75 fewer times than standard set users each year. The costs related to unrecoverable insulin during an infusion set and reservoir change in the US were estimated to range from $19.79 to $22.48, resulting in approximately $1324 to $1677 in annual cost-savings for the typical user from minimizing insulin wastage. LIMITATIONS: The study only assessed devices used within a monitored setting, that is, clinical trials. In addition, the variability associated with healthcare standards and costs and individual treatment variability including insulin dosages, contribute to the uncertainties with the calculations. CONCLUSIONS: Our analysis demonstrates that by extending the duration of infusion set wear, there may be substantial cost savings by reducing insulin wastage.

Influence of type IV pilus retraction on the architecture of the Neisseria gonorrhoeae-infected cell cortex.

Early in infection, Neisseria gonorrhoeae can be observed to attach to the epithelial cell surface as microcolonies and induce dramatic changes to the host cell cortex. We tested the hypothesis that type IV pili (Tfp) retraction plays a role in the ultrastructure of both the host cell cortex and the bacterial microcolony. Using serial ultrathin sectioning, transmission electron microscopy and 3D reconstruction of serial 2D images, we have obtained what we believe to be the first 3D reconstructions of the N. gonorrhoeae-host cell interface, and determined the architecture of infected cell microvilli as well as the attached microcolony. Tfp connect both wild-type (wt) and Tfp retraction-deficient bacteria with each other, and with the host cell membrane. Tfp fibres and microvilli form a lattice in the wt microcolony and at its periphery. Wt microcolonies induce microvilli formation and increases of surface area, leading to an approximately ninefold increase in the surface area of the host cell membrane at the site of attachment. In contrast, Tfp retraction-deficient microcolonies do not affect these parameters. Wt microcolonies had a symmetrical, dome-shaped structure with a circular 'footprint', while Tfp retraction-deficient microcolonies were notably less symmetrical. These findings support a major role for Tfp retraction in microvilli and microcolony architecture. They are consistent with the biophysical attributes of Tfp and the effects of Tfp retraction on epithelial cell signalling.

Four distinct pathways of hemoglobin uptake in the malaria parasite Plasmodium falciparum.

During the bloodstage of malaria infection, the parasite internalizes and degrades massive amounts of hemoglobin from the host red blood cell. Using serial thin-section electron microscopy and three-dimensional reconstruction, we demonstrate four independent, but partially overlapping, hemoglobin-uptake processes distinguishable temporally, morphologically, and pharmacologically. Early ring-stage parasites undergo a profound morphological transformation in which they fold, like a cup, onto themselves and in so doing take a large first gulp of host cell cytoplasm. This event, which we term the "Big Gulp," appears to be independent of actin polymerization and marks the first step in biogenesis of the parasite's lysosomal compartment-the food vacuole. A second, previously identified uptake process, uses the cytostome, a well characterized and morphologically distinct structure at the surface of the parasite. This process is more akin to classical endocytosis, giving rise to small (<0.004 fl) vesicles that are marked by the early endosomal regulatory protein Rab5a. A third process, also arising from cytostomes, creates long thin tubes previously termed cytostomal tubes in an actin-dependent manner. The fourth pathway, which we term phagotrophy, is similar to the Big Gulp in that it more closely resembles phagocytosis, except that phagotrophy does not require actin polymerization. Each of these four processes has aspects that are unique to Plasmodium, thus opening avenues to antimalarial therapy.

Population structure of Y chromosome SNP haplogroups in the United States and forensic implications for constructing Y chromosome STR databases.

A set of 61 Y chromosome single-nucleotide-polymorphisms (Y-SNPs) is typed in a sample of 2517 individuals from 38 populations to infer the geographic origins of Y chromosomes in the United States and to test for paternal admixture among African-, European-, Hispanic-, Asian-, and Native-Americans. All of the samples were previously typed with the 11 core U.S. Y chromosome short tandem repeats (Y-STRs) recommended by SWGDAM, which revealed high levels of among ethnic group variation and low levels of among-population-within-ethnic-group variation. Admixture estimates vary greatly among populations and ethnic groups. The frequencies of non-European (3.4%) and non-Asian (4.5%) Y chromosomes are generally low in European-American and Asian-American populations, respectively. The frequencies of European Y chromosomes in Native-American populations range widely (i.e., 7-89%) and follow a West to East gradient, whereas they are relatively consistent in African-American populations (26.4+/-8.9%) from different locations. The European (77.8+/-9.3%) and Native-American (13.7+/-7.4%) components of the Hispanic paternal gene pool are also relatively constant among geographic regions; however, the African contribution is much higher in the Northeast (10.5+/-6.4%) than in the Southwest (1.5+/-0.9%) or Midwest (0%). To test for the effects of inter-ethnic admixture on the structure of Y-STR diversity in the U.S., we perform subtraction analyses in which Y chromosomes inferred to be admixed by Y-SNP analysis are removed from the database and pairwise population differentiation tests are implemented on the remaining Y-STR haplotypes. Results show that low levels of heterogeneity previously observed between pairs of Hispanic-American populations disappear when African-derived chromosomes are removed from the analysis. This is not the case for an unusual sample of European-Americans from New York City when its African-derived chromosomes are removed, or for Native-American populations when European-derived chromosomes are removed. We infer that both inter-ethnic admixture and population structure in ancestral source populations may contribute to fine scale Y-STR heterogeneity within U.S. ethnic groups.