Fanconi Anemia Proteins Function in Mitophagy and Immunity.

Fanconi anemia (FA) pathway genes are important tumor suppressors whose best-characterized function is repair of damaged nuclear DNA. Here, we describe an essential role for FA genes in two forms of selective autophagy. Genetic deletion of Fancc blocks the autophagic clearance of viruses (virophagy) and increases susceptibility to lethal viral encephalitis. Fanconi anemia complementation group C (FANCC) protein interacts with Parkin, is required in vitro and in vivo for clearance of damaged mitochondria, and decreases mitochondrial reactive oxygen species (ROS) production and inflammasome activation. The mitophagy function of FANCC is genetically distinct from its role in genomic DNA damage repair. Moreover, additional genes in the FA pathway, including FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2, are required for mitophagy. Thus, members of the FA pathway represent a previously undescribed class of selective autophagy genes that function in immunity and organellar homeostasis. These findings have implications for understanding the pathogenesis of FA and cancers associated with mutations in FA genes.

Population-level management of type 1 diabetes via continuous glucose monitoring and algorithm-enabled patient prioritization: Precision health meets population health.

OBJECTIVE: To develop and scale algorithm-enabled patient prioritization to improve population-level management of type 1 diabetes (T1D) in a pediatric clinic with fixed resources, using telemedicine and remote monitoring of patients via continuous glucose monitor (CGM) data review. RESEARCH DESIGN AND METHODS: We adapted consensus glucose targets for T1D patients using CGM to identify interpretable clinical criteria to prioritize patients for weekly provider review. The criteria were constructed to manage the number of patients reviewed weekly and identify patients who most needed provider contact. We developed an interactive dashboard to display CGM data relevant for the patients prioritized for review. RESULTS: The introduction of the new criteria and interactive dashboard was associated with a 60% reduction in the mean time spent by diabetes team members who remotely and asynchronously reviewed patient data and contacted patients, from 3.2 ± 0.20 to 1.3 ± 0.24 min per patient per week. Given fixed resources for review, this corresponded to an estimated 147% increase in weekly clinic capacity. Patients who qualified for and received remote review (n = 58) have associated 8.8 percentage points (pp) (95% CI = 0.6-16.9 pp) greater time-in-range (70-180 mg/dl) glucoses compared to 25 control patients who did not qualify at 12 months after T1D onset. CONCLUSIONS: An algorithm-enabled prioritization of T1D patients with CGM for asynchronous remote review reduced provider time spent per patient and was associated with improved time-in-range.

Equitable implementation of a precision digital health program for glucose management in individuals with newly diagnosed type 1 diabetes.

Few young people with type 1 diabetes (T1D) meet glucose targets. Continuous glucose monitoring improves glycemia, but access is not equitable. We prospectively assessed the impact of a systematic and equitable digital-health-team-based care program implementing tighter glucose targets (HbA1c < 7%), early technology use (continuous glucose monitoring starts <1 month after diagnosis) and remote patient monitoring on glycemia in young people with newly diagnosed T1D enrolled in the Teamwork, Targets, Technology, and Tight Control (4T Study 1). Primary outcome was HbA1c change from 4 to 12 months after diagnosis; the secondary outcome was achieving the HbA1c targets. The 4T Study 1 cohort (36.8% Hispanic and 35.3% publicly insured) had a mean HbA1c of 6.58%, 64% with HbA1c < 7% and mean time in the range (70-180 mg dl-1) of 68% at 1 year after diagnosis. Clinical implementation of the 4T Study 1 met the prespecified primary outcome and improved glycemia without unexpected serious adverse events. The strategies in the 4T Study 1 can be used to implement systematic and equitable care for individuals with T1D and translate to care for other chronic diseases. ClinicalTrials.gov registration: NCT04336969 .

Management of Neonatal Diabetes due to a KCNJ11 Mutation with Automated Insulin Delivery System and Remote Patient Monitoring.

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes. Management of hyperglycemia in neonates with subcutaneous insulin is challenging because of frequent feeding, variable quantity of milk intake with each feed, low insulin dose requirements, and high risk for hypoglycemia and associated complications in this population. We present a case of NDM in a proband initially presenting with focal seizures and diabetic ketoacidosis due to a pathologic mutation in the beta cell potassium ATP channel gene KCNJ11 c.679G > A (p.E227K). We describe the use of continuous glucose monitoring (CGM), insulin pump, automated insulin delivery system, and remote patient monitoring technologies to facilitate rapid and safe outpatient cross-titration from insulin to oral sulfonylurea. Our case highlights the safety and efficacy of these technologies for infants with diabetes, including improvements in glycemia, quality of life, and cost-effectiveness by shortening hospital stay.

Overcoming Barriers to Diabetes Technology in Youth with Type 1 Diabetes and Public Insurance: Cases and Call to Action.

Advancements in diabetes technology such as continuous glucose monitoring (CGM), insulin pumps, and automated insulin delivery provide opportunities to improve glycemic control for youth with type 1 diabetes (T1D). However, diabetes technology use is lower in youth on public insurance, and this technology use gap is widening in the US. There is a significant need to develop effective interventions and policies to promote equitable care. The dual purpose of this case series is as follows: (1) describe success stories of the CGM Time in Range Program (CGM TIPs), which removed barriers for initiating CGM and provided asynchronous remote glucose monitoring for youth on public insurance, and (2) advocate for improving CGM coverage by public insurance. We describe a series of six youths with T1D and public insurance who obtained and sustained use of CGM with assistance from the program. Three youths had improved engagement with the care team while on CGM and the remote monitoring protocol, and three youths were able to leverage sustained CGM wear to obtain insurance coverage for automated insulin delivery systems. CGM TIPs helped these youths achieve lower hemoglobin A1c and improved time in range (TIR). Despite the successes, expansion of CGM TIPs is limited by stringent barriers for CGM approval and difficult postapproval patient workflows to receive shipments. These cases highlight the potential for combining diabetes technology and asynchronous remote monitoring to support continued use and provide education to improve glycemic control for youth with T1D on public insurance and the need to reduce barriers for obtaining CGM coverage by public insurance.

Algorithm-Enabled, Personalized Glucose Management for Type 1 Diabetes at the Population Scale: Prospective Evaluation in Clinical Practice.

BACKGROUND: The use of continuous glucose monitors (CGMs) is recommended as the standard of care by the American Diabetes Association for individuals with type 1 diabetes (T1D). Few hardware-agnostic, open-source, whole-population tools are available to facilitate the use of CGM data by clinicians such as physicians and certified diabetes educators. OBJECTIVE: This study aimed to develop a tool that identifies patients appropriate for contact using an asynchronous message through electronic medical records while minimizing the number of patients reviewed by a certified diabetes educator or physician using the tool. METHODS: We used consensus guidelines to develop timely interventions for diabetes excellence (TIDE), an open-source hardware-agnostic tool to analyze CGM data to identify patients with deteriorating glucose control by generating generic flags (eg, mean glucose [MG] >170 mg/dL) and personalized flags (eg, MG increased by >10 mg/dL). In a prospective 7-week study in a pediatric T1D clinic, we measured the sensitivity of TIDE in identifying patients appropriate for contact and the number of patients reviewed. We simulated measures of the workload generated by TIDE, including the average number of time in range (TIR) flags per patient per review period, on a convenience sample of eight external data sets, 6 from clinical trials and 2 donated by research foundations. RESULTS: Over the 7 weeks of evaluation, the clinical population increased from 56 to 64 patients. The mean sensitivity was 99% (242/245; SD 2.5%), and the mean reduction in the number of patients reviewed was 42.6% (182/427; SD 10.9%). The 8 external data sets contained 1365 patients with 30,017 weeks of data collected by 7 types of CGMs. The rates of generic and personalized TIR flags per patient per review period were, respectively, 0.15 and 0.12 in the data set with the lowest average MG (141 mg/dL) and 0.95 and 0.22 in the data set with the highest average MG (207 mg/dL). CONCLUSIONS: TIDE is an open-source hardware-agnostic tool for personalized analysis of CGM data at the clinical population scale. In a pediatric T1D clinic, TIDE identified 99% of patients appropriate for contact using an asynchronous message through electronic medical records while reducing the number of patients reviewed by certified diabetes care and education specialists by 43%. For each of the 8 external data sets, simulation of the use of TIDE produced fewer than 0.25 personalized TIR flags per patient per review period. The use of TIDE to support telemedicine-based T1D care may facilitate sensitive and efficient guideline-based population health management.

Apicomplexan parasites co-opt host calpains to facilitate their escape from infected cells.

Apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii (the causative agents of malaria and toxoplasmosis, respectively), are responsible for considerable morbidity and mortality worldwide. These pathogenic protozoa replicate within an intracellular vacuole inside of infected host cells, from which they must escape to initiate a new lytic cycle. By integrating cell biological, pharmacological, and genetic approaches, we provide evidence that both Plasmodium and Toxoplasma hijack host cell calpain proteases to facilitate parasite egress. Immunodepletion or inhibition of calpain-1 in hypotonically lysed and resealed erythrocytes prevented the escape of P. falciparum parasites, which was restored by adding purified calpain-1. Similarly, efficient egress of T. gondii from mammalian fibroblasts was blocked by either small interfering RNA-mediated suppression or genetic deletion of calpain activity and could be restored by genetic complementation.