Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes.

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

De novo protein design by citizen scientists.

Online citizen science projects such as GalaxyZoo1, Eyewire2 and Phylo3 have proven very successful for data collection, annotation and processing, but for the most part have harnessed human pattern-recognition skills rather than human creativity. An exception is the game EteRNA4, in which game players learn to build new RNA structures by exploring the discrete two-dimensional space of Watson-Crick base pairing possibilities. Building new proteins, however, is a more challenging task to present in a game, as both the representation and evaluation of a protein structure are intrinsically three-dimensional. We posed the challenge of de novo protein design in the online protein-folding game Foldit5. Players were presented with a fully extended peptide chain and challenged to craft a folded protein structure and an amino acid sequence encoding that structure. After many iterations of player design, analysis of the top-scoring solutions and subsequent game improvement, Foldit players can now-starting from an extended polypeptide chain-generate a diversity of protein structures and sequences that encode them in silico. One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes; 56 were found to be expressed and soluble in Escherichia coli, and to adopt stable monomeric folded structures in solution. The diversity of these structures is unprecedented in de novo protein design, representing 20 different folds-including a new fold not observed in natural proteins. High-resolution structures were determined for four of the designs, and are nearly identical to the player models. This work makes explicit the considerable implicit knowledge that contributes to success in de novo protein design, and shows that citizen scientists can discover creative new solutions to outstanding scientific challenges such as the protein design problem.

Macromolecular modeling and design in Rosetta: recent methods and frameworks.

The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at http://www.rosettacommons.org.

Building de novo cryo-electron microscopy structures collaboratively with citizen scientists.

With the rapid improvement of cryo-electron microscopy (cryo-EM) resolution, new computational tools are needed to assist and improve upon atomic model building and refinement options. This communication demonstrates that microscopists can now collaborate with the players of the computer game Foldit to generate high-quality de novo structural models. This development could greatly speed the generation of excellent cryo-EM structures when used in addition to current methods.

Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial.

BACKGROUND: The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. METHODS: We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220. FINDINGS: We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7-1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8-1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0·52 [SD 0·83]) than in the comparator period (0·05 [0·17]; difference 0·47, 95% CI 0·21-0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. INTERPRETATION: Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

Foldit Standalone: a video game-derived protein structure manipulation interface using Rosetta.

SUMMARY: Foldit Standalone is an interactive graphical interface to the Rosetta molecular modeling package. In contrast to most command-line or batch interactions with Rosetta, Foldit Standalone is designed to allow easy, real-time, direct manipulation of protein structures, while also giving access to the extensive power of Rosetta computations. Derived from the user interface of the scientific discovery game Foldit (itself based on Rosetta), Foldit Standalone has added more advanced features and removed the competitive game elements. Foldit Standalone was built from the ground up with a custom rendering and event engine, configurable visualizations and interactions driven by Rosetta. Foldit Standalone contains, among other features: electron density and contact map visualizations, multiple sequence alignment tools for template-based modeling, rigid body transformation controls, RosettaScripts support and an embedded Lua interpreter. AVAILABILITY AND IMPLEMENTATION: Foldit Standalone is available for download at https://fold.it/standalone , under the Rosetta license, which is free for academic and non-profit users. It is implemented in cross-platform C ++ and binary executables are available for Windows, macOS and Linux. CONTACT: scooper@ccs.neu.edu.

Outpatient glycemic control with a bionic pancreas in type 1 diabetes.

BACKGROUND: The safety and effectiveness of automated glycemic management have not been tested in multiday studies under unrestricted outpatient conditions. METHODS: In two random-order, crossover studies with similar but distinct designs, we compared glycemic control with a wearable, bihormonal, automated, "bionic" pancreas (bionic-pancreas period) with glycemic control with an insulin pump (control period) for 5 days in 20 adults and 32 adolescents with type 1 diabetes mellitus. The automatically adaptive algorithm of the bionic pancreas received data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. RESULTS: Among the adults, the mean plasma glucose level over the 5-day bionic-pancreas period was 138 mg per deciliter (7.7 mmol per liter), and the mean percentage of time with a low glucose level (<70 mg per deciliter [3.9 mmol per liter]) was 4.8%. After 1 day of automatic adaptation by the bionic pancreas, the mean (±SD) glucose level on continuous monitoring was lower than the mean level during the control period (133±13 vs. 159±30 mg per deciliter [7.4±0.7 vs. 8.8±1.7 mmol per liter], P<0.001) and the percentage of time with a low glucose reading was lower (4.1% vs. 7.3%, P=0.01). Among the adolescents, the mean plasma glucose level was also lower during the bionic-pancreas period than during the control period (138±18 vs. 157±27 mg per deciliter [7.7±1.0 vs. 8.7±1.5 mmol per liter], P=0.004), but the percentage of time with a low plasma glucose reading was similar during the two periods (6.1% and 7.6%, respectively; P=0.23). The mean frequency of interventions for hypoglycemia among the adolescents was lower during the bionic-pancreas period than during the control period (one per 1.6 days vs. one per 0.8 days, P<0.001). CONCLUSIONS: As compared with an insulin pump, a wearable, automated, bihormonal, bionic pancreas improved mean glycemic levels, with less frequent hypoglycemic episodes, among both adults and adolescents with type 1 diabetes mellitus. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01762059 and NCT01833988.).

Predicting protein structures with a multiplayer online game.

People exert large amounts of problem-solving effort playing computer games. Simple image- and text-recognition tasks have been successfully 'crowd-sourced' through games, but it is not clear if more complex scientific problems can be solved with human-directed computing. Protein structure prediction is one such problem: locating the biologically relevant native conformation of a protein is a formidable computational challenge given the very large size of the search space. Here we describe Foldit, a multiplayer online game that engages non-scientists in solving hard prediction problems. Foldit players interact with protein structures using direct manipulation tools and user-friendly versions of algorithms from the Rosetta structure prediction methodology, while they compete and collaborate to optimize the computed energy. We show that top-ranked Foldit players excel at solving challenging structure refinement problems in which substantial backbone rearrangements are necessary to achieve the burial of hydrophobic residues. Players working collaboratively develop a rich assortment of new strategies and algorithms; unlike computational approaches, they explore not only the conformational space but also the space of possible search strategies. The integration of human visual problem-solving and strategy development capabilities with traditional computational algorithms through interactive multiplayer games is a powerful new approach to solving computationally-limited scientific problems.

WeFold: a coopetition for protein structure prediction.

The protein structure prediction problem continues to elude scientists. Despite the introduction of many methods, only modest gains were made over the last decade for certain classes of prediction targets. To address this challenge, a social-media based worldwide collaborative effort, named WeFold, was undertaken by 13 labs. During the collaboration, the laboratories were simultaneously competing with each other. Here, we present the first attempt at "coopetition" in scientific research applied to the protein structure prediction and refinement problems. The coopetition was possible by allowing the participating labs to contribute different components of their protein structure prediction pipelines and create new hybrid pipelines that they tested during CASP10. This manuscript describes both successes and areas needing improvement as identified throughout the first WeFold experiment and discusses the efforts that are underway to advance this initiative. A footprint of all contributions and structures are publicly accessible at http://www.wefold.org.

Algorithm discovery by protein folding game players.

Foldit is a multiplayer online game in which players collaborate and compete to create accurate protein structure models. For specific hard problems, Foldit player solutions can in some cases outperform state-of-the-art computational methods. However, very little is known about how collaborative gameplay produces these results and whether Foldit player strategies can be formalized and structured so that they can be used by computers. To determine whether high performing player strategies could be collectively codified, we augmented the Foldit gameplay mechanics with tools for players to encode their folding strategies as "recipes" and to share their recipes with other players, who are able to further modify and redistribute them. Here we describe the rapid social evolution of player-developed folding algorithms that took place in the year following the introduction of these tools. Players developed over 5,400 different recipes, both by creating new algorithms and by modifying and recombining successful recipes developed by other players. The most successful recipes rapidly spread through the Foldit player population, and two of the recipes became particularly dominant. Examination of the algorithms encoded in these two recipes revealed a striking similarity to an unpublished algorithm developed by scientists over the same period. Benchmark calculations show that the new algorithm independently discovered by scientists and by Foldit players outperforms previously published methods. Thus, online scientific game frameworks have the potential not only to solve hard scientific problems, but also to discover and formalize effective new strategies and algorithms.

Randomized Trial of the Insulin-Only iLet Bionic Pancreas for the Treatment of Cystic Fibrosis- Related Diabetes.

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) affects up to 50% of adults with cystic fibrosis and adds significant morbidity and treatment burden. We evaluated the safety and efficacy of automated insulin delivery with the iLet bionic pancreas (BP) in adults with CFRD in a single-center, open-label, random-order, crossover trial. RESEARCH DESIGN AND METHODS: Twenty participants with CFRD were assigned in random order to 14 days each on the BP or their usual care (UC). No restrictions were placed on diet or activity. The primary outcome was the percent time sensor-measured glucose was in target range 70-180 mg/dL (time in range [TIR]) on days 3-14 of each arm, and key secondary outcomes included mean continuous glucose monitoring (CGM) glucose and the percent time sensor-measured glucose was in hypoglycemic range <54 mg/dL. RESULTS: TIR was significantly higher in the BP arm than the UC arm (75 ± 11% vs. 62 ± 22%, P = 0.001). Mean CGM glucose was lower in the BP arm than in the UC arm (150 ± 19 vs. 171 ± 45 mg/dL, P = 0.007). There was no significant difference in percent time with sensor-measured glucose <54 mg/dL (0.27% vs. 0.36%, P = 1.0), although self-reported symptomatic hypoglycemia episodes were higher during the BP arm than the UC arm (0.7 vs. 0.4 median episodes per day, P = 0.01). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either arm. CONCLUSIONS: Adults with CFRD had improved glucose control without an increase in CGM-measured hypoglycemia with the BP compared with their UC, suggesting that this may be an important therapeutic option for this patient population.

Utility and Safety of Backup Insulin Regimens Generated by the Bionic Pancreas: A Randomized Study.

The bionic pancreas (BP) is initialized with body weight only and doses insulin autonomously without carbohydrate counting, instead using qualitative meal announcements. In case of device malfunction, the BP generates and continuously updates backup insulin doses for injection or pump users, including long-acting insulin dose, a four-period basal insulin profile, short-acting meal doses, and a glucose correction factor. Following a 13-week trial in type 1 diabetes, participants using the BP (6-83 years) completed 2-4 days, in which they were randomly assigned to their prestudy insulin regimen (N = 147) or to follow BP-provided guidance (N = 148). Glycemic outcomes with BP guidance were similar to those reinstituting their prestudy insulin regimen, with both groups having higher mean glucose and lower time-in-range than while using the BP during the 13-week trial. In conclusion, a backup insulin regimen automatically generated by the BP can be safely implemented if need arises to discontinue use of the BP. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

Psychosocial Impact of the Insulin-Only iLet Bionic Pancreas for Adults, Youth, and Caregivers of Youth with Type 1 Diabetes.

Objective: To evaluate the psychosocial impact and user experience for the insulin-only configuration of iLet bionic pancreas (BP) in persons 6-83 years years of age with type 1 diabetes. Research Design and Methods: In this multicenter, randomized controlled, 13-week trial, 275 adults (221 randomly assigned to the BP group and 54 to the standard of care [SC] group) and 165 youth and their caregivers (112 randomly assigned to the BP group and 53 to the SC group) completed psychosocial questionnaires at baseline, mid-study, and the end of the trial. Results: In all age groups, most participants would recommend using the BP, including those with previous experience using automated insulin delivery devices. Similarly, the vast majority of participants reported a high level of perceived benefits and a low number of perceived burdens. Adult participants reported significant decreases in the fear of hypoglycemia and in diabetes-specific emotional distress, as well as improvements in their perceived well-being. Conclusion: Findings demonstrate acceptability, reduced burden, and positive psychosocial outcomes for adults. Children and teenagers also report high acceptability and reduced burden, but less clear improvements in psychosocial outcomes. Clinical Trial Registration Number: NCT04200313.

Structure of the divergent human astrovirus MLB capsid spike.

Despite their worldwide prevalence and association with human disease, the molecular bases of human astrovirus (HAstV) infection and evolution remain poorly characterized. Here, we report the structure of the capsid protein spike of the divergent HAstV MLB clade (HAstV MLB). While the structure shares a similar folding topology with that of classical-clade HAstV spikes, it is otherwise strikingly different. We find no evidence of a conserved receptor-binding site between the MLB and classical HAstV spikes, suggesting that MLB and classical HAstVs utilize different receptors for host-cell attachment. We provide evidence for this hypothesis using a novel HAstV infection competition assay. Comparisons of the HAstV MLB spike structure with structures predicted from its sequence reveal poor matches, but template-based predictions were surprisingly accurate relative to machine-learning-based predictions. Our data provide a foundation for understanding the mechanisms of infection by diverse HAstVs and can support structure determination in similarly unstudied systems.

A Multicenter Randomized Trial Evaluating Fast-Acting Insulin Aspart in the Bionic Pancreas in Adults with Type 1 Diabetes.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) using fast-acting insulin aspart (Fiasp®) in adults with type 1 diabetes (T1D). Research Design and Methods: In this multicenter, randomized trial, 275 adults with T1D (18-83 years old, baseline HbA1c 5.3%-14.9%) were randomly assigned 2:2:1 to use the BP with fast-acting insulin aspart (BP-F group, N = 114), BP with aspart or lispro (BP-A/L group, N = 107), or a control group using their standard-care insulin delivery (SC group, N = 54) plus real-time continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. The BP-F versus SC comparison was considered primary and BP-F versus BP-A/L secondary. Results: Mean ± standard deviation (SD) HbA1c decreased from 7.8% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks with BP-F versus 7.6% ± 1.2% to 7.5% ± 0.9% with SC (adjusted difference = -0.5%, 95% CI -0.7 to -0.3, P < 0.001). CGM-measured percent time <54 mg/dL over 13 weeks with BP-F was noninferior to SC (adjusted difference = 0.00%, 95% CI -0.07 to 0.05, P < 0.001 for noninferiority based on a prespecified noninferiority limit of 1%). Over 13 weeks, mean time in range 70-180 mg/dL (TIR) increased by 14% (3.4 h/day) and mean CGM glucose was reduced by 18 mg/dL with BP-F compared with SC (P < 0.001). Analyses of time >180 mg/dL, time >250 mg/dL, and the SD of CGM glucose all favored BP-F compared with SC (P < 0.001). Differences between BP-F and BP-A/L were minimal, with no difference in HbA1c at 13 weeks (adjusted difference = -0.0%, 95% CI -0.2 to 0.1, P = 0.67) or mean glucose (adjusted difference = -2.0 mg/dL, 95% CI -4.3 to 0.4, P = 0.10). Mean TIR was 2% greater with BP-F than BP-A/L (95% CI 1 to 4, P = 0.005), but the percentages of participants improving TIR by ≥5% were not significantly different (P = 0.49) and there were no significant differences comparing BP-F versus BP-A/L across nine patient-reported outcome surveys. The rate of severe hypoglycemia events did not differ among the three groups. Conclusions: In adults with T1D, HbA1c was improved with the BP using fast-acting insulin aspart compared with standard care without increasing CGM-measured hypoglycemia. However, the effect was no better than the reduction observed with the BP using aspart or lispro. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

The Insulin-Only Bionic Pancreas Pivotal Trial Extension Study: A Multi-Center Single-Arm Evaluation of the Insulin-Only Configuration of the Bionic Pancreas in Adults and Youth with Type 1 Diabetes.

Objective: To evaluate a transition from standard-of-care (SC) management of type 1 diabetes (any insulin delivery method including hybrid closed-loop systems plus real-time continuous glucose monitoring [CGM]) to use of the insulin-only configuration of the iLet® bionic pancreas (BP) in 90 adults and children (age 6-71 years). Research Design and Methods: After the SC group completed the randomized controlled trial (RCT) portion of the Insulin-Only BP Pivotal Trial, 90 of the 107 participants participated in a 13-week study using the BP. The key outcomes were change from baseline in HbA1c and CGM metrics after 13 weeks on the BP. Results: Using the BP, mean HbA1c decreased from 7.7% ± 1.0% (61 ± 10.9 mmol/mol) at baseline to 7.1% ± 0.6% (54 ± 6.6 mmol/mol) at 13 weeks (mean change -0.55% ± 0.72% [-6 ± 7.9 mmol/mol], P < 0.001), time in range 70-180 mg/dL increased by 12.0% ± 12.5% (from 53% ± 17% to 65% ± 9%, P < 0.001), and mean glucose decreased by -18 ± 23 mg/dL (from 182 ± 32 to 164 ± 15 mg/dL, P < 0.001). The higher the baseline HbA1c level, the greater the change in HbA1c. Results were similar in the adult (N = 42) and pediatric (N = 48) cohorts. Time <70 mg/dL decreased from baseline over the 13 weeks by -0.50% ± 1.86% (P = 0.02), and time <54 mg/dL was similar (change from baseline -0.08% ± 0.59%, P = 0.24). Two severe hypoglycemia events (in same participant) and one diabetic ketoacidosis event occurred. Conclusions: Glycemic control improved after adult and pediatric participants in the SC arm in the Insulin-Only BP Pivotal Trial transitioned to use of the BP. Improvement using the BP was of similar magnitude to that observed during the RCT. ClinicalTrials.gov number, NCT04200313.

WITHDRAWN: Positive Impact of the Bionic Pancreas on Diabetes Control in Youth 6-17 Years Old with Type 1 Diabetes: A Multicenter Randomized Trial.

The publisher of Diabetes Technologies & Therapeutics officially withdraws the Just Accepted version of the article entitled, "Positive Impact of the Bionic Pancreas on Diabetes Control in Youth 6-17 Years Old with Type 1 Diabetes: A Multicenter Randomized Trial," by Laurel H Messer, et al. (epub 28 Jun 2022; DOI: 10.1089/dia.2022.0201) due to its erroneous release before being finalized. The correct version will be republished in due course. The publisher extends its sincerest apologies to the authors of the article and to the journal's readership for this regrettable mishap.

A Multicenter Randomized Trial Evaluating the Insulin-Only Configuration of the Bionic Pancreas in Adults with Type 1 Diabetes.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) using insulin aspart or insulin lispro in adults with type 1 diabetes (T1D). Methods: In this multicenter, randomized, controlled trial, 161 adults with T1D (18-79 years old, baseline HbA1c 5.5%-13.1%, 32% using multiple daily injections, 27% using a pump without automation, 5% using a pump with predictive low glucose suspend, and 36% using a hybrid closed loop system before the study) were randomly assigned 2:1 to use the BP (N = 107) with insulin aspart or insulin lispro (BP group) or a standard-of-care (SC) control group (N = 54) using their usual insulin delivery plus continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 7.6% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks with BP versus 7.6% ± 1.2% to 7.5% ± 0.9% with SC (adjusted difference = -0.5%, 95% confidence interval -0.6% to -0.3%, P < 0.001). Over 13 weeks, mean time in range 70-180 mg/dL (TIR) increased by 11% (2.6 h/d) and mean CGM glucose was reduced by 16 mg/dL with BP compared with SC (P < 0.001). Improvement in these metrics was seen during the first day of BP use and by the end of the first week reached levels that remained relatively stable through 13 weeks. Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose all favored the BP group (P < 0.001). The CGM-measured hypoglycemia was low at baseline (median time <54 mg/dL of 0.21% [3 min/d] for the BP group and 0.11% [1.6 min/d] for the SC group) and not significantly different between groups over the 13 weeks (P = 0.51 for time <70 mg/dL and 0.33 for time <54 mg/dL). There were 7 (6.5% of 107 participants) severe hypoglycemic events in the BP group and 2 events in the SC group (1.9% of 54 participants, P = 0.40). Conclusions: In adults with T1D, use of the BP with insulin aspart or insulin lispro improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

Positive Impact of the Bionic Pancreas on Diabetes Control in Youth 6-17 Years Old with Type 1 Diabetes: A Multicenter Randomized Trial.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) in youth 6-17 years old with type 1 diabetes (T1D). Research Design and Methods: In this multicenter, randomized, controlled trial, 165 youth with T1D (6-17 years old; baseline HbA1c 5.8%-12.2%; 35% using multiple daily injections, 36% using an insulin pump without automation, 4% using an insulin pump with low glucose suspend, and 25% using a hybrid closed-loop system before the study) were randomly assigned 2:1 to use BP (n = 112) with insulin aspart or insulin lispro (BP group) or to a control group (n = 53) using their personal standard care insulin delivery (SC group) plus real-time continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 8.1% ± 1.2% at baseline to 7.5% ± 0.7% at 13 weeks with BP versus 7.8% ± 1.1% at both baseline and 13 weeks with SC (adjusted difference = -0.5%, 95% CI -0.7% to -0.2%, P < 0.001). Participants with baseline HbA1c ≥9.0% (n = 34) decreased mean HbA1c from 9.7% ± 0.8% to 7.9% ± 0.6% after 13 weeks with BP compared with 9.7% ± 0.5% to 9.8% ± 0.8% with SC. Over 13 weeks, mean time in range (TIR) 70-180 mg/dL increased by 10% (2.4 h per day) and mean CGM glucose was reduced by 15 mg/dL with BP compared with SC (P < 0.001). Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose favored BP (P < 0.001). Time <54 mg/dL was low at baseline (median 0.2%) and not significantly different between groups over 13 weeks (P = 0.24). A severe hypoglycemia event occurred in 3 (2.7%) participants in the BP group and in 1 (1.9%) in the SC group. Conclusions: In youth 6-17 years old with T1D, use of insulin-only configuration of BP improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Improvement in glycemic metrics was most pronounced in participants with high baseline HbA1c levels. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

High-resolution structure of a retroviral protease folded as a monomer.

Mason-Pfizer monkey virus (M-PMV), a D-type retrovirus assembling in the cytoplasm, causes simian acquired immunodeficiency syndrome (SAIDS) in rhesus monkeys. Its pepsin-like aspartic protease (retropepsin) is an integral part of the expressed retroviral polyproteins. As in all retroviral life cycles, release and dimerization of the protease (PR) is strictly required for polyprotein processing and virion maturation. Biophysical and NMR studies have indicated that in the absence of substrates or inhibitors M-PMV PR should fold into a stable monomer, but the crystal structure of this protein could not be solved by molecular replacement despite countless attempts. Ultimately, a solution was obtained in mr-rosetta using a model constructed by players of the online protein-folding game Foldit. The structure indeed shows a monomeric protein, with the N- and C-termini completely disordered. On the other hand, the flap loop, which normally gates access to the active site of homodimeric retropepsins, is clearly traceable in the electron density. The flap has an unusual curled shape and a different orientation from both the open and closed states known from dimeric retropepsins. The overall fold of the protein follows the retropepsin canon, but the C(α) deviations are large and the active-site 'DTG' loop (here NTG) deviates up to 2.7 Å from the standard conformation. This structure of a monomeric retropepsin determined at high resolution (1.6 Å) provides important extra information for the design of dimerization inhibitors that might be developed as drugs for the treatment of retroviral infections, including AIDS.