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1.
N Engl J Med ; 387(13): 1161-1172, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36170500

RESUMO

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.).


Assuntos
Diabetes Mellitus Tipo 1 , Hipoglicemiantes , Insulina Aspart , Sistemas de Infusão de Insulina , Insulina Lispro , Adolescente , Adulto , Idoso , Biônica/instrumentação , Glicemia/análise , Automonitorização da Glicemia/instrumentação , Automonitorização da Glicemia/métodos , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/efeitos adversos , Insulina/uso terapêutico , Insulina Aspart/administração & dosagem , Insulina Aspart/efeitos adversos , Insulina Aspart/uso terapêutico , Sistemas de Infusão de Insulina/efeitos adversos , Insulina Lispro/administração & dosagem , Insulina Lispro/efeitos adversos , Insulina Lispro/uso terapêutico , Pessoa de Meia-Idade , Adulto Jovem
2.
J Bacteriol ; 206(2): e0032923, 2024 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-38289064

RESUMO

Synonymous mutations are changes to DNA sequence, which occur within translated genes but which do not affect the protein sequence. Although often referred to as silent mutations, evidence suggests that synonymous mutations can affect gene expression, mRNA stability, and even translation efficiency. A collection of both experimental and bioinformatic data has shown that synonymous mutations can impact cell phenotype, yet less is known about the molecular mechanisms and potential of beneficial or adaptive effects of such changes within evolved populations. Here, we report a beneficial synonymous mutation acquired via experimental evolution in an essential gene variant encoding the translation elongation factor protein EF-Tu. We demonstrate that this particular synonymous mutation increases EF-Tu mRNA and protein levels as well as global polysome abundance on RNA transcripts. Although presence of the synonymous mutation is clearly causative of such changes, we also demonstrate that fitness benefits are highly contingent on other potentiating mutations present within the genetic background in which the mutation arose. Our results underscore the importance of beneficial synonymous mutations, especially those that affect levels of proteins that are key for cellular processes.IMPORTANCEThis study explores the degree to which synonymous mutations in essential genes can influence adaptation in bacteria. An experimental system whereby an Escherichia coli strain harboring an engineered translation protein elongation factor-Tu (EF-Tu) was subjected to laboratory evolution. We find that a synonymous mutation acquired on the gene encoding for EF-Tu is conditionally beneficial for bacterial fitness. Our findings provide insight into the importance of the genetic background when a synonymous substitution is favored by natural selection and how such changes have the potential to impact evolution when critical cellular processes are involved.


Assuntos
Escherichia coli , Fator Tu de Elongação de Peptídeos , Fator Tu de Elongação de Peptídeos/genética , Fator Tu de Elongação de Peptídeos/metabolismo , Mutação , Escherichia coli/genética , Escherichia coli/metabolismo , Sequência de Aminoácidos , Patrimônio Genético
3.
Diabetologia ; 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39126488

RESUMO

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) improves glycaemic outcomes in the outpatient setting; however, there are limited data regarding CGM accuracy in hospital. METHODS: We conducted a prospective, observational study comparing CGM data from blinded Dexcom G6 Pro sensors with reference point of care and laboratory glucose measurements during participants' hospitalisations. Key accuracy metrics included the proportion of CGM values within ±20% of reference glucose values >5.6 mmol/l or within ±1.1 mmol/l of reference glucose values ≤5.6 mmol/l (%20/20), the mean and median absolute relative difference between CGM and reference value (MARD and median ARD, respectively) and Clarke error grid analysis (CEGA). A retrospective calibration scheme was used to determine whether calibration improved sensor accuracy. Multivariable regression models and subgroup analyses were used to determine the impact of clinical characteristics on accuracy assessments. RESULTS: A total of 326 adults hospitalised on 19 medical or surgical non-intensive care hospital floors were enrolled, providing 6648 matched glucose pairs. The %20/20 was 59.5%, the MARD was 19.2% and the median ARD was 16.8%. CEGA showed that 98.2% of values were in zone A (clinically accurate) and zone B (benign). Subgroups with lower accuracy metrics included those with severe anaemia, renal dysfunction and oedema. Application of a once-daily morning calibration schedule improved accuracy (MARD 11.4%). CONCLUSIONS/INTERPRETATION: The CGM accuracy when used in hospital may be lower than that reported in the outpatient setting, but this may be improved with appropriate patient selection and daily calibration. Further research is needed to understand the role of CGM in inpatient settings.

5.
Nat Rev Mol Cell Biol ; 8(9): 681-91, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17684529

RESUMO

Over the past 15 years it has become clear that mutations in genes that regulate endocrine signalling pathways can prolong lifespan. Lifespan can be increased by altered endocrine signalling in a group of cells or a single tissue, which indicates that crosstalk between tissues functions to coordinate ageing of the organism. These endocrine pathways might serve as targets for the manipulation of the ageing process and prevention of age-related diseases.


Assuntos
Envelhecimento/fisiologia , Sistema Endócrino/fisiologia , Transdução de Sinais , Animais , Glucuronidase/genética , Glucuronidase/farmacologia , Humanos , Insulina/fisiologia , Proteínas Klotho , Longevidade/fisiologia
6.
Lancet ; 389(10067): 369-380, 2017 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-28007348

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucagon/administração & dosagem , Hormônios/administração & dosagem , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Pâncreas Artificial , Adulto , Biônica , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Glucagon/uso terapêutico , Hormônios/uso terapêutico , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Náusea/induzido quimicamente , Adulto Jovem
7.
Rheumatology (Oxford) ; 57(12): 2235-2241, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30203101

RESUMO

Objective: Approximately 30% of patients with type 2 diabetes mellitus have knee osteoarthritis. IA corticosteroids used to manage osteoarthritis pain can elevate blood glucose in these patients. We compared blood glucose levels following intra-articular injection of triamcinolone acetonide extended-release (TA-ER), an extended-release, microsphere-based triamcinolone acetonide formulation, vs standard triamcinolone acetonide crystalline suspension (TAcs) in patients with knee osteoarthritis and comorbid type 2 diabetes. Methods: In this double-blind, randomized, parallel-group, phase 2 study (NCT02762370), 33 patients with knee osteoarthritis (American College of Rheumatology criteria) and type 2 diabetes mellitus (HbA1c 6.5-9.0% [48-75 mmol/mol]; 1-2 oral hypoglycaemic agents) were treated with intra-articular TA-ER (32 mg n = 18) or TAcs 40 mg (n = 15). Continuous glucose monitoring-measured glucose (CGMG) was assessed from 1 week pre-injection through 2 weeks postinjection. Endpoints included change in average daily CGMG from baseline (days -3 to -1) to days 1-3 postinjection (CGMGdays1-3) (primary) and percent time average hourly CGMG levels remained in prespecified glycaemic ranges. Results: The change CGMGdays1-3 was significantly lower following TA-ER vs TAcs (14.7 vs 33.9 mg/dl, least-squares-mean-difference [95% CI]: -19.2 [-38.0, -0.4]; P = 0.0452). The percentage of time over days 1-3 that CGMG was in the target glycaemic range (70-180 mg/dl) was numerically greater for TA-ER (63.3%) vs TAcs (49.7%), and that CGMG was >180 mg/dl was lower for TA-ER (34.5%) vs TAcs (49.9%). Non-glycaemic adverse events were mild and comparable between groups. Conclusion: TA-ER may enable intra-articular corticosteroid treatment with minimal blood glucose disruption in patients with knee osteoarthritis and type 2 diabetes mellitus. Trial registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02762370.


Assuntos
Corticosteroides/administração & dosagem , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Osteoartrite do Joelho/tratamento farmacológico , Triancinolona Acetonida/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Automonitorização da Glicemia , Preparações de Ação Retardada , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Humanos , Injeções Intra-Articulares , Articulação do Joelho , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/complicações , Resultado do Tratamento
8.
N Engl J Med ; 371(4): 313-325, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-24931572

RESUMO

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.).


Assuntos
Diabetes Mellitus Tipo 1/terapia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Pâncreas Artificial , Adolescente , Adulto , Idoso , Biônica , Glicemia/metabolismo , Criança , Estudos Cross-Over , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Humanos , Hipoglicemia/etiologia , Sistemas de Infusão de Insulina , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Pâncreas Artificial/efeitos adversos , Resultado do Tratamento , Adulto Jovem
9.
mSystems ; 9(3): e0015524, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38376168

RESUMO

A grand challenge for the next century is in facing a changing climate through bioengineering solutions. Biological nitrogen fixation, the globally consequential, nitrogenase-catalyzed reduction of atmospheric nitrogen to bioavailable ammonia, is a vital area of focus. Nitrogen fixation engineering relies upon extensive understanding of underlying genetics in microbial models, including the broadly utilized gammaproteobacterium, Azotobacter vinelandii (A. vinelandii). Here, we report the first CRISPR interference (CRISPRi) system for targeted gene silencing in A. vinelandii that integrates genomically via site-specific transposon insertion. We demonstrate that CRISPRi can repress transcription of an essential nitrogen fixation gene by ~60%. Further, we show that nitrogenase genes are suitably expressed from the transposon insertion site, indicating that CRISPRi and engineered nitrogen fixation genes can be co-integrated for combinatorial studies of gene expression and engineering. Our established CRISPRi system fills an important gap for engineering microbial nitrogen fixation for desired purposes.IMPORTANCEAll life on Earth requires nitrogen to survive. About 78% of the atmosphere alone is nitrogen, yet humans cannot use it directly. Instead, we obtain the nitrogen we need for our survival through the food we eat. For more than 100 years, a substantial portion of agricultural productivity has relied on industrial methods for nitrogen fertilizer synthesis, which consumes significant amounts of nonrenewable energy resources and exacerbates environmental degradation and human-induced climate change. Promising alternatives to these industrial methods rely on engineering the only biological pathway for generating bioaccessible nitrogen: microbial nitrogen fixation. Bioengineering strategies require an extensive understanding of underlying genetics in nitrogen-fixing microbes, but genetic tools for this critical goal remain lacking. The CRISPRi gene silencing system that we report, developed in the broadly utilized nitrogen-fixing bacterial model, Azotobacter vinelandii, is an important step toward elucidating the complexity of nitrogen fixation genetics and enabling their manipulation.


Assuntos
Azotobacter vinelandii , Fixação de Nitrogênio , Humanos , Fixação de Nitrogênio/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Nitrogenase/genética , Nitrogênio/metabolismo , Sequência de Bases , Azotobacter vinelandii/genética
10.
Diabetes Care ; 47(1): 101-108, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37874987

RESUMO

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.


Assuntos
Fibrose Cística , Diabetes Mellitus Tipo 1 , Hipoglicemia , Adulto , Humanos , Insulina/uso terapêutico , Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fibrose Cística/tratamento farmacológico , Biônica , Glicemia , Sistemas de Infusão de Insulina , Hipoglicemiantes/uso terapêutico , Hipoglicemia/tratamento farmacológico , Insulina Regular Humana/uso terapêutico , Pâncreas
11.
Clin Trials ; 10(1): 93-6, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23169873

RESUMO

BACKGROUND: Obtaining surrogate consent for clinical research studies conducted in the intensive care unit (ICU) setting is logistically challenging. PURPOSE: To determine whether differences in proportions consenting to trial enrollment existed among patients eligible to consent directly versus those requiring surrogate decision makers in a minimal-risk study to evaluate the accuracy of continuous glucose monitoring in the ICU setting. METHODS: Low initial enrollment rates prompted a detailed tracking of the screening and consent process. We analyzed the subset of eligible patients identified during a single year to document whether they were approached about trial enrollment, whether they consented or declined, the reasons for declining, and the method of consent (self or surrogate). The proportion of participants who consented and the reasons for declining were compared for self-consenting and surrogate-consenting participants. RESULTS: Of the 3041 patients screened, one-third (n = 982) were eligible; 119 of the 982 were approached regarding enrollment. Absence of a surrogate accounted for the majority of eligible patients (726; 84%) not approached. The most common reasons for refusal in the self versus surrogate groups included feeling overwhelmed (13% vs 24%), fear of discomfort (22% vs 12%), and fear of risk (7% vs 4%). Of the 57 eligible patients capable of consenting directly, 11 (19%) enrolled versus 12 (19%) of the 62 who required surrogate consent. When recruitment hours were expanded to include evening time, more eligible patients or their surrogates could be approached than during the day-shift hours alone. Consent was obtained for a larger proportion of potential participants with a history of diabetes (40%) than for those without a history of diabetes (14%). LIMITATIONS: The findings are from a subset of the entire study sample; data were available only for participants who could be approached, who may have differed from those who could not be approached. CONCLUSIONS: Surrogate and self-consent rates were similar. Surrogate unavailability was a major barrier to enrollment; overlap of staffing with usual visiting hours should be considered when planning trials in the ICU.


Assuntos
Pesquisa Biomédica/métodos , Diabetes Mellitus/tratamento farmacológico , Glucose/administração & dosagem , Unidades de Terapia Intensiva/estatística & dados numéricos , Tutores Legais , Consentimento do Representante Legal/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Massachusetts , Pessoa de Meia-Idade , Adulto Jovem
12.
bioRxiv ; 2023 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-37886545

RESUMO

Synonymous mutations are changes to DNA sequence that occur within translated genes but which do not affect the protein sequence. Although often referred to as silent mutations, evidence suggests that synonymous mutations can affect gene expression, mRNA stability, and even translation efficiency. A collection of both experimental and bioinformatic data has shown that synonymous mutations can impact cell phenotype, yet less is known about the molecular mechanisms and potential of beneficial or adaptive effects of such changes within evolved populations. Here, we report a beneficial synonymous mutation acquired via experimental evolution in an essential gene variant encoding the translation Elongation Factor protein EF-Tu. We demonstrate that this particular synonymous mutation increases EF-Tu mRNA and protein levels, as well as the polysome abundance on global transcripts. Although presence of the synonymous mutation is clearly causative of such changes, we also demonstrate that fitness benefits are highly contingent on other potentiating mutations present within the genetic background in which the mutation arose. Our results underscore the importance of beneficial synonymous mutations, especially those that affect levels of proteins that are key for cellular processes.

13.
Diabetes Technol Ther ; 25(11): 817-821, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37668666

RESUMO

Continuous glucose monitors (CGMs) have transformed the way people with type 1 diabetes can self-monitor glucose levels. Past studies have evaluated the accuracy of CGMs in clinic-based studies, but few have analyzed their accuracy in real-world settings. The Insulin-Only Bionic Pancreas Trial provided the opportunity to assess real-world accuracy of the blinded Dexcom G6 Pro sensor over the first 48-60 h of wear using a blood glucose meter (BGM) as a comparator for 1073 CGM-BGM pairs across 53 participants. The mean absolute relative difference (MARD) was 11.0% over a median period of 50 h (range 47-79 h). The MARD was 13.6% in the first 12 h, 10.5% in hours 12-24, and 10.1% after the first 24 h. These results are comparable with accuracy shown previously with laboratory-based measurements and provide real-world evidence of Dexcom G6 Pro accuracy, which improved after the first 12 h and then remained stable thereafter. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.


Assuntos
Diabetes Mellitus Tipo 1 , Insulina , Humanos , Insulina/uso terapêutico , Biônica , Diabetes Mellitus Tipo 1/tratamento farmacológico , Insulina Regular Humana , Glicemia , Automonitorização da Glicemia/métodos , Reprodutibilidade dos Testes , Pâncreas
14.
Diabetes Care ; 46(6): 1185-1190, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37000680

RESUMO

OBJECTIVE: We evaluated the performance of the iLet bionic pancreas (BP) in non-Hispanic White individuals (here referred to as "Whites") and in Black, Hispanic, and other individuals (here collectively referred to as "Minorities"). RESEARCH DESIGN AND METHODS: A multicenter, randomized controlled trial evaluated glycemic management with the BP versus standard of care (SC) in 161 adult and 165 pediatric participants with type 1 diabetes over 13 weeks. RESULTS: In Whites (n = 240), the mean baseline-adjusted difference in 13-week HbA1c between the BP and SC groups was -0.45% (95% CI -0.61 to -0.29 [-4.9 mmol/mol; -6.6 to -3.1]; P < 0.001), while this difference among Minorities (n = 84) was -0.53% (-0.83 to -0.24 [-6.0 mmol/mol; -9.2 to -2.8]; P < 0.001). In Whites, the mean baseline-adjusted difference in time in range between the BP and SC groups was 10% (95% CI 7-12; P < 0.001) and in Minorities was 14% (10-18; P < 0.001). CONCLUSIONS: The BP improves glycemic control in both Whites and Minorities and offers promise in decreasing health care disparities.


Assuntos
Órgãos Artificiais , Diabetes Mellitus Tipo 1 , Insulina , Adulto , Criança , Humanos , Biônica , Glicemia , Controle Glicêmico , Pâncreas , População Branca , Grupos Minoritários
15.
Diabetes Technol Ther ; 25(6): 437-441, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36877259

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1 , Pâncreas Artificial , Humanos , Insulina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Biônica , Glicemia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Insulina Regular Humana/uso terapêutico , Pâncreas , Glucose , Sistemas de Infusão de Insulina
16.
Diabetes Technol Ther ; 25(10): 705-717, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37523175

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1 , Insulina , Criança , Adulto , Humanos , Adolescente , Insulina/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/psicologia , Biônica , Cuidadores , Insulina Regular Humana , Pâncreas , Hipoglicemiantes
17.
J Virol ; 85(12): 5975-85, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21450813

RESUMO

Gene transfer into quiescent T and B cells is of importance for gene therapy and immunotherapy approaches to correct hematopoietic disorders. Previously, we generated lentiviral vectors (LVs) pseudotyped with the Edmonston measles virus (MV) hemagglutinin and fusion glycoproteins (Hgps and Fgps) (H/F-LVs), which, for the first time, allowed efficient transduction of quiescent human B and T cells. These target cells express both MV entry receptors used by the vaccinal Edmonston strain, CD46 and signaling lymphocyte activation molecule (SLAM). Interestingly, LVs pseudotyped with an MV Hgp, blind for the CD46 binding site, were completely inefficient for resting-lymphocyte transduction. Similarly, SLAM-blind H mutants that recognize only CD46 as the entry receptor did not allow stable LV transduction of resting T cells. The CD46-tropic LVs accomplished vector-cell binding, fusion, entry, and reverse transcription at levels similar to those achieved by the H/F-LVs, but efficient proviral integration did not occur. Our results indicate that both CD46 and SLAM binding sites need to be present in cis in the Hgp to allow successful stable transduction of quiescent lymphocytes. Moreover, the entry mechanism utilized appears to be crucial: efficient transduction was observed only when CD46 and SLAM were correctly engaged and an entry mechanism that strongly resembles macropinocytosis was triggered. Taken together, our results suggest that although vector entry can occur through the CD46 receptor, SLAM binding and subsequent signaling are also required for efficient LV transduction of quiescent lymphocytes to occur.


Assuntos
Antígenos CD/metabolismo , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Glicoproteínas/genética , Lentivirus/genética , Ativação Linfocitária , Vírus do Sarampo/genética , Proteína Cofatora de Membrana/metabolismo , Receptores de Superfície Celular/metabolismo , Adulto , Antígenos CD/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/virologia , Humanos , Lentivirus/metabolismo , Vírus do Sarampo/química , Proteína Cofatora de Membrana/genética , Pinocitose , Receptores de Superfície Celular/genética , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Transdução Genética , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
18.
Diabetes Technol Ther ; 24(10): 681-696, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36173235

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1 , Hipoglicemia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biônica , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Insulina Aspart/uso terapêutico , Insulina Lispro , Pessoa de Meia-Idade , Pâncreas , Adulto Jovem
19.
Diabetes Technol Ther ; 24(10): 726-736, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36173238

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1 , Insulina , Adolescente , Adulto , Idoso , Biônica , Glicemia , Automonitorização da Glicemia/métodos , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucose , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Sistemas de Infusão de Insulina , Insulina Regular Humana/uso terapêutico , Pessoa de Meia-Idade , Pâncreas , Adulto Jovem
20.
Diabetes Technol Ther ; 24(10): 697-711, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36173236

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1 , Hipoglicemia , Adolescente , Adulto , Idoso , Biônica , Glicemia/análise , Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Insulina Aspart , Insulina Lispro , Insulina Regular Humana , Pessoa de Meia-Idade , Pâncreas , Adulto Jovem
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