Publications by authors named "Timothy W Jones"

146 Publications

Glycaemic outcomes in Australasian children and adults with Type 1 Diabetes: failure to meet targets across the age spectrum.

Intern Med J 2021 Jun 18. Epub 2021 Jun 18.

Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Australia.

Background: The goal of therapy in Type 1 diabetes (T1D) is to achieve optimal glycaemic targets and reduce complications. Robust data representing glycaemic outcomes across the lifespan are lacking in Australasia.

Aims: To examine contemporary glycaemic outcomes and rate of use of diabetes technologies in Australasian people with T1D.

Methods: Cross-sectional analysis of de-identified data from 18 diabetes centres maintained in the Australasian Diabetes Data Network (ADDN) registry during 2019. Glycaemia was measured using glycated haemoglobin (HbA1c). The proportion of people with T1D achieving the international HbA1c target of <53 mmol/mol (7%) was calculated. Rates of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) use were determined.

Results: 7988 individuals with T1D with 30 575 visits were recorded in the registry. The median (IQR) age was 15.3 (10.0) years and diabetes duration was 5.7 (9.4) years with 49% on multiple daily injections (MDI) and 36% on CSII. The mean HbA1c for the whole cohort was 66 mmol/mol (8.2%). HbA1c increased with age; from 60 mmol/mol (7.6%) in children <10 years, increasing during adolescence and peaking at 73 mmol/mol (8.8%) in the 20-25 years age group. HbA1c target of <53 mmol/mol (7%) was met in 18% of children and 13% of adults. HbA1c was lower on CSII as compared to those on MDI (p < 0.0001).

Conclusions: Only a minority of children and adults achieve the recommended glycaemic goals despite access to specialist care in major diabetes centres. There is a need to identify factors which improve glycaemic outcomes. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15426DOI Listing
June 2021

Sleep in Aneurysmal Subarachnoid Hemorrhage Patients During Critical and Acute Care.

Dimens Crit Care Nurs 2021 Mar-Apr 01;40(2):118-124

Background: Nurses caring for intensive care patients diagnosed with an aneurysmal subarachnoid hemorrhage (aSAH) conduct frequent neurological assessments and vital signs over an extended period during which patients are at risk of vasospasm. The frequency of assessments can negatively impact sleep, resulting in altered thought processes and mood, including delirium. There are 2 types of sleep during the night: non-rapid eye movement (non-REM) sleep and REM sleep (also called stage R). Non-REM sleep is subdivided into 3 stages: stage N1, stage N2, and stage N3. These 4 stages of sleep are referred to as sleep architecture.

Objective: The aim of this study was to explore patterns of sleep in patients with aSAH over time during hospitalization.

Methods: Sleep data of stages and cycles were collected with use of a Fitbit activity tracker in this pilot, exploratory research study. Demographic data included age and gender. Six English-speaking patients, diagnosed with an aneurysmal SAH, confirmed by diagnostic angiogram, were followed in neuro-intensive care unit (ICU), neuro-step-down, neuroscience unit, and inpatient rehabilitation.

Results: There were a total of 226 sleep events. A sleep event encompassed a recorded start and end time on a single date. Each event included several sleep cycles. Each sleep cycle consisted of wakefulness, light sleep, deep sleep, and REM sleep. In 79 sleep events, light and deep sleep did add up to more than 4 hours; only 38 sleep events indicated more than 90 minutes of REM/night; 61 events showed the cycle of light-deep-light-REM cycles; 80 events showed 3 to 5 REM periods/night; and only 46 events demonstrated that the early-morning REM cycle was the longest. The average number of REM cycles increased from ICU (n = 4.6) to rehabilitation (n = 6.5). The percentage of days with sleep cycles also increased from ICU to rehabilitation (42 to 64).

Discussion: "Normal" sleep patterns are disrupted in aSAH patients throughout their hospitalization. Data in this study revealed that the patients do sleep; however, it is rarely organized. Patients were not always able to progress through the expected sleep cycle of light to deep to light to REM. Hospitalized aSAH patients do engage in REM sleep, but its pattern is abnormal. Staff should strategize on minimizing interruptions, clustering care, and minimizing sounds. Nurses should advocate for the frequency of assessments and vital signs based on hospital/unit policy and individual patient needs.
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http://dx.doi.org/10.1097/DCC.0000000000000467DOI Listing
May 2021

Additional Insulin is Required in Both the Early and Late Postprandial Periods for Meals High in Protein and Fat: A Randomised Trial.

J Clin Endocrinol Metab 2021 May 6. Epub 2021 May 6.

Perth Children's Hospital, Nedlands, WA, 6009, Australia.

Context: The pattern and quantity of insulin required for high protein high fat (HPHF) meals is not well understood.

Objective: This study aimed to determine the amount and delivery pattern of insulin required to maintain euglycaemia for five hours after consuming a HPHF meal compared to a low protein low fat (LPLF) meal.

Design: Randomised cross-over clinical trial.

Setting: Two Australian paediatric diabetes centres.

Participants: 12 - 21 year olds (n=10) with type 1 diabetes ≥1 year.

Intervention(s): Participants were randomised to HPHF meal (60g protein, 40g fat) or LPLF meal (5g protein, 5g fat) with identical carbohydrate content (30g). A modified insulin clamp technique was used to determine insulin requirements to maintain postprandial euglycaemia for five hours.

Main Outcome Measured: Total mean insulin requirements over five hours.

Results: The total mean insulin requirements for the HPHF meal were significantly greater than for the LPLF meal [11.0 (CI 9.2,12.8) units vs 5.7 (CI 3.8,7.5) units; p=0.001]. Extra intravenous insulin was required for the HPHF meal; 0-2 hours (extra 1.2 (CI 0.6, 1.6) units/hr), 2-4 hours (extra 1.1 (CI 0.6,1.6) units/hr) and 4-5 hours (extra 0.6 (CI 0.1,1.1) units/hr) after the meal. There were marked inter-individual differences in the quantity of additional insulin (0.3 to 5 times more for HPHF) and the pattern of insulin delivery (0-85% of additional insulin required in the first two hours).

Conclusions: The addition of protein and fat to a standardised carbohydrate meal almost doubled the mean insulin requirement, with most participants requiring half of the additional insulin in the first two hours.
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http://dx.doi.org/10.1210/clinem/dgab318DOI Listing
May 2021

Overview and Update on Methods for Cargo Loading into Extracellular Vesicles.

Processes (Basel) 2021 Feb 15;9(2). Epub 2021 Feb 15.

Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.

The enormous library of pharmaceutical compounds presents endless research avenues. However, several factors limit the therapeutic potential of these drugs, such as drug resistance, stability, off-target toxicity, and inadequate delivery to the site of action. Extracellular vesicles (EVs) are lipid bilayer-delimited particles and are naturally released from cells. Growing evidence shows that EVs have great potential to serve as effective drug carriers. Since EVs can not only transfer biological information, but also effectively deliver hydrophobic drugs into cells, the application of EVs as a novel drug delivery system has attracted considerable scientific interest. Recently, EVs loaded with siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, or therapeutic drugs show improved delivery efficiency and drug effect. In this review, we summarize the methods used for the cargo loading into EVs, including siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, and therapeutic drugs. Furthermore, we also include the recent advance in engineered EVs for drug delivery. Finally, both advantages and challenges of EVs as a new drug delivery system are discussed. Here, we encourage researchers to further develop convenient and reliable loading methods for the potential clinical applications of EVs as drug carriers in the future.
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http://dx.doi.org/10.3390/pr9020356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096148PMC
February 2021

Acute hyperglycaemia does not have a consistent adverse effect on exercise performance in recreationally active young people with type 1 diabetes: a randomised crossover in-clinic study.

Diabetologia 2021 May 4. Epub 2021 May 4.

Department of Endocrinology and Diabetes, Perth Children's Hospital, Nedlands, Western Australia, Australia.

Aims/hypothesis: In individuals with type 1 diabetes, chronic hyperglycaemia impairs aerobic fitness. However, the effect of acute marked hyperglycaemia on aerobic fitness is unclear, and the impact of insulin level has not been examined. In this study, we explored if acute hyperglycaemia with higher or low insulin levels affects [Formula: see text] and other exercise performance indicators in individuals with type 1 diabetes.

Methods: Eligible participants were aged 14 to 30 years, with complication-free, type 1 diabetes and HbA ≤ 75 mmol/mol (≤9%). Participants exercised in a clinical laboratory under three clamp (constant insulin, variable glucose infusion) conditions: euglycaemia (5 mmol/l) with 20 mU [m BSA] min insulin (where BSA is body surface area) (Eu20); hyperglycaemia (17 mmol/l) with 20 mU [m BSA] min insulin (Hyper20); and hyperglycaemia (17 mmol/l) with 5 mU [m BSA] min insulin (Hyper5) on separate days. Participants and the single testing assessor were blinded to condition, with participants allocated to randomised testing condition sequences as they were consecutively recruited. Standardised testing (in order) conducted on each of the three study days included: triplicate 6 second sprint cycling, grip strength, single leg static balance, vertical jump and modified Star Excursion Balance Test, ten simple and choice reaction times and one cycle ergometer [Formula: see text] test. The difference between conditions in the aforementioned testing measures was analysed, with the primary outcome being the difference in [Formula: see text].

Results: Twelve recreationally active individuals with type 1 diabetes (8 male, mean ± SD 17.9 ± 3.9 years, HbA 61 ± 11 mmol/mol [7.7 ± 1.0%], 7 ± 3 h exercise/week) were analysed. Compared with Eu20, [Formula: see text] was lower in Hyper20 (difference 0.17 l/min [95% CI 0.31, 0.04; p = 0.02] 6.6% of mean Eu20 level), but Hyper5 was not different (p = 0.39). Compared with Eu20, sprint cycling peak power was not different in Hyper20 (p = 0.20), but was higher in Hyper5 (64 W [95% CI 13, 115; p = 0.02] 13.1%). Hyper20 reaction times were not different (simple: p = 0.12) but Hyper5 reaction times were slower (simple: 11 milliseconds [95% CI 1, 22; p = 0.04] 4.7%) than Eu20. No differences between Eu20 and either hyperglycaemic condition were observed for the other testing measures (p > 0.05).

Conclusions/interpretation: Acute marked hyperglycaemia in the higher but not low insulin state impaired [Formula: see text] but to a small extent. Acute hyperglycaemia had an insulin-dependent effect on sprint cycling absolute power output and reaction time but with differing directionality (positive for sprint cycling and negative for reaction time) and no effect on the other indicators of exercise performance examined. We find that acute hyperglycaemia is not consistently adverse and does not impair overall exercise performance to an extent clinically relevant for recreationally active individuals with type 1 diabetes.

Funding: This research was funded by Diabetes Research Western Australia and Australasian Paediatric Endocrine Group grants.
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http://dx.doi.org/10.1007/s00125-021-05465-9DOI Listing
May 2021

Does Norepinephrine Exhibit a Time-Dose Relationship in Septic Shock?

Crit Care Med 2021 Mar;49(3):e345-e346

Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Augusta, GA.

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http://dx.doi.org/10.1097/CCM.0000000000004782DOI Listing
March 2021

Impact of hybrid closed loop therapy on hypoglycemia awareness in individuals with type 1 diabetes and impaired hypoglycemia awareness.

Diabetes Technol Ther 2021 Feb 8. Epub 2021 Feb 8.

Telethon Kids Institute, 117610, Children's Diabetes Centre, Nedlands, Western Australia, Australia.

Objective: This study evaluated the efficacy of using a hybrid closed loop (HCL) system in restoring hypoglycemia awareness in individuals with impaired awareness of hypoglycemia (IAH).

Research Design And Methods: Participants with IAH (Gold Score ≥4) were recruited into a randomized crossover pilot study. They participated in two 8-week periods using a HCL system (Medtronic 670GTM) (intervention) and standard insulin pump therapy (control). Hyperinsulinemic hypoglycemic clamp studies were undertaken at baseline and at the end of each study period for the evaluation of the counter-regulatory hormonal and symptomatic responses to hypoglycemia.

Results: Seventeen participants (mean age (SD) 35.8y (11.2y)) were included in the study. Peak epinephrine levels (median, IQR) in response to hypoglycemia were similar post intervention and control periods; 234.7 pmol/L (109.2; 938.9) vs 188.3 pmol/L (133.7; 402.9), p=0.233. However, both peak adrenergic and neuroglycopenic symptom scores were higher after intervention; 5.0 (4.5; 9.0) vs 4.0 (4.0; 5.5), p=0.009, and 8.5 (6.0; 15.0) vs 6.5 (6.0; 7.0) p=0.014, respectively. Self-reported hypoglycemia awareness improved: median (IQR) Gold score was 4.0 (3.0; 5.5) vs 5.5 (4.5; 6.0); intervention vs control, p=0.033. Time spent <3.9mmol/L and <3.0mmol/L was lower in the intervention group compared to control, p=0.002. Other patient reported outcomes (hypoglycemia fear and diabetes treatment satisfaction) did not change.

Conclusions: A short-term use of a HCL system failed to demonstrate an improvement in counter-regulatory hormonal responses. However, higher hypoglycemia symptom scores during controlled hypoglycemia, better self-reported hypoglycemia awareness and less time spent in hypoglycemia suggest the potential benefits of a HCL system in people with IAH.
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http://dx.doi.org/10.1089/dia.2020.0593DOI Listing
February 2021

High-Dose Daptomycin and Clinical Applications.

Ann Pharmacother 2021 Feb 4:1060028021991943. Epub 2021 Feb 4.

University of Kentucky Medical Center, Lexington, KY, USA.

Objective: To evaluate evidence for high-dose daptomycin (doses ≥ 8 mg/kg/d).

Data Sources: A PubMed/MEDLINE literature search was performed (January 2000 to December 2020) using the search terms , and . Review article references and society guidelines were reviewed.

Study Selection And Data Extraction: Clinical trials, observational studies, retrospective studies, meta-analyses, and systematic reviews reporting on high-dose daptomycin were included.

Data Synthesis: Experimentally, daptomycin outperforms other antimicrobials for high inoculum and biofilm-associated infections. Clinically, high-dose daptomycin is supported as salvage and first-line therapy for endocarditis and bacteremia, primarily when caused by methicillin-resistant (when vancomycin minimum inhibitory concentration is >1 mg/L) and . High-dose daptomycin appears effective for osteomyelitis and central nervous system infections, although comparative studies are lacking. High dosing in renal replacement therapy requires considering clearance modality to achieve exposures like normal renal function. Weight-based dosing in obesity draws concern for elevated exposures, although high doses have not been evaluated kinetically in obesity. Some data show benefits of high doses in overweight populations. Burn patients clear daptomycin more rapidly, and high doses may only achieve drug exposures similar to standard doses (6 mg/kg).

Relevance To Patient Care And Clinical Practice: This review analyzes the efficacy and safety of high-dose daptomycin in serious gram-positive infections. Discussion of specific infectious etiologies and patient populations should encourage clinicians to evaluate their daptomycin dosing standards.

Conclusions: The efficacy of high-dose daptomycin and limited safety concerns encourage clinicians to consider high-dose daptomycin more liberally in severe gram-positive infections.
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http://dx.doi.org/10.1177/1060028021991943DOI Listing
February 2021

Tunable transition metal complexes as hole transport materials for stable perovskite solar cells.

Chem Commun (Camb) 2021 Feb;57(16):2093-2096

CSIRO Energy Centre, Mayfield West, NSW 2304, Australia.

Transition metal complexes offer cost-effective alternatives as hole-transport materials (HTMs) in perovskite solar cells. However, the devices suffer from low performance. We boost the power conversion efficiency of devices with transition metal complex HTMs from 2% to above 10% through energy level tuning. We further demonstrate the excellent photostability of the device based on the additive-free HTM.
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http://dx.doi.org/10.1039/d1cc00060hDOI Listing
February 2021

The authors reply.

Crit Care Med 2021 Feb;49(2):e205-e206

All authors: Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy Athens, Athens, GA.

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http://dx.doi.org/10.1097/CCM.0000000000004756DOI Listing
February 2021

Less Nocturnal Hypoglycemia but Equivalent Time in Range Among Adults with Type 1 Diabetes Using Insulin Pumps Versus Multiple Daily Injections.

Diabetes Technol Ther 2021 Jun 27;23(6):460-466. Epub 2021 Jan 27.

Department of Medicine, University of Melbourne, Melbourne, Australia.

This prerandomization analysis from the Australian HCL-Adult trial (registration number: ACTRN12617000520336) compared masked continuous glucose monitoring (CGM) metrics among adults using insulin pumps versus multiple daily injections (MDIs), who were all self-monitoring blood glucose (SMBG). Adults with type 1 diabetes, using an insulin pump or MDIs without real-time CGM (and entering a trial of closed-loop technology), were eligible. MDI users were given an insulin dosage calculator. All participants received diabetes and carbohydrate-counting education, then wore masked CGM sensors for 3 weeks. Ethics Approval: HREC-D 088/16 Adults using MDIs ( = 61) versus pump ( = 59) did not differ by age, sex, diabetes duration, insulin total daily dose, or HbA at baseline. After education, median (interquartile range) CGM time in range (TIR) 70-180 mg/dL (3.9-10.0 mmol/L) was 54% (47, 62) for those using MDIs and 56% (48, 66) for those using pump ( = 0.40). All CGM metrics were equivalent for 24 h/day for MDI and pump users. Overnight, those using MDIs (vs. pump) spent more time with glucose <54 mg/dL (<3.0 mmol/L): 1.4% (0.1, 5.1) versus 0.5% (0.0, 2.0), respectively ( = 0.012). They also had more CGM hypoglycemia episodes (121 vs. 54, respectively; incidence rate ratio [95% confidence interval] 2.48 [1.51, 4.06];  < 0.001). Adults with type 1 diabetes using pumps versus MDIs in conjunction with SMBG experienced less nocturnal hypoglycemia, measured by masked CGM, after equivalent diabetes and dietary education in conjunction with insulin dosage calculator provision to all. However, both groups had equivalent TIR. This observation may reflect advantages afforded by flexibility in basal insulin delivery provided by pumps.
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http://dx.doi.org/10.1089/dia.2020.0589DOI Listing
June 2021

Determinants of Cardiovascular Risk in 7000 Youth With Type 1 Diabetes in the Australasian Diabetes Data Network.

J Clin Endocrinol Metab 2021 Jan;106(1):133-142

School of Public Health and Preventive Medicine, Monash University, Clayton, VIC, Australia.

Context: Cardiovascular disease occurs prematurely in type 1 diabetes. The additional risk of overweight is not well characterized.

Objective: The primary aim was to measure the impact of body mass index (BMI) in youth with type 1 diabetes on cardiovascular risk factors. The secondary aim was to identify other determinants of cardiovascular risk.

Design: Observational longitudinal study of 7061 youth with type 1 diabetes followed for median 7.3 (interquartile range [IQR] 4-11) years over 41 (IQR 29-56) visits until March 2019.

Setting: 15 tertiary care diabetes centers in the Australasian Diabetes Data Network.Participants were aged 2 to 25 years at baseline, with at least 2 measurements of BMI and blood pressure.

Main Outcome Measure: Standardized systolic and diastolic blood pressure scores and non-high-density lipoprotein (HDL) cholesterol were co-primary outcomes. Urinary albumin/creatinine ratio was the secondary outcome.

Results: BMI z-score related independently to standardized blood pressure z- scores and non-HDL cholesterol. An increase in 1 BMI z-score related to an average increase in systolic/diastolic blood pressure of 3.8/1.4 mmHg and an increase in non-HDL cholesterol (coefficient + 0.16 mmol/L, 95% confidence interval [CI], 0.13-0.18; P < 0.001) and in low-density lipoprotein (LDL) cholesterol. Females had higher blood pressure z-scores, higher non-HDL and LDL cholesterol, and higher urinary albumin/creatinine than males. Indigenous youth had markedly higher urinary albumin/creatinine (coefficient + 2.15 mg/mmol, 95% CI, 1.27-3.03; P < 0.001) and higher non-HDL cholesterol than non-Indigenous youth. Continuous subcutaneous insulin infusion was associated independently with lower non-HDL cholesterol and lower urinary albumin/creatinine.

Conclusions: BMI had a modest independent effect on cardiovascular risk. Females and Indigenous Australians in particular had a more adverse risk profile.
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http://dx.doi.org/10.1210/clinem/dgaa727DOI Listing
January 2021

Vascular Effects of ACE (Angiotensin-Converting Enzyme) Inhibitors and Statins in Adolescents With Type 1 Diabetes.

Hypertension 2020 12 26;76(6):1734-1743. Epub 2020 Oct 26.

From the Institute of Cardiovascular Science, University College London, United Kingdom (S.T.C., J.E.D.).

An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI]: 6.6% [6.0-7.2] versus 5.3% [4.7-5.9]; =0.005), whereas no effect was observed following statin use (6.2% [5.5-6.8] versus 5.8% [5.1-6.4]; =0.358). In the observational study, patients classed as high-risk based on albumin-creatinine ratio showed evidence of endothelial dysfunction at the end of follow-up (flow-mediated dilation=4.8% [3.8-5.9] versus 6.3% [5.8-6.7] for high-risk versus low-risk groups; =0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment (>0.05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03-0.12]; =0.001 and 0.5 m/s [0.4-0.6]; <0.001 for reactive hyperemia index and pulse wave velocity, respectively). ACE inhibitors improve endothelial function in high-risk adolescents as they transition through puberty. The longer-term protective effects of this intervention at this early age remain to be determined. Registration- URL: https://www.clinicaltrials.gov; Unique identifier NCT01581476.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15721DOI Listing
December 2020

Effect of Exercise Intensity on Exogenous Glucose Requirements to Maintain Stable Glycemia At High Insulin Levels in Type 1 Diabetes.

J Clin Endocrinol Metab 2021 Jan;106(1):e83-e93

Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia.

Context: Under basal insulin levels, there is an inverted U relationship between exercise intensity and exogenous glucose requirements to maintain stable blood glucose levels in type 1 diabetes (T1D), with no glucose required for intense exercise (80% V̇O2 peak), implying that high-intensity exercise is not conducive to hypoglycemia.

Objective: This work aimed to test the hypothesis that a similar inverted U relationship exists under hyperinsulinemic conditions, with high-intensity aerobic exercise not being conducive to hypoglycemia.

Methods: Nine young adults with T1D (mean ± SD age, 22.6 ± 4.7 years; glycated hemoglobin, 61 ± 14 mmol/mol; body mass index, 24.0 ± 3.3 kg/m2, V̇O2 peak, 36.6 ± 8.0 mL·kg-1 min-1) underwent a hyperinsulinemic-euglycemic clamp to maintain stable glycemia (5-6 mmol·L-1), and exercised for 40 minutes at 4 intensities (35%, 50%, 65%, and 80% V̇O2peak) on separate days following a randomized counterbalanced study design.

Main Outcome Measures: Glucose infusion rates (GIR) and glucoregulatory hormones levels were measured.

Results: The GIR (± SEM) to maintain euglycemia was 4.4 ± 0.4 mg·kg-1 min-1 prior to exercise, and increased significantly by 1.8 ± 0.4, 3.0 ± 0.4, 4.2 ± 0.7, and 3.5 ± 0.7 mg·kg-1 min-1 during exercise at 35%, 50%, 65%, and 80% V̇O2 peak, respectively, with no significant differences between the 2 highest exercise intensities (P > .05), despite differences in catecholamine levels (P < .05). During the 2-hour period after exercise at 65% and 80% V̇O2 peak, GIRs did not differ from those during exercise (P > .05).

Conclusions: Under hyperinsulinemic conditions, the exogenous glucose requirements to maintain stable glycemia during and after exercise increase with exercise intensity then plateau with exercise performed at above moderate intensity ( > 65% V̇O2 peak). High-intensity exercise confers no protection against hypoglycemia.
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http://dx.doi.org/10.1210/clinem/dgaa768DOI Listing
January 2021

Six Months of Hybrid Closed-Loop Versus Manual Insulin Delivery With Fingerprick Blood Glucose Monitoring in Adults With Type 1 Diabetes: A Randomized, Controlled Trial.

Diabetes Care 2020 12 14;43(12):3024-3033. Epub 2020 Oct 14.

Department of Endocrinology and Diabetes, Perth Children's Hospital, Nedlands, Western Australia, Australia.

Objective: To investigate glycemic and psychosocial outcomes with hybrid closed-loop (HCL) versus user-determined insulin dosing with multiple daily injections (MDI) or insulin pump (i.e., standard therapy for most adults with type 1 diabetes).

Research Design And Methods: Adults with type 1 diabetes using MDI or insulin pump without continuous glucose monitoring (CGM) were randomized to 26 weeks of HCL (Medtronic 670G) or continuation of current therapy. The primary outcome was masked CGM time in range (TIR; 70-180 mg/dL) during the final 3 weeks.

Results: Participants were randomized to HCL ( = 61) or control ( = 59). Baseline mean (SD) age was 44.2 (11.7) years, HbA was 7.4% (0.9%) (57 [10] mmol/mol), 53% were women, and 51% used MDI. HCL TIR increased from (baseline) 55% (13%) to (26 weeks) 70% (10%) with the control group unchanged: (baseline) 55% (12%) and (26 weeks) 55% (13%) (difference 15% [95% CI 11, 19]; < 0.0001). For HCL, HbA was lower (median [95% CI] difference -0.4% [-0.6, -0.2]; -4 mmol/mol [-7, -2]; < 0.0001) and diabetes-specific positive well-being was higher (difference 1.2 [95% CI 0.4, 1.9]; < 0.0048) without a deterioration in diabetes distress, perceived sleep quality, or cognition. Seventeen (9 device-related) versus 13 serious adverse events occurred in the HCL and control groups, respectively.

Conclusions: In adults with type 1 diabetes, 26 weeks of HCL improved TIR, HbA, and their sense of satisfaction from managing their diabetes compared with those continuing with user-determined insulin dosing and self-monitoring of blood glucose. For most people living with type 1 diabetes globally, this trial demonstrates that HCL is feasible, acceptable, and advantageous.
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http://dx.doi.org/10.2337/dc20-1447DOI Listing
December 2020

Electroencephalogram Reactivity to Hyperglycemia in Patients with Type 1 Diabetes.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:5224-5227

This paper is concerned with a study of hyperglycemia on four patients with type 1 diabetes at night time. We investigated the association between hyperglycemic episodes and electroencephalogram (EEG) signals using data from the central and occipital areas. The power spectral density of the brain waves was estimated to compare the difference between hyperglycemia and euglycemia using the hyperglycemic threshold of 8.3 mmol/L. The statistical results showed that alpha and beta bands were more sensitive to hyperglycemic episodes than delta and theta bands. During hyperglycemia, whereas the alpha power increased significantly in the occipital lobe (P<0.005), the power of the beta band increased significantly in all observed channels (P<0.01). Using the Pearson correlation, we assessed the relationship between EEG signals and glycemic episodes. The estimated EEG power levels of the alpha band and the beta band produced a significant correlation against blood glucose levels (P<0.005). These preliminary results show the potential of using EEG signals as a biomarker to detect hyperglycemia.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175485DOI Listing
July 2020

Copeptin Kinetics and Its Relationship to Osmolality During Rehydration for Diabetic Ketoacidosis in Children.

J Clin Endocrinol Metab 2020 11;105(11)

Pediatric Endocrinology and Diabetology, University Children's Hospital Basel UKBB, University of Basel, Basel, Switzerland.

Context: Copeptin is a surrogate marker for arginine vasopressin (AVP) release in response to hyperosmolal stimuli such as diabetic ketoacidosis (DKA).

Objective: The objective of this work is to characterize kinetics of copeptin and osmolality, and their dynamic relationship during rehydration and insulin therapy in children with type 1 diabetes (T1D) and DKA.

Design And Setting: A prospective, observational, multicenter study was conducted.

Patients And Intervention: Children with T1D admitted for DKA underwent serial serum copeptin and osmolality measurements from start of rehydration at 14 time points during 72 hours.

Main Outcome Measures: Measurements included temporal course of copeptin and osmolality (kinetics), relationship between both (dynamics), and association between-subject variability (BSV) (coefficient of variation, CV%).

Results: Twenty-eight children (20 newly diagnosed T1D) aged 1 to 16 years were included. Copeptin decreased from 95 pmol/L (95% CI, 55-136 pmol/L) (CV%, 158%) to 9.7 pmol/L (95% CI, 8.1-11.4 pmol/L) (CV%, 31%) with a 50% recovery time (t1/2) of 7.1 hours (range, 5.1-11.5 hours) (114%). Serum osmolality decreased from 321 mOsm/kg (range, 315-327 mOsm/kg) (4%) to 294 mOsm/kg (range, 292-296 mOsm/kg) (1%) with a t1/2 of 4.3 hours (range, 3.0-5.6 hours) (64%). Copeptin levels doubled with each osmolality increase by 15 mOsm/kg (range, 10-21 mOsm/kg) (59%), from 9.8 pmol/L (range, 7.3-12.3 pmol/L) (48%) to 280 mOsm/kg. Copeptin kinetics differed between newly diagnosed and known T1D patients (P = .001), and less between mild vs moderate-severe DKA (P = .04).

Conclusions: First, this study characterized for the first time copeptin kinetics and dynamics in the high hyperosmolar range in children with DKA. Second, it revealed significant differences in copeptin kinetics between newly diagnosed and known T1D patients that may be explained by changes at the osmoreceptor and renal AVP receptor level due to longstanding osmotic diuresis and DKA.
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http://dx.doi.org/10.1210/clinem/dgaa568DOI Listing
November 2020

Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes.

Pediatr Diabetes 2020 11 17;21(7):1322-1332. Epub 2020 Aug 17.

Department of Paediatrics, University of Cambridge, Cambridge, UK.

Objectives: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D.

Methods: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes <-3 and > 3 mL/min/1.73m /year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource.

Results: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: -0.19 [-0.27, -0.12], P = 7.0 × 10 ; -0.18 [-0.26, -0.11], P = 5.1 × 10 ; -0.12 [-0.20, -0.05], P = 1.6 × 10 ), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (-0.21 [-0.28, -0.14], P = 2.3 × 10 ) and cystatin C (-0.16 [-0.22, -0.09], P = 1.6 × 10 ). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10 ), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10 ). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR.

Conclusions: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.
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http://dx.doi.org/10.1111/pedi.13095DOI Listing
November 2020

Sepsis With Preexisting Heart Failure: Management of Confounding Clinical Features.

J Intensive Care Med 2020 Jun 4:885066620928299. Epub 2020 Jun 4.

Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Augusta, GA, USA.

Preexisting heart failure (HF) in patients with sepsis is associated with worse clinical outcomes. Core sepsis management includes aggressive volume resuscitation followed by vasopressors (and potentially inotropes) if fluid is inadequate to restore perfusion; however, large fluid boluses and vasoactive agents are concerning amid the cardiac dysfunction of HF. This review summarizes evidence regarding the influence of HF on sepsis clinical outcomes, pathophysiologic concerns, resuscitation targets, hemodynamic interventions, and adjunct management (ie, antiarrhythmics, positive pressure ventilatory support, and renal replacement therapy) in patients with sepsis and preexisting HF. Patients with sepsis and preexisting HF receive less fluid during resuscitation; however, evidence suggests traditional fluid resuscitation targets do not increase the risk of adverse events in HF patients with sepsis and likely improve outcomes. Norepinephrine remains the most well-supported vasopressor for patients with sepsis with preexisting HF, while dopamine may induce more cardiac adverse events. Dobutamine should be used cautiously given its generally detrimental effects but may have an application when combined with norepinephrine in patients with low cardiac output. Management of chronic HF medications warrants careful consideration for continuation or discontinuation upon development of sepsis, and β-blockers may be appropriate to continue in the absence of acute hemodynamic decompensation. Optimal management of atrial fibrillation may include β-blockers after acute hemodynamic stabilization as they have also shown independent benefits in sepsis. Positive pressure ventilatory support and renal replacement must be carefully monitored for effects on cardiac function when HF is present.
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http://dx.doi.org/10.1177/0885066620928299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970342PMC
June 2020

Multicenter validation of a novel medication-regimen complexity scoring tool.

Am J Health Syst Pharm 2020 03;77(6):474-478

Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Augusta, GA.

Background: The MRC-ICU, a novel regimen complexity scoring tool, provides an objective measure of medication regimen complexity in critically ill patients. The MRC-ICU may have the ability to evaluate the impact of critical care pharmacists on patient outcomes but requires further validation. The objective of this study was to confirm the external validity of the MRC-ICU scoring tool at multiple institutions and intensive care unit (ICU) settings.

Methods: This was a multicenter, prospective, observational study. The electronic medical record was reviewed to collect patient demographics and patient outcomes, and the medication administration record was reviewed to collect MRC-ICU scores at 24 hours, 48 hours, and ICU discharge. Validation was performed by assessing convergent and divergent validity of the score. Spearman rank-order correlation was used to determine correlation.

Results: A total of 230 patients were evaluated across both centers in both medical ICUs and surgical ICUs. Differences between the original center and the new site included that total number of orders (29 vs 126; P < 0.001) and total number of medication orders (17 vs 36; P < 0.001) were higher at the new site, whereas the original site had higher overall MRC-ICU scores (14 vs 11; P = 0.004). The MRC-ICU showed appropriate convergent validity with number of orders and medication orders (all P < 0.001) and appropriate divergent validity with no significant correlation found between age, weight, or gender (all P > 0.05).

Conclusions: External validity of the MRC-ICU has been confirmed through evaluation at an external site and in the surgical ICU population. The MRC-ICU scoring tool requires prospective evaluation to provide objective data regarding optimal pharmacist use.
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http://dx.doi.org/10.1093/ajhp/zxz330DOI Listing
March 2020

Medication Adherence During Adjunct Therapy With Statins and ACE Inhibitors in Adolescents With Type 1 Diabetes.

Diabetes Care 2020 05 27;43(5):1070-1076. Epub 2020 Feb 27.

Department of Paediatrics, University of Cambridge, Cambridge, U.K.

Objective: Suboptimal adherence to insulin treatment is a main issue in adolescents with type 1 diabetes. However, to date, there are no available data on adherence to adjunct noninsulin medications in this population. Our aim was to assess adherence to ACE inhibitors and statins and explore potential determinants in adolescents with type 1 diabetes.

Research Design And Methods: There were 443 adolescents with type 1 diabetes recruited into the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and exposed to treatment with two oral drugs-an ACE inhibitor and a statin-as well as combinations of both or placebo for 2-4 years. Adherence was assessed every 3 months with the Medication Event Monitoring System (MEMS) and pill count.

Results: Median adherence during the trial was 80.2% (interquartile range 63.6-91.8) based on MEMS and 85.7% (72.4-92.9) for pill count. Adherence based on MEMS and pill count dropped from 92.9% and 96.3%, respectively, at the first visit to 76.3% and 79.0% at the end of the trial. The percentage of study participants with adherence ≥75% declined from 84% to 53%. A good correlation was found between adherence based on MEMS and pill count ( = 0.82, < 0.001). Factors associated with adherence were age, glycemic control, and country.

Conclusions: We report an overall good adherence to ACE inhibitors and statins during a clinical trial, although there was a clear decline in adherence over time. Older age and suboptimal glycemic control at baseline predicted lower adherence during the trial, and, predictably, reduced adherence was more prevalent in subjects who subsequently dropped out.
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http://dx.doi.org/10.2337/dc19-0884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282885PMC
May 2020

Getting to the Heart of the Matter: What We Know About Fluid Resuscitation in Septic Heart Failure Patients.

Crit Care Med 2020 03;48(3):e259-e260

Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy Athens, Athens, GA University of Georgia College of Pharmacy Athens, Athens, GA Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy Athens, Athens, GA.

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http://dx.doi.org/10.1097/CCM.0000000000004126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984412PMC
March 2020

Nocturnal Hypoglycemia Detection using EEG Spectral Moments under Natural Occurrence Conditions.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:7177-7180

This paper is concerned with a study of hypoglycemia under natural occurrence conditions at night time. Five adolescents with type 1 diabetes (T1D) participated in the experiments. Patients' blood glucose profiles were interpolated to estimate the intermediate values. The proposed system used spectral moments of electroencephalogram (EEG) signals from central and occipital areas as features for detecting hypoglycemia. We found that hypoglycemia could be detected non-invasively using EEG spectral moments. During hypoglycemic episodes, theta moments increased significantly (P<; 0.005) whereas beta moments decreased significantly (P<; 0.001). Based on the optimal network architecture associated with the highest log evidence, the proposed optimal Bayesian neural network resulted in a sensitivity of 82% and a specificity of 52%. In addition, the estimated blood glucose profiles showed a significant correlation (P<; 1e-6) with interpolated blood glucose values in the test set.
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http://dx.doi.org/10.1109/EMBC.2019.8856695DOI Listing
July 2019

Nocturnal Hypoglycemia Detection using Optimal Bayesian Algorithm in an EEG Spectral Moments Based System.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:5439-5442

This paper presents a hypoglycemia detection system using electroencephalogram (EEG) spectral moments from 8 patients with type 1 diabetes (T1D) at night time. Four channels (C3, C4, O1, and O2) associated with glycemic episodes were analyzed. Spectral moments were applied to EEG signal and its corresponding speed and acceleration. During hypoglycemia, theta moments increased significantly (P<; 0.001) and alpha moments decreased significantly (P<; 0.001). The system used an optimal Bayesian neural network for detecting hypoglycemic episodes. Based on the optimal network architecture with the highest log evidence, the final classification results for the test set were 79% and 51% in sensitivity and specificity, respectively. Essentially, the estimated blood glucose profiles correlated significantly to actual values in the test set (P<; 0.0001). Using error grid analysis, 93% of the estimated values were clinically acceptable.
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http://dx.doi.org/10.1109/EMBC.2019.8857594DOI Listing
July 2019

Interprofessional Shared Decision-Making: Who Is at the Table?

Crit Care Med 2020 02;48(2):e158-e159

Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Augusta, GA Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Augusta, GA, and Department of Pharmacy, Augusta University Medical Center, Augusta, GA Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Athens, GA Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Augusta, GA, and Department of Pharmacy, Augusta University Medical Center, Augusta, GA.

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http://dx.doi.org/10.1097/CCM.0000000000004029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984276PMC
February 2020

Effect of frequency of sensor use on glycaemic control in individuals on sensor-augmented pump therapy with and without Predictive Low Glucose Management System.

Diabetes Res Clin Pract 2020 Jan 19;159:107989. Epub 2019 Dec 19.

Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Australia; Department of Endocrinology and Diabetes, Women's and Children's Hospital, Adelaide, Australia; Department of Endocrinology and Diabetes, John Hunter Children's Hospital, Newcastle, Australia; Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, The University of Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, Royal Children's Hospital, Melbourne, Australia.

Improved frequency of sensor use improves glycaemic control. Furthermore, there is no deterioration of glycaemic control with increased sensor use in individuals on Predictive Low Glucose Management (PLGM) system. Younger children are more likely to have better sensor uptake than older children.
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http://dx.doi.org/10.1016/j.diabres.2019.107989DOI Listing
January 2020

Pharmacists Are Associated With Reduced Mortality in Critically Ill Patients: Now What?

Crit Care Med 2019 12;47(12):e1036-e1037

Clinical & Administrative Pharmacy, University of Georgia, Augusta, GA.

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http://dx.doi.org/10.1097/CCM.0000000000003934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975629PMC
December 2019

Longitudinal trajectories of BMI z-score: an international comparison of 11,513 Australian, American and German/Austrian/Luxembourgian youth with type 1 diabetes.

Pediatr Obes 2020 02 5;15(2):e12582. Epub 2019 Nov 5.

Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany.

Background: BMI fluctuations during puberty are common. Data on individual change in BMI from childhood to young adulthood are limited in youth with type 1 diabetes.

Objectives: To compare longitudinal trajectories of body mass index z score (BMIz) from childhood to adolescence across three registries spanning five countries.

Methods: Data sources: T1DX (USA), DPV (Germany/Austria/Luxembourg) and ADDN (Australia). The analysis included 11,513 youth with type 1 diabetes, duration >1 year, at least one BMI measure at baseline (age 8-10 years) and >5 aggregated BMI measures by year of age during follow-up until age 17 years. BMIz was calculated based on WHO charts. Latent class growth modelling was used to identify subgroups following a similar trajectory of BMIz over time.

Results: Five distinct trajectories of BMIz were present in the T1DX and ADDN cohorts, while six trajectories were identified in the DPV cohort. Boys followed more often a low/near-normal pattern while elevated BMIz curves were more likely in girls (ADDN; DPV). For T1DX cohort, no sex differences were observed. Comparing the reference group (BMIz ~0) with the other groups during puberty, higher BMIz was significantly associated with older age at T1D onset, racial/ethnic minority and elevated HbA1c (all p<0.05).

Conclusion: This multinational study presents unique BMIz trajectories in youth with T1D across three continents. The prevalence of overweight and the longitudinal persistence of overweight support the need for close monitoring of weight and nutrition in this population. The international and individual differences likely result from diverse genetic, environmental and therapeutic factors.
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http://dx.doi.org/10.1111/ijpo.12582DOI Listing
February 2020

Electroencephalogram Spectral Moments for the Detection of Nocturnal Hypoglycemia.

IEEE J Biomed Health Inform 2020 05 29;24(5):1237-1245. Epub 2019 Jul 29.

Hypoglycemia or low blood glucose is the most feared complication of insulin treatment of diabetes. For people with diabetes, the mismatch between the insulin therapy and the body's physiology could increase the risk of hypoglycemia. Nocturnal hypoglycemia is particularly dangerous for type-1 diabetes patients because its symptoms may obscure during sleep. The early onset detection of hypoglycemia at night time is necessary because it can result in unconsciousness and even death. This paper presents new electroencephalogram spectral features for nocturnal hypoglycemia detection. The system uses high-order spectral moments for feature extraction and Bayesian neural network for classification. From a clinical study of hypoglycemia of eight patients with type-1 diabetes at night, we find that these spectral moments of theta band and alpha band changed significantly. During hypoglycemia episodes, the theta moments increased significantly (P < 0.001) while the features of alpha band reduced significantly (P < 0.001). Using the optimal Bayesian neural network, the classification results were 85% and 52% in sensitivity and specificity, respectively. The significant correlation (P < 0.001) with real blood glucose profiles shows the effectiveness of the proposed features for the detection of nocturnal hypoglycemia.
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http://dx.doi.org/10.1109/JBHI.2019.2931782DOI Listing
May 2020