Hyperpolarized (HP) 3He magnetic resonance imaging (MRI) of the lungs is one example of a functional lung imaging method that provides reproducible regional detection of ventilation defects in ...asthma.1 These ventilation defects are associated with areas of airway obstruction and air trapping.2 The most common metric for measuring defect extent is the ventilation defect percent (VDP).2-4 Here, we measure VDP using HP 3He MRI and compare VDP to asthma outcomes indicative of severe exacerbation, analogous to similar studies comparing VDP and exacerbation history in chronic obstructive pulmonary disease.5,6 Our study population included healthy normal volunteers (N = 11 10.8%) and subjects with mild/moderate (N = 75 73.5%) or severe (N = 16 15.7%) asthma as defined by the Severe Asthma Research Program (SARP) criteria.7 Subjects with forced expiratory volume in 1 second (FEV1) percent predicted (PP) value of less than 60% were excluded for safety reasons. Receiver-operating characteristic (ROC) curves, ROC area under the curve (AUC) values, and Wilcoxon rank-sum test results assessing VDP and other biomarkers as indicators of history of severe outcomes among patients with asthma are shown in Fig E1 and Table E3 in this article's Online Repository at www.jacionline.org. Characteristic Normals Mild/Moderate Severe Significant difference N (row %) 11 (10.8%) 75 (73.5%) 16 (15.7%) NA Sex (column %) 7 F (63.6%) 46 F (61.3%) 11 F (68.8%) (None) Age (y) 22.7 ± 3.6 28.8 ± 11.3 35.8 ± 15.3 Severe vs normal (P = .02) FEV1 PP 99.0 (83.6-121.0) 92.0 (61.2-129.0) 88.1 (73.0-115.7) (None) FEV1/FVC PP 101.0 (82.7-111.0) 92.5 (62.2-113.8) 89.6 (73.0-105.0) M/M vs normal (P < .01)Severe vs normal (P = .01) Whole lung VDP (%) 0.2 (0.0-1.6) 0.9 (0-22.0) 2.8 (0-15.1) M/M vs normal (P = .01)Severe vs normal (P = .02) RV/TLC PP 117.3 (92.9-132.1) 109.4 (67.9-184.0) 105.7 (81.3-162.1) (None) ED visit, n (%)† 0 (0.0) 32 (47.1%) 13 (86.7%) Severe vs M/M (P < .01)∗ Hospitalization, n (%)† 0 (0.0) 12 (17.6%) 7 (46.7%) Severe vs M/M (P = .02)∗ Table E2 Correlation between VDP and pulmonary function tests M/M, Mild to moderate; P, Spearman P value; r, Spearman rank correlation coefficient. Asthma severity FEV1 PP FEV1/FVC PP RV/TLC PP N r P N r P N r P Normal 11 0.06 .86 11 −0.45 .17 8 −0.69 .07 M/M 75 −0.33 <.01 70 −0.49 <.001 67 0.17 .17 Severe 16 −0.22 .42 16 −0.52 .04 13 −0.06 .84 Total 102 −0.32 <.01 97 −0.54 <.001 88 0.08 .46 Table E3 Measures of inflammation and lung function as indicators of severe asthma outcomes Source Measurement ED Hospitalization ROC AUC P value ROC AUC P value Blood Eosinophil count 0.62 .07 0.66 .04 Neutrophil count 0.49 .91 0.49 .90 Monocyte count 0.53 .64 0.50 .97 Sputum Eosinophil differential 0.61 .09 0.62 .10 Neutrophil differential 0.56 .41 0.52 .80 Macrophage differential 0.53 .70 0.55 .50 Spirometry FEV1 PP 0.54 .59 0.62 .12 FEV1/FVC PP 0.64 .04 0.61 .16 Plethysmography RV/TLC PP 0.56 .39 0.49 .99 MRI VDP 0.69 <.01 0.78 <.001 1 D.J. Niles, S.J. Kruger, B.J. Dardzinski, A. Harman, N.N. Jarjour, M. Ruddy, Exercise-induced bronchoconstriction: reproducibility of hyperpolarized 3He MR imaging, Radiology, Vol. 266, 2013, 618-625 2 S.B. Fain, G. Gonzalez-Fernandez, E.T. Peterson, M.D. Evans, R.L. Sorkness, N.N. Jarjour, Evaluation of structure-function relationships in asthma using multidetector CT and hyperpolarized He-3 MRI, Acad Radiol, Vol. 15, 2008, 753-762 3 N. Woodhouse, J.M. Wild, M.N. Paley, S. Fichele, Z. Said, A.J. Swift, J Magn Reson Imaging, Vol. 21, 2005, 365-369 4 M. Kirby, S. Svenningsen, H. Ahmed, A. Wheatley, R. Etemad-Rezai, N.A. Paterson, Quantitative evaluation of hyperpolarized helium-3 magnetic resonance imaging of lung function variability in cystic fibrosis, Acad Radiol, Vol. 18, 2011, 1006-1013 5 M. Kirby, D. Pike, D.D. Sin, H.O. Coxson, D.G. McCormack, G. Parraga, Radiology, Vol. 277, 2015, 872-880 6 M. Kirby, D. Pike, H.O. Coxson, D.G. McCormack, G. Parraga, Hyperpolarized (3)He ventilation defects used to predict pulmonary exacerbations in mild to moderate chronic obstructive pulmonary disease, Radiology, Vol. 273, 2014, 887-896 7 W.C. Moore, E.R. Bleecker, D. Curran-Everett, S.C. Erzurum, B.T. Ameredes, L. Bacharier, Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s severe asthma research program, J Allergy Clin Immunol, Vol. 119, 2007, 405-413 8 J.H. Friedman, Greedy function approximation: a gradient boosting machine, Ann Stat, Vol. 29, 2001, 1189-1232
Polycyclic aromatic compounds (PACs) are ubiquitous across environmental media in Canada, including surface water, soil, sediment and snowpack. Information is presented according to pan-Canadian ...sources, and key geographical areas including the Great Lakes, the Alberta Oil Sands Region (AOSR) and the Canadian Arctic. Significant PAC releases result from exploitation of fossil fuels containing naturally-derived PACs, with anthropogenic sources related to production, upgrading and transport which also release alkylated PACs. Continued expansion of the oil and gas industry indicates contamination by PACs may increase. Monitoring networks should be expanded, and include petrogenic PACs in their analytical schema, particularly near fuel transportation routes. National-scale roll-ups of emission budgets may not expose important details for localized areas, and on local scales emissions can be substantial without significantly contributing to total Canadian emissions. Burning organic matter produces mainly parent or pyrogenic PACs, with forest fires and coal combustion to produce iron and steel being major sources of pyrogenic PACs in Canada. Another major source is the use of carbon electrodes at aluminum smelters in British Columbia and Quebec. Temporal trends in PAC levels across the Great Lakes basin have remained relatively consistent over the past four decades. Management actions to reduce PAC loadings have been countered by increased urbanization, vehicular emissions and areas of impervious surfaces. Major cities within the Great Lakes watershed act as diffuse sources of PACs, and result in coronas of contamination emanating from urban centres, highlighting the need for non-point source controls to reduce loadings.
•Urban centres within the Great Lakes watershed act as diffuse sources of PACs.•National roll-ups of emission budgets may not expose details for localized areas.•Expansion of the oil and gas industry indicates contamination by PACs may increase.•Coal combustion to produce aluminum and steel is a large source of pyrogenic PACs.•Oil recovery produces mainly alkylated PACs, while burning organic matter produces parent PACs.
Objective:
The objective was to explore psychosocial experiences of closed loop technology for adults, children, and adolescents with type 1 diabetes and their parents taking part in two multicenter, ...free-living, randomized crossover home studies.
Methods:
Participants using insulin pump therapy were randomized to either 12 weeks of automated closed-loop glucose control, then 12 weeks of sensor augmented insulin pump therapy (open loop), or vice versa. Closed loop was used for 24 hours by adults and overnight only by children and adolescents. Participants completed the Diabetes Technology Questionnaire (DTQ) periodically and shared their views in semistructured interviews. This analysis characterizes the impact of the technology, positive and negative aspects of living with the device, alongside participants’ expectations, hopes, and anxieties.
Results:
Participants were 32 adults, age 38.6 ± 9.6 years, 55% male, and 26 children, mean age 12 years (range 6-18 years), 54% male. DTQ results indicated moderately favorable impact of, and satisfaction with, both open and closed loop interventions, but little evidence of a comparative advantage of either. Key positive themes included perceived improved blood glucose control, improved general well-being, particularly on waking, improved sleep, reduced burden of diabetes, and visibility of data. Key negative themes included having to carry around the equipment and dislike of the pump and second cannula (ie, sensor) inserted.
Conclusions:
Overall, participants reported a positive experience of the closed loop technology. Results are consistent with previous research with size of equipment continuing to be a problem. Progress is being made in the usability of the closed-loop system.
OBJECTIVE
Hypoglycemia poses an immediate threat for cognitive function. Due to its association with acute cognitive impairment, the International Hypoglycemia Study Group (IHSG) defines a blood ...glucose level <3.0 mmol/L as “level 2 hypoglycemia.” In the current study we investigated whether having diabetes, type of diabetes, or hypoglycemia awareness moderates this association.
RESEARCH DESIGN AND METHODS
Adults with type 1 diabetes with normal (n = 26) or impaired (n = 21) hypoglycemic awareness or with insulin-treated type 2 diabetes (n = 15) and age-matched control subjects without diabetes (n = 32) underwent a hyperinsulinemic-euglycemic-hypoglycemic glucose clamp (2.80 ± 0.13 mmol/L 50.2 ± 2.3 mg/dL). At baseline and during hypoglycemia, calculation ability, attention, working memory and cognitive flexibility were measured with the Paced Auditory Serial Addition Test (PASAT) and the Test of Attentional Performance (TAP).
RESULTS
For the whole group, hypoglycemia decreased the mean ± SD proportion of correct answers on the PASAT by 8.4 ± 12.8%, increased reaction time on the TAP Alertness task by 32.1 ± 66.6 ms, and increased the sum of errors and omissions on the TAP Working Memory task by 2.0 ± 5.5 (all P < 0.001). Hypoglycemia-induced cognitive declines were largely irrespective of the presence or type of diabetes, level of symptomatic awareness, diabetes duration, or HbA1c.
CONCLUSIONS
IHSG level 2 hypoglycemia impairs cognitive function in people with and without diabetes, irrespective of type of diabetes or hypoglycemia awareness status. These findings support the cutoff value of hypoglycemia <3.0 mmol/L (<54 mg/dL) as being clinically relevant for most people with diabetes.
To evaluate a sensor-augmented insulin pump with a low glucose suspend (LGS) feature that automatically suspends basal insulin delivery for up to 2 h in response to sensor-detected hypoglycemia.
The ...LGS feature of the Paradigm Veo insulin pump (Medtronic, Inc., Northridge, CA) was tested for 3 weeks in 31 adults with type 1 diabetes.
There were 166 episodes of LGS: 66% of daytime LGS episodes were terminated within 10 min, and 20 episodes lasted the maximum 2 h. LGS use was associated with reduced nocturnal duration ≤2.2 mmol/L in those in the highest quartile of nocturnal hypoglycemia at baseline (median 46.2 vs. 1.8 min/day, P = 0.02 LGS-OFF vs. LGS-ON). Median sensor glucose was 3.9 mmol/L after 2-h LGS and 8.2 mmol/L at 2 h after basal restart.
Use of an insulin pump with LGS was associated with reduced nocturnal hypoglycemia in those at greatest risk and was well accepted by patients.
Early detection of an O2 deficit in the bloodstream is essential to initiate corrective changes in the breathing pattern of mammals. Carotid bodies serve an essential role in this respect; their type ...I cells depolarize when O2 levels fall, causing voltage-gated Ca2+ entry. Subsequent neurosecretion elicits increased afferent chemosensory fiber discharge to induce appropriate changes in respiratory function (1). Although depolarization of type I cells by hypoxia is known to arise from K+ channel inhibition, the identity of the signaling pathway has been contested, and the coupling mechanism is unknown (2). We tested the hypothesis that AMP-activated protein kinase (AMPK) is the effector of hypoxic chemotransduction. AMPK is co-localized at the plasma membrane of type I cells with O2-sensitive K+ channels. In isolated type I cells, activation of AMPK using 5-aminoimidazole-4-carboxamide riboside (AICAR) inhibited O2-sensitive K+ currents (carried by large conductance Ca2+-activated (BKCa) channels and TASK (tandem pore, acid-sensing potassium channel)-like channels, leading to plasma membrane depolarization, Ca2+ influx, and increased chemosensory fiber discharge. Conversely, the AMPK antagonist compound C reversed the effects of hypoxia and AICAR on type I cell and carotid body activation. These results suggest that AMPK activation is both sufficient and necessary for the effects of hypoxia. Furthermore, AMPK activation inhibited currents carried by recombinant BKCa channels, whereas purified AMPK phosphorylated theα subunit of the channel in immunoprecipitates, an effect that was stimulated by AMP and inhibited by compound C. Our findings demonstrate a central role for AMPK in stimulus-response coupling by hypoxia and identify for the first time a link between metabolic stress and ion channel regulation in an O2-sensing system.
Glucose management is challenging in patients who require nutritional support in hospital. We aimed to assess whether fully closed-loop insulin delivery would improve glycaemic control compared with ...conventional subcutaneous insulin therapy in inpatients receiving enteral or parenteral nutrition or both.
We did a two-centre (UK and Switzerland), open-label, randomised controlled trial in adult inpatients receiving enteral or parenteral nutrition (or both) who required subcutaneous insulin therapy. Patients recruited from non-critical care surgical and medical wards were randomly assigned (1:1) using a computer-generated minimisation schedule (stratified by type of nutritional support parenteral nutrition on or off and pre-study total daily insulin dose <50 or ≥50 units) to receive fully closed-loop insulin delivery with faster-acting insulin aspart (closed-loop group) or conventional subcutaneous insulin therapy (control group) given in accordance with local clinical practice. Continuous glucose monitoring in the control group was masked to patients, ward staff, and investigators. Patients were followed up for a maximum of 15 days or until hospital discharge. The primary endpoint was the proportion of time that sensor glucose concentration was in target range (5·6–10·0 mmol/L), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01774565.
Between Feb 8, 2018, and Sept 21, 2018, 90 patients were assessed for eligibility, of whom 43 were enrolled and randomly assigned to the closed-loop group (n=21) or the control group (n=22). The proportion of time that sensor glucose was in the target range was 68·4% SD 15·5 in the closed-loop group and 36·4% 26·6 in the control group (difference 32·0 percentage points 95% CI 18·5–45·5; p<0·0001). One serious adverse event occurred in each group (one cardiac arrest in the control group and one episode of acute respiratory failure in the closed-loop group), both of which were unrelated to study interventions. There were no adverse events related to study interventions in either group. No episodes of severe hypoglycaemia or hyperglycaemia with ketonaemia occurred in either study group.
Closed-loop insulin delivery is an effective treatment option to improve glycaemic control in patients receiving nutritional support in hospital.
Diabetes UK, Swiss National Science Foundation, National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome Trust, and European Foundation for the Study of Diabetes.
The Closing the Loop in Adults With Type 1 Diabetes (CLEAR) randomized crossover study compared a novel fully closed-loop insulin delivery system with no carbohydrate entry or mealtime bolusing ...(CamAPS HX), with standard insulin pump therapy and glucose sensor in adults with type 1 diabetes and suboptimal glycemic outcomes. This qualitative substudy aimed to understand the psychosocial impact of using the fully automated system.
Adults participating in the CLEAR study were invited to take part in a virtual semistructured interview after they had completed 8 weeks using the fully closed-loop system. Recruitment continued until there was adequate representation and data saturation occurred. Interviews were anonymized and transcribed for in-depth thematic analysis using an inductive-deductive approach. Study participants were also asked to complete questionnaires assessing diabetes distress, hypoglycemia confidence, and closed-loop treatment satisfaction.
Eleven participants (eight male and three female; age range 26-66 years) were interviewed. After an initial adjustment period, interviewees reported enjoying a reduction in diabetes burden, freed-up mental capacity, and improved mood. All were happy with overnight glycemic outcomes, with the majority reporting benefits on sleep. Although experiences of postprandial glucose outcomes varied, all found mealtimes easier and less stressful, particularly when eating out. Negatives raised by participants predominantly related to the insulin pump hardware, but some also reported increased snacking and challenges around resuming carbohydrate counting at trial closeout.
In adults with type 1 diabetes, use of a fully closed-loop insulin delivery system had significant quality-of-life benefits and provided a welcome break from the day-to-day demands of living with diabetes.
NCT04977908.
Aims/hypothesis
Recurrent hypoglycaemia in people with diabetes leads to progressive suppression of counterregulatory hormonal responses to subsequent hypoglycaemia. Recently it has been proposed ...that the mechanism underpinning this is a form of adaptive memory referred to as habituation. To test this hypothesis, we use two different durations of cold exposure to examine whether rodents exposed to recurrent hypoglycaemia exhibit two characteristic features of habituation, namely stimulus generalisation and dishabituation.
Methods
In the first study (stimulus generalisation study), hyperinsulinaemic–hypoglycaemic (2.8 mmol/l) glucose clamps were performed in non-diabetic rodents exposed to prior moderate-duration cold (4°C for 3 h) or control conditions. In the second study (dishabituation study), rodents exposed to prior recurrent hypoglycaemia or saline (154 mmol/l NaCl) injections over 4 weeks underwent a longer-duration cold (4°C for 4.5 h) exposure followed 24 h later by a hyperinsulinaemic–hypoglycaemic (2.8 mmol/l) glucose clamp. Output measures were counterregulatory hormone responses during experimental hypoglycaemia.
Results
Moderate-duration cold exposure blunted the adrenaline (epinephrine) response (15,266 ± 1920 vs 7981 ± 1258 pmol/l, Control vs Cold;
p
< 0.05) to next day hypoglycaemia in healthy non-diabetic rodents. In contrast, the suppressed adrenaline response (Control 5912 ± 1417 vs recurrent hypoglycaemia 1836 ± 736 pmol/l;
p
< 0.05) that is associated with recurrent hypoglycaemia was restored following longer-duration cold exposure (recurrent hypoglycaemia + Cold 4756 ± 826 pmol/l; not significant vs Control).
Conclusions/interpretation
Non-diabetic rodents exhibit two cardinal features of habituation, namely stimulus generalisation and dishabituation. These findings provide further support for the hypothesis that suppressed counterregulatory responses following exposure to recurrent hypoglycaemia in diabetes result from habituation.
Graphical abstract
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