Incidental Arrhythmias During Atrial Fibrillation Screening With Repeat 7-Day Holter ECGs in a Hospital-Based Patient Population.

BACKGROUND: Screening for atrial fibrillation (AF) may reveal incidental arrhythmias of relevance. The aim of this study was to describe incidental arrhythmias detected during screening for AF in the STAR-FIB (Predicting SilenT AtRial FIBrillation in Patients at High Thrombembolic Risk) cohort study. METHODS AND RESULTS: In the STAR-FIB cohort study, we screened hospitalized patients for AF with 3 repeat 7-day Holter ECGs. We analyzed all Holter ECGs for the presence of the following incidental arrhythmias: (1) sinus node dysfunction, defined as sinus pause of ≥3 seconds' duration; (2) second-degree (including Wenckebach) or higher-degree atrioventricular block (AVB); (3) sustained supraventricular tachycardia of ≥30 seconds' duration; and (4) sustained ventricular tachycardia of ≥30 seconds' duration. We furthermore report treatment decisions because of incidental arrhythmias. A total of 2077 Holter ECGs were performed in 794 patients (mean age, 74.7 years; 49% women), resulting in a mean cumulative duration of analyzable ECG signal of 414±136 hours/patient. We found incidental arrhythmias in 94 patients (11.8%). Among these were sinus node dysfunction in 14 patients (1.8%), AVB in 41 (5.2%), supraventricular tachycardia in 42 (5.3%), and ventricular tachycardia in 2 (0.3%). Second-degree AVB was found in 23 patients (2.9%), 2:1 AVB in 10 (1.3%), and complete AVB in 8 (1%). Subsequently, 8 patients underwent pacemaker implantation, 1 for sinus node dysfunction (post-AF conversion pause of 9 seconds) and 7 for advanced AVB. One patient had an implantable cardioverter-defibrillator implanted for syncopal ventricular tachycardia. CONCLUSIONS: Incidental arrhythmias were frequently detected during screening for AF in the STAR-FIB study and resulted in device therapy in 1.1% of our cohort patients.

Epicardial adipose tissue dispersion at CT and recurrent atrial fibrillation after pulmonary vein isolation.

OBJECTIVES: Epicardial adipose tissue (EAT) remodeling is associated with atrial fibrillation (AF). Left atrial (LA) EAT dispersion on cardiac CT is a non-invasive imaging biomarker reflecting EAT heterogeneity. We aimed to investigate the association of LA EAT dispersion with AF recurrence after pulmonary vein isolation (PVI). METHODS: In a prospective registry of consecutive patients undergoing first PVI, mean EAT attenuation values were measured on contrast-enhanced cardiac CT scans in Hounsfield units (HU) within low (- 195 to - 45 HU) and high (- 44 to - 15 HU) threshold EAT compartments around the left atrium (LA). EAT dispersion was defined as the difference between the mean HU values within the two EAT compartments. Continuous variables were compared between groups using the Mann-Whitney U test and cox proportional hazard models were used to calculate hazard ratios of predictors of 1-year AF recurrence. RESULTS: A total of 208 patients were included, 135 with paroxysmal AF and 73 with persistent AF. LA EAT dispersion was significantly larger in patients with persistent compared to paroxysmal AF (52.6 HU vs. 49.9 HU; p = 0.001). After 1 year of follow-up, LA EAT dispersion above the mean (> 50.8 HU) was associated with a higher risk of AF recurrence (HR 2.3, 95% CI 1.5-3.6; p < 0.001). It retained its predictive value when corrected for age, sex, body mass index, LA volume, and AF type (HR 2.8, 95% CI 1.6-4.6; p < 0.001). CONCLUSION: A larger LA EAT dispersion on contrast-enhanced cardiac CT scans, reflecting EAT heterogeneity, is independently associated with AF recurrence after PVI. CLINICAL RELEVANCE STATEMENT: Based on LA EAT dispersion assessment, a more accurate risk stratification and patient selection may be possible based on a pre-procedural cardiac CT when planning PVI. KEY POINTS: • Epicardial adipose tissue (EAT) remodeling is associated with atrial fibrillation (AF). • A larger left atrial EAT dispersion in a pre-procedural cardiac CT was associated with a higher 1-year AF recurrence risk after pulmonary vein isolation. • A pre-procedural cardiac CT with left atrial EAT dispersion assessment may provide a more accurate risk stratification and patient selection for PVI.

Islet transplantation outcomes in type 1 diabetes and transplantation of HLA-DQ8/DR4: results of a single-centre retrospective cohort in Canada.

Background: In solid organ transplantation, HLA matching between donor and recipient is associated with superior outcomes. In islet transplantation, an intervention for Type 1 diabetes, HLA matching between donor and recipient is not performed as part of allocation. Susceptibility to Type 1 diabetes is associated with the presence of certain HLA types. This study was conducted to determine the impact of these susceptibility antigens on islet allograft survival. Methods: This is a single-centre retrospective cohort study. This cohort of transplant recipients (n = 268) received islets from 661 donor pancreases between March 11th, 1999 and August 29th, 2018 at the University of Alberta Hospital (Edmonton, AB, Canada). The frequency of the Type 1 diabetes susceptibility HLA antigens (HLA-A24, -B39, -DQ8, -DQ2 and-DQ2-DQA1∗05) in recipients and donors were determined. Recipient and donor HLA antigens were examined in relation to time to first C-peptide negative status/graft failure or last observation point. Taking into account multiple transplants per patient, we fitted a Gaussian frailty survival analysis model with baseline hazard function stratified by transplant number, adjusted for cumulative islet dose and other confounders. Findings: Across all transplants recipients of donors positive for HLA-DQ8 had significantly better graft survival (adjusted HRs 0.33 95% CI 0.17-0.66; p = 0.002). At first transplant only, donors positive for HLA-DQ2-DQA1∗05 had inferior graft survival (adjusted HR 1.96 95% CI 1.10-3.46); p = 0.02), although this was not significant in the frailty analysis taking multiple transplants into account (adjusted HR 1.46 95% CI 0.77-2.78; p = 0.25). Other HLA antigens were not associated with graft survival after adjustment for confounders. Interpretation: Our findings suggest islet transplantation from HLA-DQ8 donors is associated with superior graft outcomes. A donor positive for HLA-DQ2-DQA1∗05 at first transplant was associated with inferior graft survival but not when taking into account multiple transplants per recipient. The relevance of HLA-antigens on organ allocation needs further evaluation and inclusion in islet transplant registries and additional observational and interventional studies to evaluate the role of HLA-DQ8 in islet graft survival are required. Funding: None.

C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes: an individual participant meta-analysis.

BACKGROUND: Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent ß-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of ß-cell function and metabolic outcomes in new-onset type 1 diabetes. METHODS: 21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA1c, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A1c, total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test. FINDINGS: 6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA1c (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA1c. For HbA1c, IDAAC, and BETA-2 score, sample size predictions indicated that 2-3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods. INTERPRETATION: Interventions that preserve ß-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA1c are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials. FUNDING: JDRF and Diabetes UK.

Acute and long-term outcomes of quadripolar IS-4 versus bipolar IS-1 left ventricular leads in cardiac resynchronization therapy: A retrospective registry study.

BACKGROUND: The implantation procedure of left ventricular (LV) leads and the management of cardiac resynchronization therapy (CRT) patients can be challenging. The IS-4 standard for CRT offers additional pacing vectors compared to bipolar leads (IS-1). IS-4 leads improve procedural outcome and may also result in lower adverse events during follow-up (FU) and improve clinical outcome in CRT patients. Further long-term FU data comparing the two lead designs are necessary. METHODS: In this retrospective, single-center study we included adult patients implanted with a CRT-Defibrillator (CRT-D) or CRT-Pacemaker (CRT-P) with a quadripolar (IS-4 group) or bipolar (IS-1 group) LV lead and with available ≥3 years clinical FU. The combined primary endpoint was a combination of predefined, lead-related adverse events. Secondary endpoints were all single components of the primary endpoint. RESULTS: Overall, 133 patients (IS-4 n = 66; IS-1 n = 67) with a mean FU of 4.03 ± 1.93 years were included. Lead-related adverse events were less frequent in patients with an IS-4 lead than with an IS-1 lead (n = 8, 12.1% vs. n = 23, 34.3%; p = .002). The secondary outcomes showed a lower rate of LV lead deactivation/explantation and LV lead dislodgement/dysfunction (4.5% vs. 22.4%; p = .003; 4.5% vs. 17.9%; p = .015, respectively) in the IS-4 patient group. Less patients suffered from unresolved phrenic nerve stimulation with an IS-4 lead (3.0% vs. 13.4%; p = .029). LV lead-related re-interventions were fewer in case of an IS-4 lead (6.1% vs. 17.9%; p = .036). CONCLUSION: In this retrospective analysis, the IS-4 LV lead is associated with lower lead-related complication rates than the IS-1 lead at long-term FU.

Safety and efficacy of vanzacaftor-tezacaftor-deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. METHODS: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor-tezacaftor-deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor-tezacaftor-deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor-deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)-tezacaftor-deutivacaftor or tezacaftor-ivacaftor active control for 4 weeks, following a 4-week tezacaftor-ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. FINDINGS: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI -0·8 to 7·0) and 2·7 percentage points (-1·0 to 6·5) from baseline at week 12, respectively, versus -0·8 percentage points (-6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)-tezacaftor-deutivacaftor (n=9), vanzacaftor (10 mg)-tezacaftor-deutivacaftor (n=19), vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (-1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (-4·1 to 8·0), respectively, in sweat chloride concentration of -42·8 mmol/L (-51·7 to -34·0), -45·8 mmol/L (95% CI -51·9 to -39·7), -49·5 mmol/L (-55·9 to -43·1), and 2·3 mmol/L (-7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (-10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=18) and tezacaftor-ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor-ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and -0·1 percentage points (-6·4 to 6·1), respectively, in sweat chloride concentration of -45·5 mmol/L (-49·7 to -41·3) and -2·6 mmol/L (-8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and -5·0 points (-16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor-tezacaftor-deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. INTERPRETATION: Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor-tezacaftor-deutivacaftor in phase 3 clinical trials compared with elexacaftor-tezacaftor-ivacaftor. FUNDING: Vertex Pharmaceuticals.

Acetylsalicylic Acid (Aspirin) for Primary Prevention of Cardiovascular Events in Patients with Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Evidence regarding using acetylsalicylic acid (aspirin) for the prevention of cardiovascular (CV) events in patients with diabetes mellitus (DM) is inconsistent. Therefore, we performed a meta-analysis. METHODS: A literature search was performed (January 1990 to February 2022) and publications meeting the inclusion criteria were reviewed, and a meta-analysis was performed using RevMan software. The primary outcome was a composite of CV death, non-fatal myocardial infarction (MI) and stroke. Secondary outcomes included all-cause mortality, individual components of the primary outcome and major bleeding. RESULTS: The study cohort comprised 33525 diabetic patients from 9 randomized controlled trials. The primary outcome was significantly lower for aspirin vs. placebo (7.9 vs. 8.6, RR (risk ratio) 0.92, 95% CI (confidence interval) 0.86-0.99). All-cause mortality (10 vs. 10.3%, RR 0.97, 95% CI 0.90-1.03), CV death (4.4 vs. 4.7%, RR 0.93, 95% CI 0.83-1.04), non-fatal MI (4.6 vs. 4.8% RR 0.97, 95% CI 0.83- 1.15) and stroke (3.2 vs. 3.5%, RR 0.89, 95% CI 0.75-1.06) were similar between the two treatment groups. Major bleeding was significantly higher for aspirin compared with placebo (3.4 vs. 2.8%, RR 1.18, 95% CI 1.01-1.39). CONCLUSION: Aspirin use in patients with DM reduces the composite endpoint of CV death, non-fatal MI and stroke compared with a placebo. However, routine use of aspirin for primary prevention among diabetic patients cannot be advised due to the increased risk of major bleeding. These findings suggest careful risk assessment of individual patients.

Pancreas and Islet Transplantation: Comparative Outcome Analysis of a Single-centre Cohort Over 20-years.

OBJECTIVE: To provide the largest single-center analysis of islet (ITx) and pancreas (PTx) transplantation. SUMMARY BACKGROUND DATA: Studies describing long-term outcomes with ITx and PTx are scarce. METHODS: We included adults undergoing ITx (n=266) and PTx (n=146) at the University of Alberta from January 1999 to October 2019. Outcomes include patient and graft survival, insulin independence, glycemic control, procedure-related complications, and hospital readmissions. Data are presented as medians (interquartile ranges, IQR) and absolute numbers (percentages, %) and compared using Mann-Whitney and χ2 tests. Kaplan-Meier estimates, Cox proportional hazard models and mixed main effects models were implemented. RESULTS: Crude mortality was 9.4% and 14.4% after ITx and PTx, respectively ( P= 0.141). Sex-adjusted and age-adjusted hazard-ratio for mortality was 2.08 (95% CI, 1.04-4.17, P= 0.038) for PTx versus ITx. Insulin independence occurred in 78.6% and 92.5% in ITx and PTx recipients, respectively ( P= 0.0003), while the total duration of insulin independence was 2.1 (IQR 0.8-4.6) and 6.7 (IQR 2.9-12.4) year for ITx and PTx, respectively ( P= 2.2×10 -22 ). Graft failure ensued in 34.2% and 19.9% after ITx and PTx, respectively ( P =0.002). Glycemic control improved for up to 20-years post-transplant, particularly for PTx recipients (group, P= 7.4×10 -7 , time, P =4.8×10 -6 , group*time, P= 1.2×10 -7 ). Procedure-related complications and hospital readmissions were higher after PTx ( P =2.5×10 -32 and P= 6.4×10 -112 , respectively). CONCLUSIONS: PTx shows higher sex-adjusted and age-adjusted mortality, procedure-related complications and readmissions compared with ITx. Conversely, insulin independence, graft survival and glycemic control are better with PTx. This study provides data to balance risks and benefits with ITx and PTx, which could improve shared decision-making.

C-peptide Targets and Patient-centered Outcomes of Relevance to Cellular Transplantation for Diabetes.

BACKGROUND: C-peptide levels are a key measure of beta-cell mass following islet transplantation, but threshold values required to achieve clinically relevant patient-centered outcomes are not yet established. METHODS: We conducted a cross-sectional retrospective cohort study evaluating patients undergoing islet transplantation at a single center from 1999 to 2018. Cohorts included patients achieving insulin independence without hypoglycemia, those with insulin dependence without hypoglycemia, and those with recurrent symptomatic hypoglycemia. Primary outcome was fasting C-peptide levels at 6 to 12 mo postfirst transplant; secondary outcomes included stimulated C-peptide levels and BETA-2 scores. Fasting and stimulated C-peptide and BETA-2 cutoff values for determination of hypoglycemic freedom and insulin independence were evaluated using receiver operating characteristic curves. RESULTS: We analyzed 192 patients, with 122 (63.5%) being insulin independent without hypoglycemia, 61 (31.8%) being insulin dependent without hypoglycemia, and 9 (4.7%) experiencing recurrent symptomatic hypoglycemia. Patients with insulin independence had a median (interquartile range) fasting C-peptide level of 0.66 nmol/L (0.34 nmol/L), compared with 0.49 nmol/L (0.25 nmol/L) for those being insulin dependent without hypoglycemia and 0.07 nmol/L (0.05 nmol/L) for patients experiencing hypoglycemia ( P < 0.001). Optimal fasting C-peptide cutoffs for insulin independence and hypoglycemia were ≥0.50 nmol/L and ≥0.12 nmol/L, respectively. Cutoffs for insulin independence and freedom of hypoglycemia using stimulated C-peptide were ≥1.2 nmol/L and ≥0.68 nmol/L, respectively, whereas optimal cutoff BETA-2 scores were ≥16.4 and ≥5.2. CONCLUSIONS: We define C-peptide levels and BETA-2 scores associated with patient-centered outcomes. Characterizing these values will enable evaluation of ongoing clinical trials with islet or stem cell therapies.

A Novel MIP-1-Expressing Macrophage Subtype in BAL Fluid from Healthy Volunteers.

Tissue availability remains an important limitation of single-cell genomic technologies for investigating cellular heterogeneity in human health and disease. BAL represents a minimally invasive approach to assessing an individual's lung cellular environment for diagnosis and research. However, the lack of high-quality, healthy lung reference data is a major obstacle to using single-cell approaches to study a plethora of lung diseases. Here, we performed single-cell RNA sequencing on over 40,000 cells isolated from the BAL of four healthy volunteers. Of the six cell types or lineages we identified, macrophages were consistently the most numerous across individuals. Our analysis confirmed the expression of marker genes defining cell types despite background signals because of the ambient RNA found in many single-cell studies. We assessed the variability of gene expression across macrophages and defined a distinct subpopulation of cells expressing a set of genes associated with Macrophage Inflammatory Protein 1 (MIP-1). RNA in situ hybridization and reanalysis of published lung single-cell data validated the presence of this macrophage subpopulation. Thus, our study characterizes lung macrophage heterogeneity in healthy individuals and provides a valuable resource for future studies to understand the lung environment in health and disease.

Improved Glycemia and Quality of Life Among Loop Users: Analysis of Real-world Data From a Single Center.

BACKGROUND: Despite do-it-yourself automated insulin delivery being an unapproved method of insulin delivery, an increasing number of people with type 1 diabetes (T1D) worldwide are choosing to use Loop, a do-it-yourself automated insulin delivery system. OBJECTIVE: In this study, we aimed to assess glycemic outcomes, safety, and the perceived impact on quality of life (QOL) in a local Edmonton cohort of known Loop users. METHODS: An observational study of adults with T1D who used Loop was performed. An assessment of glycemic and safety outcomes, HbA1c, time in range, hospital admissions, and time below range compared users most recent 6 months of Loop use, with their prior regulatory approved insulin delivery method. QOL outcomes were assessed using Insulin Dosing Systems: Perceptions, Ideas, Reflections, and Expectations, diabetes impact, and device satisfaction measures (with maximum scores of 100, 10, and 10, respectively) and semistructured interviews. RESULTS: The 24 adults with T1D who took part in this study 16 (67%) were female, with a median age of 33 (IQR 28-45) years, median duration of diabetes of 22 (IQR 17-32) years, median pre-Loop HbA1c of 7.9% (IQR 7.6%-8.3%), and a median duration of Loop use of 18 (IQR 12-25) months. During Loop use, the participants had median (IQR) values of 7.1% (6.5%-7.5%), 54 mmol (48-58) for HbA1c and 76.5% (64.6%-81.9%) for time in range, which were a significant improvement from prior therapy (P=.001 and P=.005), with a nonsignificant reduction in time below range; 3.0 to 3.9 mmol/L (P=.17) and <3 mmol/L (P=.53). Overall, 2 episodes of diabetic ketoacidosis occurred in a total of 470 months of Loop use, and no severe hypoglycemia occurred. The positive impact of Loop use on QOL was explored in qualitative analysis and additionally demonstrated through a median Insulin Dosing Systems: Perceptions, Ideas, Reflections, and Expectations score of 86 (IQR 79-95), a median diabetes impact score of 2.8 (IQR 2.1-3.9), and a median device satisfaction score of 9 (IQR 8.2-9.4). CONCLUSIONS: This local cohort of people with T1D demonstrated a beneficial effect of Loop use on both glycemic control and QOL, with no safety concerns being highlighted.

A scoping review of Do-It-Yourself Automated Insulin Delivery system (DIY AID) use in people with type 1 diabetes.

INTRODUCTION: User designed Automated Insulin Delivery systems (AID), termed Do-It-Yourself (DIY) AID include; AndroidAPS, OpenAPS and Loop. These unregulated systems provide challenges for healthcare providers worldwide, with potential legal and ethical barriers to supporting their use. We performed a scoping review of the currently available literature surrounding DIY AID systems, specifically to highlight the evidence available to facilitate healthcare providers to support persons with diabetes who may benefit from DIY AID. METHODS: Studies relating to DIY AID systems were searched in Embase, Medline, Web of Science, Scopus, Proquest and Cochrane library until 31st December 2021. Publications were screened through title and abstract to identify study type and AID system type described. A thematic synthesis methodology was used for analysis of studies of DIY AID use due to the heterogeneity in study designs (case reports, qualitative, cross-sectional and cohort studies), with similarity in outcome themes. RESULTS: Following implementation of the search strategy, 38 relevant full texts were identified; comprising 12 case reports, 9 qualitative studies and 17 cohort studies, and data was also available from 24 relevant conference abstracts. No randomized studies were identified. Common themes were identified in the outcomes across the studies; glycemic variability, safety, quality of life, healthcare provider attitudes and social media. CONCLUSION: There is extensive real-world data, but a lack of randomized control trial evidence supporting DIY AID system use, due to the user-driven, unregulated nature of these systems. Healthcare providers report a lack of understanding surrounding, and confidence in supporting, DIY AID despite impressive observational and user self-reported improvements in glycemic variability, without any reported safety compromises.

Do-It-Yourself and Commercial Automated Insulin Delivery Systems in Type 1 Diabetes: An Uncertain Area for Canadian Health-care Providers.

In the past century, since the discovery of insulin, methods of insulin delivery and glucose monitoring have advanced technologically. In particular, the introduction of insulin pumps, providing continuous subcutaneous insulin infusion (CSII), and continuous glucose monitors (CGMs) have been revolutionary for people living with type 1 diabetes. In this review, we have focussed on automated insulin delivery (AID) systems and discuss the implications of both approved and off-label options for the user and health-care providers. By pairing insulin pumps with CGM, AID systems facilitate automated adjustment in insulin delivery based on CGM readings. A subset of these have been developed commercially and were granted regulatory approval. In contrast, unregulated do-it-yourself AID systems, designed and set up by people living with type 1 diabetes and their families, have advanced rapidly and are gaining popularity worldwide. These patient-driven technologies have demonstrated impressive user self-reported improvements in glycemic control and quality of life, but have not been evaluated in any formal randomized controlled trials or by regulators. This presents challenging uncertainty for health-care providers, in addition to ethical and legal implications in supporting people with diabetes who wish to use these technologies. The current knowledge, opinions and practices relating to the use of AID systems across Canada are unknown. Gathering this information will highlight current practice and areas of knowledge gaps and concern and will assist in focussed education. This understanding is crucial to ensure people with type 1 diabetes using these systems have access to optimal, consistent and safe patient-centred care.

Estimation of Early Graft Function Using the BETA-2 Score Following Clinical Islet Transplantation.

Little is known about how early islet graft function evolves in the clinical setting. The BETA-2 score is a validated index of islet function that can be calculated from a single blood sample and lends itself to frequent monitoring of graft function. In this study, we characterized early graft function by calculating weekly BETA-2 score in recipients who achieved insulin independence after single transplant (group 1, n = 8) compared to recipients who required a second transplant before achieving insulin independence (group 2, n = 7). We also determined whether graft function 1-week post-transplant was associated with insulin independence in individuals who received initial transplant between 2000-2017 (n = 125). Our results show that graft function increased rapidly reaching a plateau 4-6 weeks post-transplant. The BETA-2 score was higher in group 1 compared to group 2 as early as 1-week post-transplant (15 + 3 vs. 9 + 2, p = 0.001). In an unselected cohort, BETA-2 at 1-week post-transplant was associated with graft survival as defined by insulin independence during median follow up of 12 months (range 2-119 months) with greater survival among those with BETA-2 score >10 (p < 0.001, log-rank test). These findings suggest that primary graft function is established within 4-6 weeks post-transplant and graft function at 1-week post-transplant predicts long-term transplant outcomes.

Outcomes Following Extrahepatic and Intraportal Pancreatic Islet Transplantation: A Comparative Cohort Study.

BACKGROUND: Preliminary studies show promise for extrahepatic islet transplantation (ITx). However, clinical comparisons with intraportal ITx outcomes remain limited. METHODS: This single-center cohort study evaluates patients receiving extrahepatic or intraportal ITx between 1999 and 2018. Primary outcome was stimulated C-peptide level. Secondary outcomes were fasting plasma glucose, BETA-2 scores, and fasting C-peptide level. Multivariable logistic modeling evaluated factors independently associated with a composite variable of early graft failure and primary nonfunction within 60 d of ITx. RESULTS: Of 264 patients, 9 (3.5%) received extrahepatic ITx (gastric submucosal = 2, subcutaneous = 3, omental = 4). Group demographics were similar at baseline (age, body mass index, diabetes duration, and glycemic control). At 1-3 mo post-first infusion, patients receiving extrahepatic ITx had significantly lower stimulated C-peptide (0.05 nmol/L versus 1.2 nmol/L, P < 0.001), higher fasting plasma glucose (9.3 mmol/L versus 7.3 mmol/L, P < 0.001), and lower BETA-2 scores (0 versus 11.6, P < 0.001) and SUITO indices (1.5 versus 39.6, P < 0.001) compared with those receiving intraportal ITx. Subjects receiving extrahepatic grafts failed to produce median C-peptide ≥0.2 nmol/L within the first 60 d after transplant. Subsequent intraportal infusion following extrahepatic transplants achieved equivalent outcomes compared with patients receiving intraportal transplant alone. Extrahepatic ITx was independently associated with early graft failure/primary non-function (odds ratio 1.709, confidence interval 73.8-39 616.0, P < 0.001), whereas no other factors were independently predictive. CONCLUSIONS: Using current techniques, intraportal islet infusion remains the gold standard for clinical ITx, with superior engraftment, graft function, and glycemic outcomes compared with extrahepatic transplantation of human islets.

The Relationship between Enhancing Left Atrial Adipose Tissue at CT and Recurrent Atrial Fibrillation.

Background The association of epicardial adipose tissue (EAT) and its metabolic activity with atrial fibrillation (AF) is an area of active investigation. Left atrial (LA) enhancing EAT (e-EAT) at cardiac CT may be a noninvasive surrogate marker for the metabolic activity of EAT. Purpose To determine the relationship between LA e-EAT and recurrence after AF ablation. Materials and Methods In a secondary analysis of a prospective registry of consecutive patients (from July 2018 to December 2019) undergoing first AF ablation, total and LA EAT were segmented on preprocedural noncontrast- and contrast-enhanced cardiac CT scans. LA e-EAT volume fraction was defined as the LA EAT volume difference between the noncontrast- and contrast-enhanced scan divided by the total LA EAT volume on the noncontrast-enhanced scan (threshold values, -15 HU to -195 HU). Continuous variables were compared between groups by using the Mann-Whitney U test. Cox proportional hazard models were used to calculate hazard ratios of predictors of 1-year AF recurrence. Results A total of 212 patients (mean age, 64 years; 159 men) who underwent a first AF ablation were included (paroxysmal AF, 64%; persistent AF, 36%). The LA EAT volume was higher in patients with persistent versus paroxysmal AF (50 cm3 [IQR, 37-72] vs 37 [IQR, 27-49]; P < .001), but no difference was found for LA e-EAT (P = .09). After 1 year of follow-up, AF recurrence rate was 77 of 212 (36%). LA e-EAT above the mean (>33%) was associated with a higher risk of AF recurrence (hazard ratio [HR], 2.1; 95% CI: 1.3, 3.3; P < .01). In a multivariable Cox regression analysis, LA e-EAT retained its predictive value when corrected for sex, age, AF phenotype, LA volume index, and LA EAT volume (HR, 1.9; 95% CI: 1.1, 3.1; P = .02). Conclusion Left atrial enhancing epicardial adipose tissue was independently associated with recurrence after atrial fibrillation ablation. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Stojanovska in this issue.

Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a single-centre cohort in Canada.

BACKGROUND: Islet transplantation offers an effective treatment for selected people with type 1 diabetes and intractable hypoglycaemia. Long-term experience, however, remains limited. We report outcomes from a single-centre cohort up to 20 years after islet transplantation. METHODS: This cohort study included patients older than 18 years with type 1 diabetes undergoing allogeneic islet transplantation between March 11, 1999, and Oct 1, 2019, at the University of Alberta Hospital (Edmonton, AB, Canada). Patients who underwent islet-after-kidney transplantation and islet transplantation alone or islet transplantation before whole-pancreas transplantation (follow-up was censored at the time of whole-pancreas transplantation) were included. Patient survival, graft survival (fasting plasma C-peptide >0·1 nmol/L), insulin independence, glycaemic control, and adverse events are reported. To identify factors associated with prolonged graft survival, recipients with sustained graft survival (≥90% of patient follow-up duration) were compared with those who had non-sustained graft survival (<90% of follow-up duration). Multivariate binary logistic regression analyses were done to determine predictors of sustained graft survival. FINDINGS: Between March 11, 1999, and Oct 1, 2019, 255 patients underwent islet transplantation and were included in the analyses (149 [58%] were female and 218 [85%] were White). Over a median follow-up of 7·4 years (IQR 4·4-12·2), 230 (90%) patients survived. Median graft survival was 5·9 years (IQR 3·0-9·5), and graft failure occurred in 91 (36%) patients. 178 (70%) recipients had sustained graft survival, and 77 (30%) had non-sustained graft survival. At baseline, compared with patients with non-sustained graft survival, those with sustained graft survival had longer median type 1 diabetes duration (33·5 years [IQR 24·3-41·7] vs 26·2 years [17·0-35·5]; p=0·0003), median older age (49·4 years [43·5-56·1] vs 44·2 years [35·4-54·2]; p=0·0011), and lower median insulin requirements (0·53 units/kg per day [0·45-0·67] vs 0·59 units/kg per day [0·48-0·70]; p=0·032), but median HbA1c concentrations were similar (8·2% [7·5-9·0] vs 8·5% [7·8-9·2]; p=0·23). 201 (79%) recipients had insulin independence, with a Kaplan-Meier estimate of 61% (95% CI 54-67) at 1 year, 32% (25-39) at 5 years, 20% (14-27) at 10 years, 11% (6-18) at 15 years, and 8% (2-17) at 20 years. Patients with sustained graft survival had significantly higher rates of insulin independence (160 [90%] of 178 vs 41 [53%] of 77; p<0·0001) and sustained improvements in glycaemic control mixed-main-effects model group effect, p<0·0001) compared with those with non-sustained graft survival. Multivariate analyses identified the combined use of anakinra plus etanercept (adjusted odds ratio 7·5 [95% CI 2·7-21·0], p<0·0001) and the BETA-2 score of 15 or higher (4·1 [1·5-11·4], p=0·0066) as factors associated with sustained graft survival. In recipients with sustained graft survival, the incidence of procedural complications was lower (23 [5%] of 443 infusions vs 17 [10%] of 167 infusions; p=0·027), whereas the incidence of cancer was higher (29 of [16%] of 178 vs four [5%] of 77; p=0·015) than in those with non-sustained graft survival; most were skin cancers (22 [67%] of 33). End-stage renal disease and severe infections were similar between groups. INTERPRETATION: We present the largest single-centre cohort study of long-term outcomes following islet transplantation. Although some limitations with our study remain, such as the retrospective component, a relatively small sample size, and the absence of non-transplant controls, we found that the combined use of anakinra plus etanercept and the BETA-2 score were associated with improved outcomes, and therefore these factors could inform clinical practice. FUNDING: None.

Differences in Atrial Remodeling in Hypertrophic Cardiomyopathy Compared to Hypertensive Heart Disease and Athletes' Hearts.

Background: Hypertrophic cardiomyopathy (HCM), hypertensive heart disease (HHD) and athletes' heart share an increased prevalence of atrial fibrillation. Atrial cardiomyopathy in these patients may have different characteristics and help to distinguish these conditions. Methods: In this single-center study, we prospectively collected and analyzed electrocardiographic (12-lead ECG, signal-averaged ECG (SAECG), 24 h Holter ECG) and echocardiographic data in patients with HCM and HHD and in endurance athletes. Patients with atrial fibrillation were excluded. Results: We compared data of 27 patients with HCM (70% males, mean age 50 ± 14 years), 324 patients with HHD (52% males, mean age 75 ± 5.5 years), and 215 endurance athletes (72% males, mean age 42 ± 7.5 years). HCM patients had significantly longer filtered P-wave duration (153 ± 26 ms) and PR interval (191 ± 48 ms) compared to HHD patients (144 ± 16 ms, p = 0.012 and 178 ± 31, p = 0.034, respectively) and athletes (134 ± 14 ms, p = 0.001 and 165 ± 26 ms, both p < 0.001, respectively). HCM patients had a mean of 4.9 ± 16 premature atrial complexes per hour. Premature atrial complexes per hour were significantly more frequent in HHD patients (27 ± 86, p < 0.001), but not in athletes (2.7 ± 23, p = 0.639). Left atrial volume index (LAVI) was 43 ± 14 mL/m2 in HCM patients and significantly larger than age- and sex-corrected LAVI in HHD patients 30 ± 10 mL/m2; p < 0.001) and athletes (31 ± 9.5 mL/m2; p < 0.001). A borderline interventricular septum thickness ≥13 mm and ≤15 mm was found in 114 (35%) HHD patients, 12 (6%) athletes and 3 (11%) HCM patients. Conclusions: Structural and electrical atrial remodeling is more advanced in HCM patients compared to HHD patients and athletes.

Effect of electrode size and spacing on electrograms: Optimized electrode configuration for near-field electrogram characterization.

BACKGROUND: Detailed effects of electrode size on electrograms (EGMs) have not been systematically examined. OBJECTIVES: We aimed to elucidate the effect of electrode size on EGMs and investigate an optimal configuration of electrode size and interelectrode spacing for gap detection and far-field reduction. METHODS: This study included 8 sheep in which probes with different electrode size and interelectrode spacing were epicardially placed on healthy, fatty, and lesion tissues for measurements. Between 3 electrode sizes (0.1 mm/0.2 mm/0.5 mm) with 3 mm spacing. As indices of capability in gap detection and far-field reduction, in different electrode sizes (0.1 mm/0.2 mm/0.5 mm) and interelectrode spacing (0.1 mm/0.2 mm/0.3 mm/0.5 mm/3 mm) and the optimized electrode size and interelectrode spacing were determined. Compared between PentaRay and the optimal probe determined in study 2. RESULTS: Study 1 demonstrated that unipolar voltage and the duration of EGMs increased as the electrode size increased in any tissue (P < .001). Bipolar EGMs had the same tendency in healthy/fat tissues, but not in lesions. Study 2 showed that significantly higher gap to lesion volume ratio and healthy to fat tissue voltage ratio were provided by a smaller electrode (0.2 mm or 0.3 mm electrode) and smaller spacing (0.1 mm spacing), but 0.3 mm electrode/0.1 mm spacing provided a larger bipolar voltage (P < .05). Study 3 demonstrated that 0.3 mm electrode/0.1 mm spacing provided less deflection with more discrete EGMs (P < .0001) with longer and more reproducible AF cycle length (P < .0001) compared to PentaRay. CONCLUSION: Electrode size affects both unipolar and bipolar EGMs. Catheters with microelectrodes and very small interelectrode spacing may be superior in gap detection and far-field reduction. Importantly, this electrode configuration could dramatically reduce artifactual complex fractionated atrial electrograms and may open a new era for AF mapping.

Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.

BACKGROUND: Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation. METHODS: We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV1 of 40-90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV1, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972. FINDINGS: Between Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (-1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], p<0·0001), the mean percent predicted FEV1 increased by 11·2 percentage points (95% CI 9·8 to 12·6) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·0 percentage points (-0·4 to 2·4) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 10·2 percentage points [8·2 to 12·1], p<0·0001), and the mean sweat chloride concentration decreased by 46·2 mmol/L (95% CI 43·7 to 48·7) in the elexacaftor plus tezacaftor plus ivacaftor group and by 3·4 mmol/L (1·0 to 5·8) in the tezacaftor plus ivacaftor group (least squares mean treatment difference -42·8 mmol/L [-46·2 to -39·3], nominal p<0·0001). Most participants (70 [80%] in the elexacaftor plus tezacaftor plus ivacaftor group and 74 [84%] in the tezacaftor plus ivacaftor group) had adverse events that were mild or moderate in severity; serious adverse events occurred in five (6%) of 87 participants in the elexacaftor plus tezacaftor plus ivacaftor group and 14 (16%) of 88 participants in the tezacaftor plus ivacaftor group. One (1%) participant in the elexacaftor plus tezacaftor plus ivacaftor group discontinued treatment due to an adverse event of anxiety and depression. Two (2%) participants in the tezacaftor plus ivacaftor group discontinued treatment due to adverse events of psychotic disorder (n=1) and obsessive-compulsive disorder (n=1). INTERPRETATION: The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population. FUNDING: Vertex Pharmaceuticals.