Renal hyperparathyroidism- a risk factor in the development of encapsulating peritoneal sclerosis.

Background: Encapsulating peritoneal sclerosis (EPS) is a rare complication of prolonged peritoneal dialysis (PD) exposure, characterised by peritoneal thickening, calcification, and fibrosis ultimately presenting with life-threatening bowel obstruction. The presence or role of peritoneal calcification in the pathogenesis of EPS is poorly characterised. We hypothesise that significantly aberrant bone mineral metabolism in patients on PD can cause peritoneal calcification which may trigger the development of EPS. We compared the temporal evolution of bone mineral markers during PD in EPS patients with non-EPS long-term PD controls. Methods: Linear mixed model and logistic regression analysis were used to compare four-monthly serum levels of calcium, phosphate, parathyroid hormone, and alkaline phosphatase (ALP) over the duration of PD exposure in 46 EPS and 46 controls (PD, non-EPS) patients. Results: EPS patients had higher mean calcium (2.51 vs. 2.41 mmol/L) and ALP (248.00 vs. 111.13 IU/L) levels compared with controls (p=0.01 and p<0.001 respectively, maximum likelihood estimation). Logistic regression analysis demonstrated that high serum calcium and phosphate levels during PD were associated with a 4.5 and 2.9 fold increase in the risk of developing EPS respectively. Conclusion: High levels of calcium and phosphate in patients on PD were identified to be risk factors for EPS development. Possible reasons for this may be an imbalance of pro-calcifying factors and calcification inhibitors promoting peritoneal calcification which increases peritoneal stiffness. Mechanical alterations may trigger, unregulated fibrosis and subsequent development of EPS. Improved management of secondary hyperparathyroidism during PD may ultimately diminish the EPS risk.

First Accuracy and User-Experience Evaluation of New Continuous Glucose Monitoring System for Hypoglycemia Due to Hyperinsulinism.

INTRODUCTION: Patients with congenital hyperinsulinism (HI) require constant glucose monitoring to detect and treat recurrent and severe hypoglycemia. Historically, this has been achieved with intermittent self-monitoring blood glucose (SMBG), but patients are increasingly using continuous glucose monitoring (CGM). Given the rapidity of CGM device development, and increasing calls for CGM use from HI families, it is vital that new devices are evaluated early. METHODS: We provided two months of supplies for the new Dexcom G7 CGM device to 10 patients with HI who had recently finished using the Dexcom G6. Self-monitoring blood glucose was performed concurrently with paired readings providing accuracy calculations. Patients and families completed questionnaires about device use at the end of the two-month study period. RESULTS: Compared to the G6, the G7 showed a significant reduction in mean absolute relative difference (25%-18%, P < .001) and in the over-read error (Bland Altman +1.96 SD; 3.54 mmol/L to 2.95 mmol/L). This resulted in an improvement in hypoglycemia detection from 42% to 62% (P < .001). Families reported an overall preference for the G7 but highlighted concerns about high sensor failure rates. DISCUSSION: The reduction in mean absolute relative difference and over-read error and the improvement in hypoglycemia detection implies that the G7 is a safer and more useful device in the management of hypoglycemia for patients with HI. Accuracy, while improved from previous devices, remains suboptimal with 40% of hypoglycemia episodes not detected.

Donor KIR2DL1 Allelic Polymorphism Influences Posthematopoietic Progenitor Cell Transplantation Outcomes in the T Cell Depleted and Reduced Intensity Conditioning Setting.

The majority of established KIR clinical assessment algorithms used for donor selection for hematopoietic progenitor cell transplantation (HPCT) evaluate gene content (presence/absence) of the KIR gene complex. In comparison, relatively little is known about the impact of KIR allelic polymorphism. By analyzing donors of T cell depleted (TcD) reduced intensity conditioning (RIC) HPCT, this study investigated the influence on post-transplant outcome of 2 polymorphic residues of the inhibitory KIR2DL1. The aim of this study was to expand upon existing research into the influence of KIR2DL1 allelic polymorphism upon post-transplant outcome. The effects of allele groups upon transplant outcomes were investigated within a patient cohort using a defined treatment protocol of RIC with TcD. Using phylogenetic data, KIR2DL1 allelic polymorphism was categorized into groups on the basis of variation within codons 114 and 245 (positive or negative for the following groups: KIR2DL1*002/001g, KIR2DL1*003, KIR2DL1*004g) and the identification of null alleles. The influence of these KIR2DL1 allele groups in hematopoietic progenitor cell transplantation (HPCT) donors was assessed in the post-transplant data of 86 acute myelogenous leukemia patients receiving RIC TcD HPCT at a single center. KIR2DL1 allele groups in the donor significantly impacted upon 5-year post-transplant outcomes in RIC TcD HPCT. Donor KIR2DL1*003 presented the greatest influence upon post-transplant outcomes, with KIR2DL1*003 positive donors severely reducing 5-year post-transplant overall survival (OS) compared to those receiving a transplant from a KIR2DL1*003 negative donor (KIR2DL1*003 pos versus neg: 27.0% versus 60.0%, P = .008, pc = 0.024) and disease-free survival (DFS) (KIR2DL1*003 pos versus neg: 23.5% versus 60.0%, P = .004, pc = 0.012), and increasing 5-year relapse incidence (KIR2DL1*003 pos versus neg: 63.9% versus 27.2%, P = .009, pc = 0.027). KIR2DL1*003 homozygous and KIR2DL1*003 heterozygous grafts did not present significantly different post-transplant outcomes. Donors possessing the KIR2DL1*002/001 allele group were found to significantly improve post-transplant outcomes, with donors positive for the KIR2DL1*004 allele group presenting a trend towards improvement. KIR2DL1*002/001 allele group (KIR2DL1*002/001g) positive donors improved 5-year OS (KIR2DL1*002/001g pos versus neg: 56.4% versus 27.2%, P = .009, pc = 0.024) and DFS (KIR2DL1*002/001g pos versus neg: 53.8% versus 25.5%, P = .018, pc = 0.036). KIR2DL1*004 allele group (KIR2DL1*004g) positive donors trended towards improving 5-year OS (KIR2DL1*004g pos versus neg: 53.3% versus 35.5%, P = .097, pc = 0.097) and DFS (KIR2DL1*004g pos versus neg: 50.0% versus 33.9%, P = .121, pc = 0.121), and reducing relapse incidence (KIR2DL1*004g pos versus neg: 33.1% versus 54.0%, P = .079, pc = 0.152). The presented findings suggest donor selection algorithms for TcD RIC HPCT should consider avoiding KIR2DL1*003 positive donors, where possible, and contributes to the mounting evidence that KIR assessment in donor selection algorithms should reflect the conditioning regime protocol used.

Beta-cell death and dysfunction drives hyperglycaemia in organ donors.

BACKGROUND: Donor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other mechanisms may be predominant. We aimed to determine the relationships between donor insulin use and markers of beta-cell death and beta-cell function in pancreas donors after brain death. METHODS: In pancreas donors after brain death, we compared clinical and biochemical data in 'insulin-treated' and 'not insulin-treated donors' (IT vs. not-IT). We measured plasma glucose, C-peptide and levels of circulating unmethylated insulin gene promoter cell-free DNA (INS-cfDNA) and microRNA-375 (miR-375), as measures of beta-cell death. Relationships between markers of beta-cell death and islet isolation outcomes and post-transplant function were also evaluated. RESULTS: Of 92 pancreas donors, 40 (43%) required insulin. Glycaemic control and beta-cell function were significantly poorer in IT donors versus not-IT donors [median (IQR) peak glucose: 8 (7-11) vs. 6 (6-8) mmol/L, p = .016; C-peptide: 3280 (3159-3386) vs. 3195 (2868-3386) pmol/L, p = .046]. IT donors had significantly higher levels of INS-cfDNA [35 (18-52) vs. 30 (8-51) copies/ml, p = .035] and miR-375 [1.050 (0.19-1.95) vs. 0.73 (0.32-1.10) copies/nl, p = .05]. Circulating donor miR-375 was highly predictive of recipient islet graft failure at 3 months [adjusted receiver operator curve (SE) = 0.813 (0.149)]. CONCLUSIONS: In pancreas donors, hyperglycaemia requiring IT is strongly associated with beta-cell death. This provides an explanation for the relationship of donor IT with post-transplant beta-cell dysfunction in transplant recipients.

Integration of nurse-led virtual reviews with growth hormone device-linked patient adherence information: a mixed methods feasibility study.

Introduction: Easypod-connect™ for childhood growth disorders is a unique connected system that enables transmission of injection adherence information for recombinant human growth hormone (r-hGH). Although this system has the potential to facilitate greater adherence, observational studies have shown declining adherence over prolonged periods when used without additional support. Supplemental nurse practitioner support has been envisaged but not investigated; in this study, we have undertaken feasibility analysis of nurse-led virtual reviews (NVR) in combination with easypod-connect™ in a single centre using quantitative and qualitative analyses. Aims: We aimed to test feasibility by assessing compliance with NVR, height standard deviation score (SDS) gain, adherence improvement and patient opinions. Methods: Patients using easypod™ r-hGH were recruited prospectively to a 12-month study with two telephone NVR appointments in addition to standard of care in-person hospital outpatient visits. A subset was recruited for a semi-structured interview for qualitative thematic analysis. Results: Forty-three patients of median (range) age 10.7 (6.7, 15.2) were recruited for a period of 1.1 (0.7, 1.8) years. Thirty-three (76.7%) patients were fully compliant with NVR integration with easypod-connect™, establishing feasibility. Median (inter-quartile range, IQR) height SDS improved from -1.85 (-2.44, -1.37) to -1.48 (-2.14, -1.07) (p<0.001) while adherence remained similar in the majority from study start [96.5 (88.8, 100.0)] to end [99.0 (94.0, 100.0)]. Qualitative analysis identified themes supporting patient benefit: practicalities of appointments, perceived purpose and significance of virtual reviews, and the importance of optimising growth. Four patients complained of injection pain, of whom two switched to an alternative r-hGH device. Conclusion: Our study has demonstrated the feasibility of nurse-led virtual review integration with easypod-connect™ in a mixed methods study, laying the foundation for research in larger groups over longer periods. Nurse practitioner supported application of easypod-connect™ offers the potential for improved growth outcomes in all r-hGH devices providing adherence information.

Cortisol Levels During Acute Illnesses in Children and Adolescents: A Systematic Review.

Importance: Endogenous cortisol levels in children and adolescents during acute illnesses can contribute to the evidence base required to optimize glucocorticoid (GC) stress doses for children and adolescents known to have GC deficiency. Objective: To identify endogenous cortisol levels during a range of acute illnesses in children and adolescents without GC deficiency from published evidence. Evidence Review: CINAHL, Cochrane Library, Cochrane Database of Systematic Reviews, Embase, and MEDLINE were searched for studies published between January 1, 2000, and June 30, 2020. Two reviewers independently identified relevant studies. Differences were resolved by joint discussion. Inclusion criteria were common acute illnesses, age from 1 month to 18 years, and basal blood cortisol levels obtained within 48 hours of presentation. Studies with fewer than 5 participants and those that included participants known to have GC deficiency or a history of treatment that could affect cortisol levels were excluded from the review. Data for predefined fields were extracted and independently checked by separate pairs of reviewers. Overall weighted means and pooled SDs for cortisol levels were calculated. Findings: All 15 studies included were hospital based and included 864 unique participants: 14 studies were prospective observational studies, 1 was part of a trial, and 5 included control individuals. Mean cortisol levels were higher in all participants with an acute illness (n = 689) than in controls (n = 175) (difference in weighted means, 18.95 µg/dL; 95% CI, 16.68-21.22 µg/dL). Cortisol levels were highest in patients with bacterial meningitis (weighted mean [pooled SD], 46.42 [22.24] µg/dL) and were more than 3-fold higher in the group with severe gastroenteritis (weighted mean [pooled SD], 39.64 [21.34] µg/dL) than in the control group. Among the subgroups with sepsis, those with shock had lower cortisol levels than those without shock (weighted mean [pooled SD], 27.83 [36.39] µg/dL vs 37.00 [23.30] µg/dL), but levels in nonsurvivors did not differ from levels in survivors (weighted mean [pooled SD], 24.89 [51.65] µg/dL vs 30.53 [30.60] µg/dL). Conclusions and Relevance: This systematic review found that, in children and adolescents without GC deficiency, circulating cortisol levels were higher during acute illnesses than those in controls and also varied across a range of acute illnesses. Whether these levels need to be achieved with exogenous GC stress doses tailored according to the nature and severity of the illness in children and adolescents with GC deficiency warrants investigation.

Deep Vein Thrombosis is Common After Cardiac Ablation and Pre-Procedural D-Dimer Could Predict Risk.

PURPOSE: Cardiac catheter ablations are an established treatment for supraventricular tachycardia (SVT) involving prolonged cannulation of the common femoral vein with multiple catheters. This study aimed to identify the risk of deep vein thrombosis (DVT) by studying the frequency of this complication after catheter ablation. METHODS: This was a prospective multi-centre cohort study of patients undergoing cardiac ablation for atrioventricular nodal re-entry tachycardia or right-sided accessory atrioventricular connection. Those taking anticoagulation or antiplatelet therapy prior to the procedure were excluded. Following the procedure, bilateral venous duplex ultrasonography from the popliteal vein to the inferior vena cava for DVT was undertaken at 24 hours and between 10 to 14 days. RESULTS: Eighty (80) patients (mean age 47.6 yrs [SD 13.4] with 67% female) underwent cardiac ablation (median duration 70 mins). Seven (7) patients developed acute DVT in either the femoral or external iliac vein of the intervention leg, giving a frequency of 8.8% (95% CI 3.6-17.2%). No thrombus was seen in the contralateral leg (p=0.023). An elevated D-dimer prior to the procedure was significantly more frequent in patients developing DVT (42.9% vs 4.1%, p=0.0081; OR 17.0). No other patient or procedural characteristics significantly influenced the risk of DVT. CONCLUSION: In patients without peri-procedural anticoagulation catheter ablation precipitated DVT in the catheterised femoral or iliac veins in 8.8% of patients. Peri-procedure prophylactic anticoagulation may be considered for all patients undergoing catheter ablation for SVT. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03877770.

Longitudinal assessment of lung clearance index to monitor disease progression in children and adults with cystic fibrosis.

BACKGROUND: Lung clearance index (LCI) is a valuable research tool in cystic fibrosis (CF) but clinical application has been limited by technical challenges and uncertainty about how to interpret longitudinal change. In order to help inform clinical practice, this study aimed to assess feasibility, repeatability and longitudinal LCI change in children and adults with CF with predominantly mild baseline disease. METHODS: Prospective, 3-year, multicentre, observational study of repeated LCI measurement at time of clinical review in patients with CF >5 years, delivered using a rapid wash-in system. RESULTS: 112 patients completed at least one LCI assessment and 98 (90%) were still under follow-up at study end. The median (IQR) age was 14.7 (8.6-22.2) years and the mean (SD) FEV1 z-score was -1.2 (1.3). Of 81 subjects with normal FEV1 (>-2 z-scores), 63% had raised LCI (indicating worse lung function). For repeat stable measurements within 6 months, the mean (limits of agreement) change in LCI was 0.9% (-18.8% to 20.7%). A latent class growth model analysis identified four discrete clusters with high accuracy, differentiated by baseline LCI and FEV1. Baseline LCI was the strongest factor associated with longitudinal change. The median total test time was under 19 min. CONCLUSIONS: Most patients with CF with well-preserved lung function show stable LCI over time. Cluster behaviours can be identified and baseline LCI is a risk factor for future progression. These results support the use of LCI in clinical practice in identifying patients at risk of lung function decline.

A Tale of Two Waves: Changes in the Use of Noninvasive Ventilation and Prone Positioning in Critical Care Management of Coronavirus Disease 2019.

New treatments and increased experience are changing the management of hospitalized coronavirus disease 2019 patients but the impact on ICU management is unclear. OBJECTIVES: To examine characteristics, ventilatory management, and outcomes of critically ill patients in two distinct waves of the pandemic. DESIGN SETTING AND PARTICIPANTS: Observational cohort study in an ICU in a single-center university-affiliated U.K. hospital. Two-hundred ten adults with coronavirus disease 2019 admitted to ICU between March 17, 2020, to May 31, 2020, and September 1, 2020, to December 10, 2020, with hourly data and 100% follow-up to ICU discharge. MAIN OUTCOMES AND MEASURES: Data were extracted from the electronic medical record for patient characteristics and clinical data. Patients were classified into distinct waves of the pandemic and assessed for differences between the two waves. RESULTS: The duration of noninvasive ventilation/nasal high flow increased in wave 2 versus wave 1, both in self-ventilating patients (107 vs 72 hr; p = 0.02), and in those ultimately requiring invasive mechanical ventilation (34 vs 10 hr; p = 0.02). The proportion of survivors treated without invasive mechanical ventilation increased in wave 2 (59% vs 39%; p = 0.01). In both waves, longer duration of noninvasive ventilation/nasal high flow prior to intubation was associated with higher ICU mortality (survivors 10 hr [4-21 hr] vs nonsurvivors 50 hr [23-124 hr]; p < 0.01). Proned invasive mechanical ventilation was common (54.7%) and prolonged. In wave 2, invasive mechanical ventilation patients were generally more hypoxic with proning initiated at lower Pao2/Fio2 ratios (81 vs 116 mm Hg; p = 0.02) and yielding smaller improvements in Fio2 requirements. Continued proning episodes despite poor responses were commonplace and typically futile. Length of stay for patients requiring tracheostomy increased markedly in wave 2 (51.3 vs 33.7 d; p = 0.03). Overall survival remained similar in wave 2 (68.0% vs 60.9%; p = 0.31). CONCLUSIONS AND RELEVANCE: Our data suggest that management of critically ill coronavirus disease 2019 patients is changing with more survivors avoiding invasive mechanical ventilation. Duration of noninvasive ventilation/nasal high flow use is increasing, which may be associated with worsening outcomes for individuals who require invasive mechanical ventilation. Among invasively ventilated patients, changes in the use of and response to prone positioning and increased length of stay following tracheostomy may imply that the care of these patients is becoming more challenging.

The assessment of a manikin-based low-dose, high-frequency cardiac resuscitation quality improvement program in early UK adopter hospitals.

BACKGROUND: Adult and paediatric basic life support (BLS) training are often conducted via group training with an accredited instructor every 24 months. Multiple studies have demonstrated a decline in the quality of cardio-pulmonary resuscitation (CPR) performed as soon as 3-month post-training. The 'Resuscitation Quality Improvement' (RQI) programme is a quarterly low-dose, high-frequency training, based around the use of manikins connected to a cart providing real-time and summative feedback. We aimed to evaluate the effects of the RQI Programme on CPR psychomotor skills in UK hospitals that had adopted this as a method of BLS training, and establish whether this program leads to increased compliance in CPR training. METHODS: The study took place across three adopter sites and one control site. Participants completed a baseline assessment without live feedback. Following this, participants at the adopter sites followed the RQI curriculum for adult CPR, or adult and infant CPR. The curriculum was split into quarterly training blocks, and live feedback was given on technique during the training session via the RQI cart. After following the curriculum for 12/24 months, participants completed a second assessment without live feedback. RESULTS: At the adopter sites, there was a significant improvement in the overall score between baseline and assessment for infant ventilations (N = 167, p < 0.001), adult ventilations (n = 129, p < 0.001), infant compressions (n = 163, p < 0.001) adult compressions (n = 205, p < 0.001), and adult CPR (n = 249, p < 0.001). There was no significant improvement in the overall score for infant CPR (n = 206, p = 0.08). Data from the control site demonstrated a statistically significant improvement in mean score for adult CPR (n = 22, p = 0.02), but not for adult compressions (N = 18, p = 0.39) or ventilations (n = 17, p = 0.08). No statistically significant difference in improvement of mean scores was found between the grouped adopter sites and the control site. The effect of the duration of the RQI curriculum on CPR performance appeared to be minimal in this data set. Compliance with the RQI curriculum varied by site, one site maintained hospital compliance at 90% over a 1 year period, however compliance reduced over time at all sites. CONCLUSIONS: This data demonstrated an increased adherence with guidelines for high-quality CPR post-training with the RQI cart, for all adult and most infant measures, but not infant CPR. However, the relationship between a formalised quarterly RQI curriculum and improvements in resuscitation skills is not clear. It is also unclear whether the RQI approach is superior to the current classroom-based BLS training for CPR skill acquisition in the UK. Further research is required to establish how to optimally implement the RQI system in the UK and how to optimally improve hospital wide compliance with CPR training to improve the outcomes of in-hospital cardiac arrests.

Donor insulin therapy in intensive care predicts early outcomes after pancreas transplantation.

AIMS/HYPOTHESIS: Approximately 50% of organ donors develop hyperglycaemia in intensive care, which is managed with insulin therapy. We aimed to determine the relationships between donor insulin use (DIU) and graft failure in pancreas transplantation. METHODS: UK Transplant Registry organ donor data were linked with national data from the UK solid pancreas transplant programme. All pancreas transplants performed between 2004 and 2016 with complete follow-up data were included. Logistic regression models determined associations between DIU and causes of graft failure within 3 months. Area under the receiver operating characteristic curve (aROC) and net reclassification improvement (NRI) assessed the added value of DIU as a predictor of graft failure. RESULTS: In 2168 pancreas transplant recipients, 1112 (51%) donors were insulin-treated. DIU was associated with a higher risk of graft loss from isolated islet failure: OR (95% CI), 1.79 (1.05, 3.07), p = 0.03, and this relationship was duration/dose dependent. DIU was also associated with a higher risk of graft loss from anastomotic leak (2.72 [1.07, 6.92], p = 0.04) and a lower risk of graft loss from thrombosis (0.62 [0.39, 0.96], p = 0.03), although duration/dose-dependent relationships were only identified in pancreas transplant alone/pancreas after kidney transplant recipients with grafts failing due to thrombosis (0.86 [0.74, 0.99], p = 0.03). The relationships between donor insulin characteristics and isolated islet failure remained significant after adjusting for potential confounders: DIU 1.75 (1.02, 2.99), p = 0.04; duration 1.08 (1.01, 1.16), p = 0.03. In multivariable analyses, donor insulin characteristics remained significant predictors of lower risk of graft thrombosis in pancreas transplant alone/pancreas after kidney transplant recipients: DIU, 0.34 (0.13, 0.90), p = 0.03; insulin duration/dose, 0.02 (0.001, 0.85), p = 0.04. When data on insulin were added to models predicting isolated islet failure, a significant improvement in discrimination and risk reclassification was observed in all models: no DIU aROC 0.56; DIU aROC 0.57, p = 0.86; NRI 0.28, p < 0.00001; insulin duration aROC 0.60, p = 0.47; NRI 0.35, p < 0.00001. CONCLUSIONS/INTERPRETATION: DIU predicts graft survival in pancreas transplant recipients. This assessment could help improve donor selection and thereby improve patient and graft outcomes.

Peri-transplant glycaemic control as a predictor of pancreas transplant survival.

AIMS: The relationship between peri-transplant glycaemic control and outcomes following pancreas transplantation is unknown. We aimed to relate peri-transplant glycaemic control to pancreas graft survival and to develop a framework for defining early graft dysfunction. METHODS: Peri-transplant glycaemic control profiles over the first 5 days postoperatively were determined by an area under the curve [AUC; average daily glucose level (mmol/L) × time (days)] and the coefficient of variation of mean daily glucose levels. Peri-transplant hyperglycaemia was defined as an AUC ≥35 mmol/day/L (daily mean blood glucose ≥7 mmol/L). Risks of graft failure associated with glycaemic control and variability and peri-transplant hyperglycaemia were determined using covariate-adjusted Cox regression. RESULTS: We collected 7606 glucose readings over 5 days postoperatively from 123 pancreas transplant recipients. Glucose AUC was a significant predictor of graft failure during 3.6 years of follow-up (unadjusted HR [95% confidence interval] 1.17 [1.06-1.30], P = .002). Death censored non-technical graft failure occurred in eight (10%) recipients with peri-transplant normoglycaemia, and eight (25%) recipients with peri-transplant hyperglycaemia such that hyperglycaemia predicted a 3-fold higher risk of graft failure [HR (95% confidence interval): 3.0 (1.1-8.0); P = .028]. CONCLUSION: Peri-transplant hyperglycaemia is strongly associated with graft loss and could be a valuable tool guiding individualized graft monitoring and treatment. The 5-day peri-transplant glucose AUC provides a robust and responsive framework for comparing graft function.

Diagnosis of Neuropathy and Risk Factors for Corneal Nerve Loss in Type 1 and Type 2 Diabetes: A Corneal Confocal Microscopy Study.

OBJECTIVE: To assess the diagnostic utility of corneal confocal microscopy (CCM) for diabetic peripheral neuropathy (DPN) and the risk factors for corneal nerve loss. RESEARCH DESIGN AND METHODS: A total of 490 participants, including 72 healthy control subjects, 149 with type 1 diabetes, and 269 with type 2 diabetes, underwent detailed assessment of peripheral neuropathy and CCM in relation to risk factors. RESULTS: Corneal nerve fiber density (CNFD) (P < 0.0001 and P < 0.0001), corneal nerve fiber branch density (CNBD) (P < 0.0001 and P < 0.0001), and corneal nerve fiber length (CNFL) (P < 0.0001 and P = 0.02) were significantly lower in patients with type 1 and type 2 diabetes compared with control subjects. CNFD (P < 0.0001), CNBD (P < 0.0001), and CNFL (P < 0.0001) were lower in type 1 diabetes compared with type 2 diabetes. Receiver operating characteristic curve analysis for the diagnosis of DPN demonstrated a good area under the curve for CNFD of 0.81, CNBD of 0.74, and CNFL of 0.73. Multivariable regression analysis showed a significant association among reduced CNFL with age (ß = -0.27, P = 0.007), HbA1c (ß = -1.1; P = 0.01), and weight (ß = -0.14; P = 0.03) in patients with type 2 diabetes and with duration of diabetes (ß = -0.13; P = 0.02), LDL cholesterol (ß = 1.8, P = 0.04), and triglycerides (ß = -2.87; P = 0.009) in patients with type 1 diabetes. CONCLUSIONS: CCM identifies more severe corneal nerve loss in patients with type 1 diabetes compared with type 2 diabetes and shows good diagnostic accuracy for DPN. Furthermore, the risk factors for a reduction in corneal nerve fiber length differ between type 1 and type 2 diabetes.

Use of Factory-Calibrated Real-time Continuous Glucose Monitoring Improves Time in Target and HbA1c in a Multiethnic Cohort of Adolescents and Young Adults With Type 1 Diabetes: The MILLENNIALS Study.

OBJECTIVE: International type 1 diabetes registries have shown that HbA1c levels are highest in young people with type 1 diabetes; however, improving their glycemic control remains a challenge. We propose that use of the factory-calibrated Dexcom G6 CGM system would improve glycemic control in this cohort. RESEARCH DESIGN AND METHODS: We conducted a randomized crossover trial in young people with type 1 diabetes (16-24 years old) comparing the Dexcom G6 CGM system and self-monitoring of blood glucose (SMBG). Participants were assigned to the interventions in random order during two 8-week study periods. During SMBG, blinded continuous glucose monitoring (CGM) was worn by each participant for 10 days at the start, week 4, and week 7 of the control period. HbA1c measurements were drawn after enrollment and before and after each treatment period. The primary outcome was time in range 70-180 mg/dL. RESULTS: Time in range was significantly higher during CGM compared with control (35.7 ± 13.5% vs. 24.6 ± 9.3%; mean difference 11.1% [95% CI 7.0-15.2]; P < 0.001). CGM use reduced mean sensor glucose (219.7 ± 37.6 mg/dL vs. 251.9 ± 36.3 mg/dL; mean difference -32.2 mg/dL [95% CI -44.5 to -20.0]; P < 0.001) and time above range (61.7 ± 15.1% vs. 73.6 ± 10.4%; mean difference 11.9% [95% CI -16.4 to -7.4]; P < 0.001). HbA1c level was reduced by 0.76% (95% CI -1.1 to -0.4) (-8.5 mmol/mol [95% CI -12.4 to -4.6]; P < 0.001). Times spent below range (<70 mg/dL and <54 mg/dL) were low and comparable during both study periods. Sensor wear was 84% during the CGM period. CONCLUSIONS: CGM use in young people with type 1 diabetes improves time in target and HbA1c levels compared with SMBG.

Donor insulin use predicts beta-cell function after islet transplantation.

Insulin is routinely used to manage hyperglycaemia in organ donors and during the peri-transplant period in islet transplant recipients. However, it is unknown whether donor insulin use (DIU) predicts beta-cell dysfunction after islet transplantation. We reviewed data from the UK Transplant Registry and the UK Islet Transplant Consortium; all first-time transplants during 2008-2016 were included. Linear regression models determined associations between DIU, median and coefficient of variation (CV) peri-transplant glucose levels and 3-month islet graft function. In 91 islet cell transplant recipients, DIU was associated with lower islet function assessed by BETA-2 scores (ß [SE] -3.5 [1.5], P = .02), higher 3-month post-transplant HbA1c levels (5.4 [2.6] mmol/mol, P = .04) and lower fasting C-peptide levels (-107.9 [46.1] pmol/l, P = .02). Glucose at 10 512 time points was recorded during the first 5 days peri-transplant: the median (IQR) daily glucose level was 7.9 (7.0-8.9) mmol/L and glucose CV was 28% (21%-35%). Neither median glucose levels nor glucose CV predicted outcomes post-transplantation. Data on DIU predicts beta-cell dysfunction 3 months after islet transplantation and could help improve donor selection and transplant outcomes.

Lung clearance index in healthy volunteers, measured using a novel portable system with a closed circuit wash-in.

INTRODUCTION: Lung clearance index (LCI) is a sensitive measure of early lung disease, but adoption into clinical practice has been slow. Challenges include the time taken to perform each test. We recently described a closed-circuit inert gas wash-in method that reduces overall testing time by decreasing the time to equilibration. The aim of this study was to define a normative range of LCI in healthy adults and children derived using this method. We were also interested in the feasibility of using this system to measure LCI in a community setting. METHODS: LCI was assessed in healthy volunteers at three hospital sites and in two local primary schools. Volunteers completed three washout repeats at a single visit using the closed circuit wash-in method (0.2% SF6 wash-in tracer gas to equilibrium, room air washout). RESULTS: 160 adult and paediatric subjects successfully completed LCI assessment (95%) (100 in hospital, 60 in primary schools). Median coefficient of variation was 3.4% for LCI repeats and 4.3% for FRC. Mean (SD) LCI for the analysis cohort (n = 53, age 5-39 years) was 6.10 (0.42), making the upper limit of normal LCI 6.8. There was no relationship between LCI and multiple demographic variables. Median (interquartile range) total test time was 18.7 (16.0-22.5) minutes. CONCLUSION: The closed circuit method of LCI measurement can be successfully and reproducibly measured in healthy volunteers, including in out-of-hospital settings. Normal range appears stable up to 39 years. With few subjects older than 40 years, further work is required to define the normal limits above this age.