Wild type cardiac amyloidosis: is it time to order a nuclear technetium pyrophosphate SPECT imaging study?

Transthyretin (ATTR) amyloidosis is a debilitating systemic disease often associated with symptomatic cardiac involvement. Diagnosis has dramatically changed with the advent of Technetium-99 m pyrophosphate (Tc-PYP) single-photon emission computed tomography (SPECT). With the ability to diagnose ATTR amyloidosis noninvasively and offer newer therapies, it is increasingly important to identify which patients should be referred for this testing. Relative apical sparing of longitudinal strain on echocardiogram can be potentially used to screen such patients. We sought to describe electrocardiogram (ECG) and echocardiogram (TTE) findings, including relative apical sparing of longitudinal strain, in ATTR amyloidosis patients diagnosed non-invasively with 99mTc-PYP imaging. This was a single-center, retrospective study with 64 patients who underwent 99mTc-PYP imaging between June 2016 and February 2019. Relative apical longitudinal strain was calculated from left ventricular longitudinal strain (LV LS) values. No ECG parameters were meaningfully associated with of 99 m Tc-PYP positive patients. LV mass index (p = 0.001), IVSd (p < 0.001), and LVPWd (< 0.001) demonstrated a highly significant difference between positive and negative 99mTc-PYP groups. 99mTc-PYP positive patients had a higher relative apical sparing of LV LS (p < 0.001), and notably, no 99mTc-PYP negative patient had a ratio > 1.0. The finding of relative apical sparing of longitudinal strain can reliably guide clinicians in triaging which patients to consider ordering 99mTc-PYP imaging for the noninvasive diagnosis of wild type cardiac amyloidosis. A patient with clinically suggestive features and an LV LS relative apical sparing ratio > 0.8 can be considered for 99mTc-PYP imaging to evaluate for ATTR cardiac amyloidosis.

SLE strikes the heart! A rare presentation of SLE myocarditis presenting as cardiogenic shock.

BACKGROUND: Although systemic lupus erythematosus (SLE) can affect the cardiovascular system in many ways with diverse presentations, a severe cardiogenic shock secondary to SLE myocarditis is infrequently described in the medical literature. Variable presenting features of SLE myocarditis can also make the diagnosis challenging. This case report will allow learners to consider SLE myocarditis in the differential and appreciate the diagnostic uncertainty. CASE PRESENTATION: A 20-year-old Filipino male presented with acute dyspnea, pleuritic chest pain, fevers, and diffuse rash after being diagnosed with SLE six months ago and treated with hydroxychloroquine. Labs were notable for leukopenia, non-nephrotic range proteinuria, elevated cardiac biomarkers, inflammatory markers, low complements, and serologies suggestive of active SLE. Broad-spectrum IV antibiotics and corticosteroids were initiated for sepsis and SLE activity. Blood cultures were positive for MSSA with likely skin source. An electrocardiogram showed diffuse ST-segment elevations without ischemic changes. CT chest demonstrated bilateral pleural and pericardial effusions with dense consolidations. Transthoracic and transesophageal echocardiogram demonstrated reduced left ventricular ejection fraction (LVEF) 45% with no valvular pathology suggestive of endocarditis. Although MSSA bacteremia resolved, the patient rapidly developed cardiopulmonary decline with a repeat echocardiogram demonstrating LVEF < 10%. A Cardiac MRI was a nondiagnostic study to elucidate an etiology of decompensation given inability to perform late gadolinium enhancement. Later, cardiac catheterization revealed normal cardiac output with non-obstructive coronary artery disease. As there was no clear etiology explaining his dramatic heart failure, endomyocardial biopsy was obtained demonstrating diffuse myofiber degeneration and inflammation. These pathological findings, in addition to skin biopsy demonstrating lichenoid dermatitis with a granular "full house" pattern was most consistent with SLE myocarditis. Furthermore, aggressive SLE-directed therapy demonstrated near full recovery of his heart failure. CONCLUSION: Although myocarditis during SLE flare is a well-described cardiac manifestation, progression to cardiogenic shock is infrequent and fatal. As such, SLE myocarditis should be promptly considered. Given the heterogenous presentation of SLE, combination of serologic evaluation, advanced imaging, and myocardial biopsies can be helpful when diagnostic uncertainty exists. Our case highlights diagnostic methods and clinical course of a de novo presentation of cardiogenic shock from SLE myocarditis, then rapid improvement.

Clinical Utility of Fluid Volume Assessment in Heart Failure Patients Using Bioimpedance Spectroscopy.

Background: Bioimpedance spectroscopy (BIS) is a non-invasive method used to measure fluid volumes. In this report, we compare BIS measurements from patients with heart failure (HF) to those from healthy adults, and describe how these point-of-care fluid volume assessments may be applied to HF management. Methods and results: Fluid volumes were measured in 64 patients with NYHA class II or III HF and 69 healthy control subjects. BIS parameters including extracellular fluid (ECF), intracellular fluid (ICF), total body water (TBW), and ECF as a percentage of TBW (ECF%TBW) were analyzed. ECF%TBW values for the HF and control populations differed significantly (49.2 ± 3.2% vs. 45.2 ± 2.1%, respectively; p < 0.001); both distributions satisfied criteria for normality. Interquartile ranges did not overlap (46.7-51.0% vs. 43.8-46.4%, respectively; p < 0.001). Subgroup analyses of HF patients who underwent transthoracic echocardiography showed that impedance measurements correlated with inferior vena cava size (Pearson correlation -0.73, p < 0.0001). A case study is presented for illustrative purposes. Conclusions: BIS-measured ECF%TBW values were significantly higher in HF patients as compared to adults without HF. We describe three strata of ECF%TBW (normal, elevated, fluid overload) that may aid in clinical risk stratification and fluid volume monitoring of HF patients. Clinical Trial Registration: COMPARE - www.ClinicalTrials.gov; IMPEL - www.ClinicalTrials.gov; Heart Failure at Home - www.ClinicalTrials.gov, identifier: NCT02939053; NCT02857231; NCT04013373.

Novel doses of sacubitril/valsartan in patients unable to tolerate traditional therapy: Effects on N-terminal pro B-type natriuretic peptide levels.

BACKGROUND: Widespread use of angiotensin receptor blocker and neprilysin inhibitor (ARNI) remains low, and many patients are unable to tolerate the medication due to hypotension at the currently recommended starting dose. HYPOTHESIS: The aim of this study is to assess if lower than standard doses of ARNI, sacubitril/valsartan (S/V), significantly reduces NT-proBNP and leads to any change in diuretic dose, serum potassium, or creatinine. METHODS: In a retrospective study of 278 patients who were started on a low dose S/V at a single medical center, 45 patients were selected for the study cohort. Patients were subcategorized to Group 1 (n = 10): very low dose S/V (half a tab of 24/26 mg BID), Group 2 (n = 10): very low dose titrated to low dose S/V, and Group 3 (n = 25): low dose S/V (24/26 mg BID). NT-proBNP, diuretic dose, serum potassium, and creatinine were compared before and after initiation of S/V. RESULTS: Among all groups, there was a significant reduction in NT-proBNP level (Group 1: p < .01, Group 2: p < .01, and Group 3: p < .001). In addition, there was a significant reduction in diuretic dose across all groups combined (furosemide 53 mg/day vs. 73 mg/day; p = .03), with 17.8% (8/45) patients being able to discontinue their diuretic completely. There was no significant change in potassium or creatinine. CONCLUSIONS: Lower than standard dose of S/V significantly reduces NT-proBNP and diuretic requirement without change in potassium or creatinine, which provides hope that patients who cannot tolerate standard doses of S/V due to hypotension may be able to receive the benefits of S/V therapy.

A Modular Health-Related Quality of Life Instrument for Electronic Assessment and Treatment Monitoring: Web-Based Development and Psychometric Validation of Core Thrive Items.

BACKGROUND: Patient-reported outcome (PRO) measures describe natural history, manage disease, and measure the effects of interventions in trials. Patients themselves increasingly use Web-based PRO tools to track their progress, share their data, and even self-experiment. However, existing PROs have limitations such as being: designed for paper (not screens), long and burdensome, negatively framed, under onerous licensing restrictions, either too generic or too specific. OBJECTIVE: This study aimed to develop and validate the core items of a modular, patient-centric, PRO system (Thrive) that could measure health status across a range of chronic conditions with minimal burden. METHODS: Thrive was developed in 4 phases, largely consistent with Food and Drug Administration guidance regarding PRO development. First, preliminary core items (common across multiple conditions: core Thrive items) were developed through literature review, analysis of approximately 20 existing PROs on PatientsLikeMe, and feedback from psychometric and content experts. Second, 2 rounds of cognitive interviews were iteratively conducted with patients (N=14) to obtain feedback on the preliminary items. Third, core Thrive items were administered electronically along with comparator measures, including 20-item Short-Form General Health Survey (SF)-20 and Patient Health Questionnaire (PHQ)-9, to a large sample (N=2002) of adults with chronic diseases through the PatientsLikeMe platform. On the basis of theoretical and empirical rationale, items were revised or removed. Fourth, the revised core Thrive items were administered to another sample of patients (N=704) with generic and condition-specific comparator measures. A psychometric evaluation, which included both modern and classical test theory approaches, was conducted on these items, and several more items were removed. RESULTS: Cognitive interviews helped to remove confusing or redundant items. Empirical testing of subscales revealed good internal consistency (Cronbach alpha=.712-.879), test-retest reliability (absolute intraclass correlations=.749-.912), and convergent validity with legacy PRO scales (eg, Pearson r=.5-.75 between Thrive subscales and PHQ-9 total). The finalized instrument consists of a 19-item core including 5 multi-item subscales: Core symptoms, Abilities, Mobility, Sleep, and Thriving. Results provide evidence of construct (content, convergent) validity, high levels of test-retest and internal consistency reliability, and the ability to detect change over time. The items did not exhibit bias based on gender or age, and the items generally functioned similarly across conditions. These results support the use of Thrive Core items across diverse chronic patient populations. CONCLUSIONS: Thrive appears to be a useful approach for capturing important domains for patients with chronic conditions. This core set serves as a foundation to begin developing modular condition-specific versions in the near future. Cross-walking against traditional PROs from the PatientsLikeMe platform is underway, in addition to clinical validation and comparison with biomarkers. Thrive is licensed under Creative Commons Attribution ShareAlike 4.0.

Stiff Left Atrial Syndrome; Prospects and Possibilities. Retrospective Analysis and Review of the Literature.

OBJECTIVES: Stiff left atrial syndrome is an intriguing clinical phenomena characterized by reduced left atrial compliance, pulmonary venous hypertension and exacerbations of volume overload. We conducted a retrospective review of patients diagnosed with stiff left atrial syndrome at our center. METHODS: All patients admitted to our hospital with volume overload and pulmonary venous hypertension who were diagnosed with stiff left atrial syndrome based on evidence by echocardiogram and right heart catheterization between July 2011 and July 2013 were included in this retrospective review. RESULTS: Twentythree patients (mean age 73 ± 11 years, 39% male and 61% female) were diagnosed with stiff left atrial syndrome at our center. Thirty-five percent had persistent while 39% had permanent atrial fibrillation. Mean duration of atrial fibrillation was 7.6 ± 2.1 years. Forty-three percent of patients had long standing hypertension. There was no mitral regurgitation in 39% of patients while 48% had mild mitral regurgitation. On right heart catheterization, mean right atrial pressure was 12.6±4.8 mm of Hg, mean pulmonary arterial pressure was 33±7.2 mm of Hg, mean pulmonary capillary wedge pressure was 24.8± 4.2mm of Hg while peak V waves were seen at mean of 37.8± 5.3 mm of Hg. Mean left atrial volume index was 49.8±17.1 mL/m 2. After the initial diagnosis with a two year follow- up, there were no readmissions in 65% of patients who were on appropriate diuretic therapy and had regular clinical visits. Frequent readmissions were seen in 35% of patients inspite of appropriate diuretic therapy. All-cause mortality rate was 4.3% at two year follow up. CONCLUSION: In patients with stiff left atrial syndrome, the presence of left atrial dilation, long standing atrial fibrillation and hypertension are the key factors associated with pathogenesis and clinical course. Close follow up and monitoring of volume status is essential to prevent hospital readmissions and improve long term prognosis.

The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic ß cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs. METHODS: DILfrequency is a nonrandomized, open-label, response-adaptive study of participants, aged 18-70 years, with T1D. The initial learning phase allocated 12 participants to 6 different predefined regimens. Then, 3 cohorts of 8 participants were sequentially allocated dose frequencies, based on repeated interim analyses of all accumulated trial data. The coprimary endpoints were percentage change in Tregs and Teffs and CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. RESULTS: Thirty-eight participants were enrolled, with thirty-six completing treatment. The optimal regimen to maintain a steady-state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI -0.007 to 0.485) every 3 days. Tregs and CD25 were dose-frequency responsive, Teffs were not. The commonest adverse event was injection site reaction (464 of 694 events). CONCLUSIONS: Using a response-adaptive design, aldesleukin treatment can be optimized. Our methodology can generally be employed to immediately access proof of mechanism, thereby leading to more efficient and safe drug development. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register, ISRCTN40319192; ClinicalTrials.gov, NCT02265809. FUNDING: Sir Jules Thorn Trust, the Swiss National Science Foundation, Wellcome, JDRF, and NIHR Cambridge Biomedical Research Centre.

PATIENT-CENTERED DECISION MAKING: LESSONS FROM MULTI-CRITERIA DECISION ANALYSIS FOR QUANTIFYING PATIENT PREFERENCES.

OBJECTIVES: Patient preferences should be a central consideration in healthcare decision making. However, stories of patients challenging regulatory and reimbursement decisions has led to questions on whether patient voices are being considered sufficiently during those decision making processes. This has led some to argue that it is necessary to quantify patient preferences before they can be adequately considered. METHODS: This study considers the lessons from the use of multi-criteria decision analysis (MCDA) for efforts to quantify patient preferences. It defines MCDA and summarizes the benefits it can provide to decision makers, identifies examples of MCDAs that have involved patients, and summarizes good practice guidelines as they relate to quantifying patient preferences. RESULTS: The guidance developed to support the use of MCDA in healthcare provide some useful considerations for the quantification of patient preferences, namely that researchers should give appropriate consideration to: the heterogeneity of patient preferences, and its relevance to decision makers; the cognitive challenges posed by different elicitation methods; and validity of the results they produce. Furthermore, it is important to consider how the relevance of these considerations varies with the decision being supported. CONCLUSIONS: The MCDA literature holds important lessons for how patient preferences should be quantified to support healthcare decision making.

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the ß chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.

Aquapheresis Versus Intravenous Diuretics and Hospitalizations for Heart Failure.

OBJECTIVES: The AVOID-HF (Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure) trial tested the hypothesis that patients hospitalized for HF treated with adjustable ultrafiltration (AUF) would have a longer time to first HF event within 90 days after hospital discharge than those receiving adjustable intravenous loop diuretics (ALD). BACKGROUND: Congestion in hospitalized heart failure (HF) patients portends unfavorable outcomes. METHODS: The AVOID-HF trial, designed as a multicenter, 1-to-1 randomized study of 810 hospitalized HF patients, was terminated unilaterally and prematurely by the sponsor (Baxter Healthcare, Deerfield, Illinois) after enrollment of 224 patients (27.5%). Aquadex FlexFlow System (Baxter Healthcare) was used for AUF. A Clinical Events Committee, blinded to the randomized treatment, adjudicated whether 90-day events were due to HF. RESULTS: A total of 110 patients were randomized to AUF and 114 to ALD. Baseline characteristics were similar. Estimated days to first HF event for the AUF and ALD group were, respectively, 62 and 34 (p = 0.106). At 30 days, compared with the ALD group, the AUF group had fewer HF and cardiovascular events. Renal function changes were similar. More AUF patients experienced an adverse effect of special interest (p = 0.018) and a serious study product-related adverse event (p = 0.026). The 90-day mortality was similar. CONCLUSIONS: Compared with the ALD group, the AUF group trended toward a longer time to first HF event within 90 days and fewer HF and cardiovascular events. More patients in the AUF group experienced special interest or serious product-related adverse event. Due to the trial's untimely termination, additional AUF investigation is warranted.

New approach for analyzing self-reporting of insomnia symptoms reveals a high rate of comorbid insomnia across a wide spectrum of chronic diseases.

BACKGROUND: Insomnia is increasingly recognized to be comorbid with one or more medical conditions. This study used an online research platform to characterize insomnia across different mental and physical conditions. METHODS: A custom cross-sectional survey was fielded online to 31,208 users of the patient community PatientsLikeMe. The survey queried members on National Sleep Foundation-defined insomnia risk (waking up feeling unrefreshed, difficulty falling asleep, waking in the middle of the night, or waking too early). RESULTS: Complete results were obtained from 5256 patients with 11 comorbid conditions. Seventy-six percent of US-based respondents were at risk for insomnia. Patients who reported difficulty falling asleep were found to have nearly twice the odds of self-reporting insomnia (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.5-2.1) when compared to those who do not have difficulty falling asleep, whereas those who reported waking during the night or waking up unrefreshed were no more likely (OR: 1.025 and 1.032, respectively) to report that they suffered from insomnia than those who did not experience these issues. Although insomnia was self-reported as severe or very severe across most conditions, few respondents had actually been diagnosed with insomnia by a physician. After adjustment for age and gender, there was an independent and strong effect of primary condition severity on insomnia risk, and those with severe epilepsy (0.93), depressive disorders (0.92), and fibromyalgia (0.92) occupied the highest risk probabilities. CONCLUSIONS: The high rate of severity and frequency of insomnia across a multitude of mental and physical conditions reveals an opportunity for better disease management through enhanced insomnia awareness.

Effective recruitment of participants to a phase I study using the internet and publicity releases through charities and patient organisations: analysis of the adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D).

BACKGROUND: A barrier to the successful development of new disease treatments is the timely recruitment of participants to experimental medicine studies that are primarily designed to investigate biological mechanisms rather than evaluate clinical efficacy. The aim of this study was to analyse the performance of three recruitment sources and the effect of publicity events during the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D). METHODS: The final study outcome, demography, disease duration, residence and the effect of publicity events on the performance of three recruitment sources (clinics, type 1 diabetes (T1D) disease register and the internet) were analysed from a bespoke DILT1D recruitment database. For the internet source, the origin of website hits in relation to publicity events was also evaluated. RESULTS: A total of 735 potentially eligible participants were approached to identify the final 45 DILT1D participants. A total of 477 (64%) were identified via the disease register, but only 59 (12%) responded to contact. A total of 317 individuals registered with the DILT1D study team. Self-referral via the study website generated 170 (54%) registered individuals and was the most popular and successful source, with 88 (28%) sourced from diabetes clinics and 59 (19%) from the disease register. Of those with known T1D duration (N = 272), the internet and clinics sources identified a larger number (57, 21%) of newly diagnosed T1D (<100 days post-diagnosis) compared to the register (1, 0.4%). The internet extended the geographical reach of the study, enabling both national and international participation. Targeted website posts and promotional events from organisations supporting T1D research and treatment during the trial were essential to the success of the internet recruitment strategy. CONCLUSIONS: Analysis of the DILT1D study recruitment outcomes illustrates the utility of an active internet recruitment strategy, supported by patient groups and charities, funding agencies and sponsors, in successfully conducting an early phase study in T1D. This recruitment strategy should now be evaluated in late-stage trials to develop treatments for T1D and other diseases. TRIAL REGISTRATION: NCT01827735 (registered: 4 April 2013); ISRCTN27852285 (registered: 23 March 2013); DRN767 (registered: 21 January 2013).

The contribution of glycemic control to impaired growth during puberty in young people with type 1 diabetes and microalbuminuria.

BACKGROUND: In adults with type 1 diabetes (T1D), short stature has been associated with risk for cardiovascular disease and nephropathy. However, there are no available data on the potential relationship between growth patterns during puberty and the development of vascular complications. Our aim was to assess whether pubertal growth is impaired in young people with T1D who develop microalbuminuria (MA). METHODS: Repeated height measurements performed during adolescence were available for 206 young people (107 boys) with T1D followed in the Oxford Regional Prospective Study. Longitudinal data on albumin-creatinine ratios and hemoglobin A1c (HbA1c) were also collected from the study participants. Height standard deviations score (SDS) was compared between subjects with (MA+; n = 66) and without MA (MA-; n = 140). RESULTS: In the group as a whole, mean [95% CI] height SDS progressively declined during puberty, from 0.145 [0.015; 0.274] to -0.003 [-0.145; 0.138], p < 0.001. However, the decline in height SDS was significantly different between the MA+ and MA- groups (p = 0.023), with a mean difference in final height of 4.29 [1.87; 6.72] cm, p = 0.001. Final height was inversely associated with MA (HR [95%CI]: 0.942 [0.908; 0.979], p = 0.002), although this association was no longer significant after adjusting for HbA1c, which was higher in the MA+ group. CONCLUSION: In this study, we found a significant impairment in growth during puberty in young people with T1D, particularly in those developing MA. Poor glycemic control as well as other genetic or environmental factors could explain these associations.

Home urine C-peptide creatinine ratio (UCPCR) testing can identify type 2 and MODY in pediatric diabetes.

BACKGROUND: Making the correct diabetes diagnosis in children is crucial for lifelong management. Type 2 diabetes and maturity onset diabetes of the young (MODY) are seen in the pediatric setting, and can be difficult to discriminate from type 1 diabetes. Postprandial urinary C-peptide creatinine ratio (UCPCR) is a non-invasive measure of endogenous insulin secretion that has not been tested as a diagnostic tool in children or in patients with diabetes duration <5 yr. We aimed to assess whether UCPCR can discriminate type 1 diabetes from MODY and type 2 in pediatric diabetes. METHODS: Two-hour postprandial UCPCR was measured in 264 patients aged <21 yr (type 1, n = 160; type 2, n = 41; and MODY, n = 63). Receiver operating characteristic curves were used to identify the optimal UCPCR cutoff for discriminating diabetes subtypes. RESULTS: UCPCR was lower in type 1 diabetes [0.05 (<0.03-0.39) nmol/mmol median (interquartile range)] than in type 2 diabetes [4.01 (2.84-5.74) nmol/mmol, p < 0.0001] and MODY [3.51 (2.37-5.32) nmol/mmol, p < 0.0001]. UCPCR was similar in type 2 diabetes and MODY (p = 0.25), so patients were combined for subsequent analyses. After 2-yr duration, UCPCR ≥ 0.7 nmol/mmol has 100% sensitivity [95% confidence interval (CI): 92-100] and 97% specificity (95% CI: 91-99) for identifying non-type 1 (MODY + type 2 diabetes) from type 1 diabetes [area under the curve (AUC) 0.997]. UCPCR was poor at discriminating MODY from type 2 diabetes (AUC 0.57). CONCLUSIONS: UCPCR testing can be used in diabetes duration greater than 2 yr to identify pediatric patients with non-type 1 diabetes. UCPCR testing is a practical non-invasive method for use in the pediatric outpatient setting.

Threshold crossing of device-based intrathoracic impedance trends identifies relatively increased mortality risk.

AIMS: Threshold crossings of impedance trends detected by implanted devices have been associated with clinically relevant heart failure events, but long-term prognosis of such events has not been demonstrated. The aim of this study is to examine the relationship between alterations in intrathoracic impedance and mortality risk in patients with implantable devices. METHODS AND RESULTS: We reviewed remote monitoring data in the de-identified Medtronic CareLink(®) Discovery Link that captured intrathoracic impedance trends for >6 months. The initial 6 months of the cardiac and impedance trends were used as the observation period to create the patient groups and cross-referenced with the Social Security Death Index for mortality data. In our study cohort of 21 217 patients, 36% experienced impedance threshold crossing within the initial 6 months of monitoring (defined as the 'early threshold crossing' group). Patients with early threshold crossings demonstrated an increased risk of age- and gender-adjusted all-cause mortality [hazard ratio (HR) 2.15, 95% confidence interval (CI) 1.95-2.38, P< 0.0001]. Increased mortality risk remained significant when analysed in subgroups of patients without defibrillator shock (HR 2.10, 95% CI 1.90-2.34, P< 0.0001, n= 1621) or within those patients without device-detectable atrial fibrillation (AF) during the initial 6 months of monitoring (HR 2.09, 95% CI 1.86-2.34, P< 0.0001, n= 17 235). Both the number and the duration of early threshold crossings of impedance trends detectable by implanted devices were associated with increased mortality risk. Furthermore, the improvement of altered impedance trends portends more favourable prognosis. CONCLUSIONS: Threshold crossing of impedance trends detectable by implanted devices is associated with relatively increased mortality risk even after adjusted for demographic, device-detected AF, or defibrillator shocks.

An independent effect of parental lipids on the offspring lipid levels in a cohort of adolescents with type 1 diabetes.

BACKGROUND: Genetic factors modulate lipid levels and an intrafamilial aggregation of abnormal lipid profiles has been reported in the general population. As dyslipidemia is common among people with diabetes and has been related to diabetic nephropathy, we investigated whether parental lipid levels were related to lipids and albumin excretion in young offspring with childhood-onset type 1 diabetes (T1D). METHODS: Non-fasting blood samples were collected from 895 offspring, 808 mothers and 582 fathers. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and non-HDL-C were measured. Three early morning urinary albumin-creatinine ratios (ACR), hemoglobin A1C (HbA1c) and anthropometric parameters were also assessed. RESULTS: The offspring's mean age (±SD) was 14.5 ± 2.2 yr, mean diabetes duration 5.5 ± 3.7 yr; the fathers' age was 45.7 ± 6.1 yr and the mothers' age was 42.8 ± 5.5 yr. After adjusting for the offspring age, gender, body mass index, HbA1c, maternal (TC: ß = 0.242; TG: ß = 0.152; HDL-C: ß = 0.285; LDL-C: ß = 0.278; non-HDL-C: ß = 0.253; all p < 0.001) and paternal lipid levels (TC: ß = 0.188; TG: ß = 0.108; HDL-C: ß = 0.253; LDL-C: ß = 0.187; non-HDL-C: ß = 0.173; all p < 0.001) were significantly associated with the offspring's lipid parameters. In contrast, no significant association was found between parental lipid levels and the offspring's ACR. CONCLUSIONS: In the present study, parental lipid levels were independently associated with the same traits in the offspring, suggesting a role of genetic influences and/or shared environmental factors in modulating the metabolic profile of adolescents with T1D. In contrast, there was no significant association between parental lipid levels and the offspring's albumin excretion.