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.

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.

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.

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.

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.

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.

Perceived benefits of sharing health data between people with epilepsy on an online platform.

An epilepsy community was developed on PatientsLikeMe.com to share data between patients to improve their outcomes by finding other patients like them. In a 14-day response period, 221 patients with epilepsy (mean age: 40 years, SD: 12, range: 17-72, 66% female) completed a survey about benefits they perceived. Prior to using the site, a third of respondents (30%) did not know anyone else with epilepsy with whom they could talk; of these, 63% now had at least one other patient with whom they could connect. Perceived benefits included: finding another patient experiencing the same symptoms (59%), gaining a better understanding of seizures (58%), and learning more about symptoms or treatments (55%). Number of benefits was associated with number of relationships with other patients, F(4,216)=8.173, P<0.001). Patients with epilepsy reported an array of perceived benefits similar to those reported by populations with other diseases. Controlled sharing of health data may have the potential to improve disease self-management of people with epilepsy.

Patient-reported outcomes as a source of evidence in off-label prescribing: analysis of data from PatientsLikeMe.

BACKGROUND: Evaluating a new use for an existing drug can be expensive and time consuming. Providers and patients must all too often rely upon their own individual-level experience to inform clinical practice, which generates only anecdotal and unstructured data. While academic-led clinical trials are occasionally conducted to test off-label uses of drugs with expired patents, this is relatively rare. In this work, we explored how a patient-centered online research platform could supplement traditional trials to create a richer understanding of medical products postmarket by efficiently aggregating structured patient-reported data. PatientsLikeMe is a tool for patients, researchers, and caregivers (currently 82,000 members across 11 condition-based communities) that helps users make treatment decisions, manage symptoms, and improve outcomes. Members enter demographic information, longitudinal treatment, symptoms, outcome data, and treatment evaluations. These are reflected back as longitudinal health profiles and aggregated reports. Over the last 3 years, patients have entered treatment histories and evaluations on thousands of medical products. These data may aid in evaluating the effectiveness and safety of some treatments more efficiently and over a longer period of time course than is feasible through traditional trials. OBJECTIVE: The objective of our study was to examine the illustrative cases of amitriptyline and modafinil - drugs commonly used off-label. METHODS: We analyzed patient-reported treatment histories and drug evaluations for each drug, examining prevalence, treatment purpose, and evaluations of effectiveness, side effects, and burden. RESULTS: There were 1948 treatment histories for modafinil and 1394 treatment reports for amitriptyline reported across five PatientsLikeMe communities (multiple sclerosis, Parkinson's disease, mood conditions, fibromyalgia/chronic fatigue syndrome, and amyotrophic lateral sclerosis). In these reports, the majority of members reported taking the drug for off-label uses. Only 34 of the 1755 (1%) reporting purpose used modafinil for an approved purpose (narcolepsy or sleep apnea). Only 104 out of 1197 members (9%) reported taking amitriptyline for its approved indication, depression. Members taking amitriptyline for off-label purposes rated the drug as more effective than those who were taking it for its approved indication. While dry mouth is a commonly reported side effect of amitriptyline for most patients, 88 of 220 (40%) of people with amyotrophic lateral sclerosis on the drug reported taking advantage of this side effect to treat their symptom of excess saliva. CONCLUSIONS: Patient-reported outcomes, like those entered within PatientsLikeMe, offer a unique real-time approach to understand utilization and performance of treatments across many conditions. These patient-reported data can provide a new source of evidence about secondary uses and potentially identify targets for treatments to be studied systematically in traditional efficacy trials.

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.

Modifiable barriers to enrollment in American ALS research studies.

Enrollment in ALS research studies is surprisingly low. Here we report on two online patient surveys that help identify some of the reasons. These include failure to invite patients to enroll, especially patients who have already participated in prior studies. Also included are patient concerns about the cost of participation, and confusion about several aspects of studies being offered. Along with prior work, these data suggest specific steps that can be taken to improve enrollment.

Sharing health data for better outcomes on PatientsLikeMe.

BACKGROUND: PatientsLikeMe is an online quantitative personal research platform for patients with life-changing illnesses to share their experience using patient-reported outcomes, find other patients like them matched on demographic and clinical characteristics, and learn from the aggregated data reports of others to improve their outcomes. The goal of the website is to help patients answer the question: "Given my status, what is the best outcome I can hope to achieve, and how do I get there?" OBJECTIVE: Using a cross-sectional online survey, we sought to describe the potential benefits of PatientsLikeMe in terms of treatment decisions, symptom management, clinical management, and outcomes. METHODS: Almost 7,000 members from six PatientsLikeMe communities (amyotrophic lateral sclerosis [ALS], Multiple Sclerosis [MS], Parkinson's Disease, human immunodeficiency virus [HIV], fibromyalgia, and mood disorders) were sent a survey invitation using an internal survey tool (PatientsLikeMe Lens). RESULTS: Complete responses were received from 1323 participants (19% of invited members). Between-group demographics varied according to disease community. Users perceived the greatest benefit in learning about a symptom they had experienced; 72% (952 of 1323) rated the site "moderately" or "very helpful." Patients also found the site helpful for understanding the side effects of their treatments (n = 757, 57%). Nearly half of patients (n = 559, 42%) agreed that the site had helped them find another patient who had helped them understand what it was like to take a specific treatment for their condition. More patients found the site helpful with decisions to start a medication (n = 496, 37%) than to change a medication (n = 359, 27%), change a dosage (n = 336, 25%), or stop a medication (n = 290, 22%). Almost all participants (n = 1,249, 94%) were diagnosed when they joined the site. Most (n = 824, 62%) experienced no change in their confidence in that diagnosis or had an increased level of confidence (n = 456, 34%). Use of the site was associated with increasing levels of comfort in sharing personal health information among those who had initially been uncomfortable. Overall, 12% of patients (n = 151 of 1320) changed their physician as a result of using the site; this figure was doubled in patients with fibromyalgia (21%, n = 33 of 150). Patients reported community-specific benefits: 41% of HIV patients (n = 72 of 177) agreed they had reduced risky behaviors and 22% of mood disorders patients (n = 31 of 141) agreed they needed less inpatient care as a result of using the site. Analysis of the Web access logs showed that participants who used more features of the site (eg, posted in the online forum) perceived greater benefit. CONCLUSIONS: We have established that members of the community reported a range of benefits, and that these may be related to the extent of site use. Third party validation and longitudinal evaluation is an important next step in continuing to evaluate the potential of online data-sharing platforms.

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.

Design, power, and interpretation of studies in the standard murine model of ALS.

Identification of SOD1 as the mutated protein in a significant subset of familial amyotrophic lateral sclerosis (FALS) cases has led to the generation of transgenic rodent models of autosomal dominant SOD1 FALS. Mice carrying 23 copies of the human SOD1(G93A) transgene are considered the standard model for FALS and ALS therapeutic studies. To date, there have been at least 50 publications describing therapeutic agents that extend the lifespan of this mouse. However, no therapeutic agent besides riluzole has shown corresponding clinical efficacy. We used computer modeling and statistical analysis of 5429 SOD1(G93A) mice from our efficacy studies to quantify the impact of several critical confounding biological variables that must be appreciated and should be controlled for when designing and interpreting efficacy studies. Having identified the most critical of these biological variables, we subsequently instituted parameters for optimal study design in the SOD1(G93A) mouse model. We retested several compounds reported in major animal studies (minocycline, creatine, celecoxib, sodium phenylbutyrate, ceftriaxone, WHI-P131, thalidomide, and riluzole) using this optimal study design and found no survival benefit in the SOD1(G93A) mouse for any compounds (including riluzole) administered by their previously reported routes and doses. The presence of these uncontrolled confounding variables in the screening system, and the failure of these several drugs to demonstrate efficacy in adequately designed and powered repeat studies, leads us to conclude that the majority of published effects are most likely measurements of noise in the distribution of survival means as opposed to actual drug effect. We recommend a minimum study design for this mouse model to best address and manage this inherent noise and to facilitate more significant and reproducible results among all laboratories employing the SOD1(G93A) mouse.

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.