Tamoxifen may contribute to preserve cardiac function in Duchenne muscular dystrophy.

Duchenne muscular dystrophy is life-limiting. Cardiomyopathy, which mostly ensues in the second decade of life, is the main cause of death. Treatment options are still limited. The TAMDMD (NCT03354039) trial assessed motor function, muscle strength and structure, laboratory biomarkers, and safety in 79 ambulant boys with genetically confirmed Duchenne muscular dystrophy, 6.5-12 years of age, receiving either daily tamoxifen 20 mg or placebo for 48 weeks. In this post-hoc analysis, available echocardiographic data of ambulant patients recruited at one study centre were retrieved and compared before and after treatment. Data from 14 patients, median 11 (interquartile range, IQR, 11-12) years of age was available. Baseline demographic characteristics were similar in participants assigned to placebo (n = 7) or tamoxifen (n = 7). Left ventricular end-diastolic diameter in the placebo group (median and IQR) was 39 (38-41) mm at baseline and 43 (38-44) mm at study end, while it was 44 (41-46) mm at baseline and 41 (37-46) mm after treatment in the tamoxifen group. Left ventricular fractional shortening in the placebo group was 35% (32-38%) before and 33% (32-36%) after treatment, while in the tamoxifen group it was 34% (33-34%) at baseline and 35% (33-35%) at study end. No safety signals were detected. CONCLUSION: This hypothesis-generating post-hoc analysis suggests that tamoxifen over 48 weeks is well tolerated and may help preserving cardiac structure and function in Duchenne muscular dystrophy. Further studies are justified. CLINICALTRIALS: gov Identifier: EudraCT 2017-004554-42, NCT03354039 What is known: • Duchenne muscular dystrophy (DMD) is life-limiting. Cardiomyopathy ensues in the second decade of life and is the main cause of death. Treatment options are still limited. • Tamoxifen reduced cardiac fibrosis in mice and improved cardiomyocyte function in human-induced pluripotent stem cell-derived cardiomyocytes. WHAT IS NEW: • In this post-hoc analysis of the TAMDMD trial among 14 boys, median 11 years of age, treated with either tamoxifen or placebo for 48 weeks, treatment was well-tolerated. • A visual trend of improved left-ventricular dimensions and better systolic function preservation generates the hypothesis of a potential beneficial effect of tamoxifen in DMD cardiomyopathy.

Glucose control after glucocorticoid administration in hospitalized patients - a retrospective analysis.

BACKGROUND: Glucocorticoid (GC)-induced hyperglycemia is a frequent adverse effect in hospitalized patients. Guidelines recommend insulin treatment to a target range of 6-10 mmol/L (108-180 mg/dl), but efficacies of particular regimes have not been well-studied. METHODS: In this retrospective cohort study, hospitalized patients receiving GCs at the medical ward were analyzed by treatment (basal-bolus vs. bolus-only vs. pre-mixed insulin) and compared to a non-insulin-therapy reference group. Coefficients of glucose variation (CV), percentage of glucose readings in range (4-10 mmol/L (72-180 mg/dl)) and hypoglycemia (< 4 mmol/L (< 72 mg/dl)) were evaluated. RESULTS: Of 2424 hospitalized patients receiving systemic GCs, 875 (36%) developed GC-induced hyperglycemia. 427 patients (17%) had a previous diagnosis of diabetes. Adjusted relative risk ratios (RRR) for the top tertile of CV (> 29%) were 1.47 (95% Cl 1.01-2.15) for bolus-only insulin, 4.77 (95% CI 2.67-8.51) for basal-bolus insulin, and 4.98 (95% CI 2.02-12.31) for premixed insulin, respectively. Adjusted RRR for percentages of glucose readings in range were 0.98 (95% Cl 0.97-0.99) for basal-bolus insulin, 0.99 (95% Cl 0.98-1.00) for premixed insulin, and 1.01 (95% Cl 1.00-1.01) for bolus-only insulin, respectively. Adjusted RRR for hypoglycemia was 13.17 (95% Cl 4.35-39.90) for basal-bolus insulin, 8.92 (95% Cl 2.60-30.63) for premixed insulin, and 2.99 (95% Cl 1.01-8.87) for bolus-only insulin, respectively. CONCLUSIONS: Current guidelines recommend a basal-bolus regimen for treatment of GC-induced hyperglycemia, but we found similar outcomes with pre-mixed and bolus-only insulin regimens. As GC-induced hyperglycemia is a frequent issue in hospitalized patients, it might be reasonable to prospectively study the ideal regimen.

Treatment of glucocorticoid- induced hyperglycemia in hospitalized patients - a systematic review and meta- analysis.

PURPOSE: Glucocorticoid (GC)-induced hyperglycemia is a frequent issue, however there are no specific guidelines for this diabetes subtype. Although treat-to-target insulin is recommended in general to correct hyperglycemia, it remains unclear which treatment strategy has a positive effect on outcomes. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess whether treating GC-induced hyperglycemia improves clinical outcomes. METHODS: MEDLINE and EMBASE were systematically searched for RCTs on adults reporting treatment and outcomes of GC-induced hyperglycemia since the beginning of the data bases until October 21, 2023. Glucose-lowering strategies as compared to usual care were investigated. RESULTS: We found 17 RCTs with 808 patients and included seven trials in the quantitative analysis. Patients with an intensive glucose-lowering strategy had lower standardized mean glucose levels of - 0.29 mmol/l (95%CI -0.64 to -0.05) compared to usual care group patients. There was no increase in hypoglycemic events in the intensively treated groups (RR 0.91, 95%CI 0.70-1.17). Overall, we did not have enough trials reporting clinical outcomes for a quantitative analysis with only one trial reporting mortality. CONCLUSION: In GC-induced hyperglycemia, tight glucose control has a moderate effect on mean glucose levels with no apparent harmful effect regarding hypoglycemia. There is insufficient data whether insulin treatment improves clinical outcomes, and data on non-insulin based treatment regimens are currently too sparse to draw any conclusions. SYSTEMATIC REVIEW REGISTRATION: Registered as CRD42020147409 at PROSPERO ( https://www.crd.york.ac.uk/prospero/ ) on April 28, 2020.

External validation of the myocardial-ischaemic-injury-index machine learning algorithm for the early diagnosis of myocardial infarction: a multicentre cohort study.

BACKGROUND: The myocardial-ischaemic-injury-index (MI3) is a novel machine learning algorithm for the early diagnosis of type 1 non-ST-segment elevation myocardial infarction (NSTEMI). The performance of MI3, both when using early serial blood draws (eg, at 1 h or 2 h) and in direct comparison with guideline-recommended algorithms, remains unknown. Our aim was to externally validate MI3 and compare its performance with that of the European Society of Cardiology (ESC) 0/1h-algorithm. METHODS: In this secondary analysis of a multicentre international diagnostic cohort study, adult patients (age >18 years) presenting to the emergency department with symptoms suggestive of myocardial infarction were prospectively enrolled from April 21, 2006, to Feb 27, 2019 in 12 centres from five European countries (Switzerland, Spain, Italy, Poland, and Czech Republic). Patients were excluded if they presented with ST-segment-elevation myocardial infarction, did not have at least two serial high-sensitivity cardiac troponin I (hs-cTnI) measurements, or if the final diagnosis remained unclear. The final diagnosis was centrally adjudicated by two independent cardiologists using all available medical records, including serial hs-cTnI measurements and cardiac imaging. The primary outcome was type 1 NSTEMI. The performance of MI3 was directly compared with that of the ESC 0/1h-algorithm. FINDINGS: Among 6487 patients, (median age 61·0 years [IQR 49·0-73·0]; 2122 [33%] female and 4365 [67%] male), 882 (13·6%) patients had type 1 NSTEMI. The median time difference between the first and second hs-cTnI measurement was 60·0 mins (IQR 57·0-70·0). MI3 performance was very good, with an area under the receiver-operating-characteristic curve of 0·961 (95% CI 0·957 to 0·965) and a good overall calibration (intercept -0·09 [-0·2 to 0·02]; slope 1·02 [0·97 to 1·08]). The originally defined MI3 score of less than 1·6 identified 4186 (64·5%) patients as low probability of having a type 1 NSTEMI (sensitivity 99·1% [95% CI 98·2 to 99·5]; negative predictive value [NPV] 99·8% [95% CI 99·6 to 99·9]) and an MI3 score of 49·7 or more identified 915 (14·1%) patients as high probability of having a type 1 NSTEMI (specificity 95·0% [94·3 to 95·5]; positive predictive value [PPV] 69·1% [66·0-72·0]). The sensitivity and NPV of the ESC 0/1h-algorithm were higher than that of MI3 (difference for sensitivity 0·88% [0·19 to 1·60], p=0·0082; difference for NPV 0·18% [0·05 to 0·32], p=0·016), and the rule-out efficacy was higher for MI3 (11% difference, p<0·0001). Specificity and PPV for MI3 were superior (difference for specificity 3·80% [3·24 to 4·36], p<0·0001; difference for PPV 7·84% [5·86 to 9·97], p<0·0001), and the rule-in efficacy was higher for the ESC 0/1h-algorithm (5·4% difference, p<0·0001). INTERPRETATION: MI3 performs very well in diagnosing type 1 NSTEMI, demonstrating comparability to the ESC 0/1h-algorithm in an emergency department setting when using early serial blood draws. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, the EU, the University Hospital Basel, the University of Basel, Abbott, Beckman Coulter, Roche, Idorsia, Ortho Clinical Diagnostics, Quidel, Siemens, and Singulex.

Clinical and Analytical Performance of a Novel Point-of-Care High-Sensitivity Cardiac Troponin I Assay.

BACKGROUND: Point-of-care (POC) high-sensitivity cardiac troponin assays may further accelerate the diagnosis of myocardial infarction (MI). OBJECTIVES: This study sought to assess the clinical and analytical performance of the novel high-sensitivity cardiac troponin I (hs-cTnI)-SPINCHIP POC test. METHODS: Adult patients presenting with acute chest discomfort to the emergency department were enrolled in an international, diagnostic, multicenter study. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all clinical information. We compared the discriminatory performance of hs-cTnI-SPINCHIP with current established central laboratory assays and derived an assay-specific hs-cTnI-SPINCHIP 0/1-hour algorithm. Secondary analyses included sample type comparisons (whole blood, fresh/frozen plasma, and capillary finger prick) and precision analysis. RESULTS: MI was the adjudicated final diagnosis in 214 (19%) of 1,102 patients. Area under the receiver-operating characteristic curve was 0.94 (95% CI: 0.92-0.95) for hs-cTnI-SPINCHIP vs 0.94 (95% CI: 0.92-0.95) for hs-cTnI-Architect (P = 0.907) and 0.93 (95% CI: 0.91-0.95) for high-sensitivity cardiac troponin T Elecsys (P = 0.305). A cutoff <7 ng/L at presentation (if chest pain onset was >3 hours) or <7 ng/L together with a 0/1-hour delta of <4 ng/L ruled out 51% with a sensitivity and negative predictive value of 100% (95% CI: 97.7%-100%) and 100% (95% CI: 99.0%-100%), respectively. A hs-cTnI-SPINCHIP concentration ≥36 ng/L or a 0/1-hour delta ≥11 ng/L ruled in 27% with a specificity and positive predictive value of 90.9% (95% CI: 88.3%-92.9%) and 72.9% (95% CI: 66.4%-78.6%), respectively. Bootstrap internal validation confirmed excellent diagnostic performance. High agreement was observed between different sample types. CONCLUSIONS: The SPINCHIP hs-cTnI POC test has very high diagnostic accuracy. Its assay-specific 0/1-hour algorithm achieved very high sensitivity/negative predictive value and specificity/positive predictive value for rule-out/in MI. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] Study [APACE]; NCT00470587).