Effect of Diflunisal in Patients with Transthyretin Cardiomyopathy: A Pilot Study.

Background: ATTR-CM is becoming more prevalent, and disease-modifying therapy has been investigated in recent years with promising results. Diflunisal has shown TTR-stabilizing properties assessed by biomarkers and echocardiography, but there are no trials addressing the evolution of morphological changes with CMR. Methods and Results: AMILCA-DIFLU is an exploratory pilot study prospective, single-center, non-randomized, open-label clinical trial. Patients diagnosed with ATTR-CM underwent clinical, functional, biochemical and imaging assessment before and one year after diflunisal therapy initiation. Of the twelve ATTR-CM patients included, only nine patients completed treatment and study protocol in 12 months. To increase the sample size, we included seven real-world patients with one year of diflunisal treatment. Among the group of patients who completed treatment, diflunisal therapy did not show improvement in cardiac disease status as assessed by many cardiac and inflammatory biomarkers, 6MWT and CMR parameters after one year of treatment. However, a non-significant trend towards stabilization of CMR parameters such as LVEF, ECV and T2 at one year was found. When comparing the group of patients who completed diflunisal therapy and those who did not, a significant decrease in the distance performed in the 6MWT was found in the group of patients who completed treatment at one year (-14 ± 81.8 vs. -173 ± 122.2; p = 0.032). Diflunisal was overall well tolerated, showing only a statistically significant worsening in renal function in the group of diflunisal-treatment patients with no clinical relevance or need for treatment discontinuation. Conclusions: In patients with ATTR-CM, treatment with diflunisal was overall well tolerated and tended to stabilize or slow down amyloid cardiac disease progression assessed by CMR parameters, cardiac and inflammatory biomarkers and functional capacity.

Serum Biomarkers and Their Association with Myocardial Function and Exercise Capacity in Cardiac Transthyretin Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR amyloidosis) is a frequent etiology of heart failure. Inflammation and mineral metabolism are associated with myocardial dysfunction and clinical performance. Cardiac global longitudinal strain (GLS) allows function assessment and is associated with prognosis. Our aim was to describe possible correlations between GLS, biomarker levels and clinical performance in ATTR amyloidosis. METHODS: Thirteen patients with ATTR amyloidosis were included. Clinical characteristics; echocardiographic features, including strain assessment and 6 min walk test (6MWT); and baseline inflammatory, mineral metabolism and cardiovascular biomarker levels were assessed. RESULTS: Of the 13 patients, 46.2% were women, and the mean age was 79 years. TAPSE correlated with NT-ProBNP (r -0.65, p < 0.05) and galectin-3 (r 0.76, p < 0.05); E/E' ratio correlated with hsCRP (r 0.58, p < 0.05). Left ventricular GLS was associated with NT-ProBNP (r 0.61, p < 0.05) (patients have a better prognosis if the strain value is more negative) and left atrial GLS with NT-ProBNP (r -0.73, p < 0.05) and MCP1 (r 0.55, p < 0.05). Right ventricular GLS was correlated with hsTnI (r 0.62, p < 0.05) and IL6 (r 0.881, p < 0.05). Klotho levels were correlated with 6MWT (r 0.57, p < 0.05). CONCLUSIONS: While inflammatory biomarkers were correlated with cardiac function, klotho levels were associated with clinical performance in the population with TTR-CA.

Prognostic Utility of Society for Cardiovascular Angiography and Interventions Shock Stage Approach for Classifying Cardiogenic Shock Severity in Takotsubo Syndrome.

BACKGROUND: Cardiogenic shock (CS) is a significant complication of Takotsubo syndrome (TTS), contributing to heightened mortality and morbidity. Despite this, the Society for Cardiovascular Angiography and Interventions (SCAI) staging system for CS severity lacks validation in patients with TTS and CS. This study aimed to characterize a patient cohort with TTS using the SCAI staging system and assess its utility in cases of TTS complicated by CS. METHODS AND RESULTS: From a TTS national registry, 1591 consecutive patients were initially enrolled and stratified into 5 SCAI stages (A through E). Primary outcome was all-cause in-hospital mortality; secondary end points were TTS-related in-hospital complications and 1-year all-cause mortality. After exclusions, the final cohort comprised 1163 patients, mean age 71.0±11.8 years, and 87% were female. Patients were categorized across SCAI shock stages as follows: A 72.1%, B 12.2%, C 11.2%, D 2.7%, and E 1.8%. Significant variations in baseline demographics, comorbidities, clinical presentations, and in-hospital courses were observed across SCAI shock stages. After multivariable adjustment, each higher SCAI shock stage showed a significant association with increased in-hospital mortality (adjusted odds ratio: 1.77-29.31) compared with SCAI shock stage A. Higher SCAI shock stages were also associated with increased 1-year mortality. CONCLUSIONS: In a large multicenter patient cohort with TTS, the functional SCAI shock stage classification effectively stratified mortality risk, revealing a continuum of escalating shock severity with higher stages correlating with increased in-hospital mortality. This study highlights the applicability and prognostic value of the SCAI staging system in TTS-related CS.

Is novel research worth doing? Evidence from peer review at 49 journals.

There are long-standing concerns that peer review, which is foundational to scientific institutions like journals and funding agencies, favors conservative ideas over novel ones. We investigate the association between novelty and the acceptance of manuscripts submitted to a large sample of scientific journals. The data cover 20,538 manuscripts submitted between 2013 and 2018 to the journals Cell and Cell Reports and 6,785 manuscripts submitted in 2018 to 47 journals published by the Institute of Physics Publishing. Following previous work that found that a balance of novel and conventional ideas predicts citation impact, we measure the novelty and conventionality of manuscripts by the atypicality of combinations of journals in their reference lists, taking the 90th percentile most atypical combination as "novelty" and the 50th percentile as "conventionality." We find that higher novelty is consistently associated with higher acceptance; submissions in the top novelty quintile are 6.5 percentage points more likely than bottom quintile ones to get accepted. Higher conventionality is also associated with acceptance (+16.3% top-bottom quintile difference). Disagreement among peer reviewers was not systematically related to submission novelty or conventionality, and editors select strongly for novelty even conditional on reviewers' recommendations (+7.0% top-bottom quintile difference). Manuscripts exhibiting higher novelty were more highly cited. Overall, the findings suggest that journal peer review favors novel research that is well situated in the existing literature, incentivizing exploration in science and challenging the view that peer review is inherently antinovelty.

Prevalence and prognostic value of monoclonal gammopathy in heart failure patients with preserved ejection fraction: A prospective study.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) and monoclonal gammopathy of uncertain significance (MGUS) are two entities that share pathophysiological mechanisms. The aim herein, was to assess the prevalence of MGUS in patients with HFpEF and no left ventricular (LV) hypertrophy, as well as its association with a pre-specified clinical endpoint at 12 months. METHODS: The present study prospectively enrolled 69 patients admitted with HF, with ejection fraction ≥ 50%, and LV wall thickness < 12 mm. All patients were screened for MGUS. Clinical events were determined over a 12 month follow-up. The pre-specified composite clinical endpoint was readmission for HF or death. RESULTS: The prevalence of MGUS in this population was 13%. There were no differences in the incidence of the composite clinical endpoint between patients with and without MGUS. Multivariate analysis showed that treatment with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) was associated with fewer clinical events (HR: 0.153, 95% CI: 0.037-0.622, p = 0.009) and indicated a trend to lower risk of readmission for HF and death. Beta-blockers were associated with lower rates of the composite clinical endpoint (HR: 0.192, 95% CI: 0.05-0.736, p = 0.016), readmission for HF (HR: 0.272, 95% CI: 0.087-0.851, p = 0.025) and indicated a trend to lower mortality. Moreover, potassium serum levels > 5 mEq/L were associated with higher rates of the composite endpoint (HR: 6.074, 95% CI: 1.6-22.65, p = 0.007). CONCLUSIONS: The prevalence of MGUS in patients with HFpEF without hypertrophy was 3-fold that of the general population. There was no significant correlation between clinical outcomes and the presence of MGUS. Beta-blockers and ACEIs/ARBs reduced the composite of mortality and readmissions for HF in HFpEF patients. Hyperpotassemia was related to worse prognosis.

Prevalence of transthyretin amyloidosis in patients with heart failure and no left ventricular hypertrophy.

AIMS: As evidenced by scintigraphy imaging, the prevalence of transthyretin (TTR) cardiac amyloidosis in heart failure patients with preserved ejection fraction (HFpEF) and left ventricular hypertrophy (LVH) ranges between 13% and 19%. The natural evolution of cardiac amyloidosis begins with the deposition of amyloid material in the myocardium, with LVH ensuing at later stages. With current imaging modalities, it is possible to detect TTR cardiac amyloidosis before the hypertrophic stage. The aim of this study was to determine the prevalence of TTR cardiac amyloidosis in HFpEF patients without LVH. METHODS AND RESULTS: The study prospectively enrolled patients admitted for HF with LV ejection fraction (LVEF) ≥ 50% and LV wall thickness <12 mm. TTR cardiac amyloidosis was diagnosed according to accepted criteria, which include positive cardiac 99-Tc-DPD scintigraphy in the absence of monoclonal protein expansion in blood. Transthyretin gene sequencing was performed in positive patients. From July 2017 to January 2020, 329 patients with HFpEF and LV thickness <12 mm were identified. After exclusions, 58 patients completed the study with cardiac scintigraphy (79 years, 54% men; median LVEF 60% and LV wall thickness 10.5 mm). Three patients (5.2%) were positive for TTR cardiac amyloidosis; genetic analysis excluded the presence of hereditary TTR amyloidosis. Positive patients baseline characteristics (84 years, 67% men, LVEF 60%, and LV wall thickness 11 mm) were similar to patients without TTR, except for troponin levels (0.05 vs. 0.02 ng/mL, P = 0.03) and glomerular filtration rate (82 vs. 60 mL/min, P = 0.032), which were higher in TTR patients. CONCLUSIONS: In a cohort of patients with HFpEF without LVH, the prevalence of TTR cardiac amyloidosis was 5%. Early diagnosis of cardiac involvement in TTR amyloidosis (before manifest LVH) would seem recommendable because newly approved specific treatments can prevent additional deposition of amyloid material.

Improving deconvolution methods in biology through open innovation competitions: an application to the connectivity map.

MOTIVATION: Do machine learning methods improve standard deconvolution techniques for gene expression data? This article uses a unique new dataset combined with an open innovation competition to evaluate a wide range of approaches developed by 294 competitors from 20 countries. The competition's objective was to address a deconvolution problem critical to analyzing genetic perturbations from the Connectivity Map. The issue consists of separating gene expression of individual genes from raw measurements obtained from gene pairs. We evaluated the outcomes using ground-truth data (direct measurements for single genes) obtained from the same samples. RESULTS: We find that the top-ranked algorithm, based on random forest regression, beat the other methods in accuracy and reproducibility; more traditional gaussian-mixture methods performed well and tended to be faster, and the best deep learning approach yielded outcomes slightly inferior to the above methods. We anticipate researchers in the field will find the dataset and algorithms developed in this study to be a powerful research tool for benchmarking their deconvolution methods and a resource useful for multiple applications. AVAILABILITY AND IMPLEMENTATION: The data is freely available at clue.io/data (section Contests) and the software is on GitHub at https://github.com/cmap/gene_deconvolution_challenge. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Innovation contest: Effect of perceived support for learning on participation.

BACKGROUND: Frontline staff are well positioned to conceive improvement opportunities based on first-hand knowledge of what works and does not work. The innovation contest may be a relevant and useful vehicle to elicit staff ideas. However, the success of the contest likely depends on perceived organizational support for learning; when staff believe that support for learning-oriented culture, practices, and leadership is low, they may be less willing or able to share ideas. PURPOSE: We examined how staff perception of organizational support for learning affected contest participation, which comprised ideation and evaluation of submitted ideas. METHODOLOGY/APPROACH: The contest held in a hospital cardiac center invited all clinicians and support staff (n ≈ 1,400) to participate. We used the 27-item Learning Organization Survey to measure staff perception of learning-oriented environment, practices and processes, and leadership. RESULTS: Seventy-two frontline staff submitted 138 ideas addressing wide-ranging issues including patient experience, cost of care, workflow, utilization, and access. Two hundred forty-five participated in evaluation. Supportive learning environment predicted participation in ideation and idea evaluation. Perceptions of insufficient experimentation with new ways of working also predicted participation. CONCLUSION: The contest enabled frontline staff to share input and assess input shared by other staff. Our findings indicate that the contest may serve as a fruitful outlet through which frontline staff can share and learn new ideas, especially for those who feel safe to speak up and believe that new ideas are not tested frequently enough. PRACTICE IMPLICATIONS: The contest's potential to decentralize innovation may be greater under stronger learning orientation. A highly visible intervention, like the innovation contest, has both benefits and risks. Our findings suggest benefits such as increased engagement with work and community as well as risks such as discontent that could arise if staff suggestions are not acted upon or if there is no desired change after the contest.

Advancing computational biology and bioinformatics research through open innovation competitions.

Open data science and algorithm development competitions offer a unique avenue for rapid discovery of better computational strategies. We highlight three examples in computational biology and bioinformatics research in which the use of competitions has yielded significant performance gains over established algorithms. These include algorithms for antibody clustering, imputing gene expression data, and querying the Connectivity Map (CMap). Performance gains are evaluated quantitatively using realistic, albeit sanitized, data sets. The solutions produced through these competitions are then examined with respect to their utility and the prospects for implementation in the field. We present the decision process and competition design considerations that lead to these successful outcomes as a model for researchers who want to use competitions and non-domain crowds as collaborators to further their research.