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Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Background: Several studies suggest that environmental and climatic factors are linked to the risk of mortality due to cardiovascular and respiratory diseases; however, it is still unclear which are the most influential ones. This study sheds light on the potentiality of a data-driven statistical approach by providing a case study analysis. Methods: Daily admissions to the emergency room for cardiovascular and respiratory diseases are jointly analyzed with daily environmental and climatic parameter values (temperature, atmospheric pressure, relative humidity, carbon monoxide, ozone, particulate matter, and nitrogen dioxide). The Random Forest (RF) model and feature importance measure (FMI) techniques (permutation feature importance (PFI), Shapley Additive exPlanations (SHAP) feature importance, and the derivative-based importance measure (κALE)) are applied for discriminating the role of each environmental and climatic parameter. Data are pre-processed to remove trend and seasonal behavior using the Seasonal Trend Decomposition (STL) method and preliminary analyzed to avoid redundancy of information. Results: The RF performance is encouraging, being able to predict cardiovascular and respiratory disease admissions with a mean absolute relative error of 0.04 and 0.05 cases per day, respectively. Feature importance measures discriminate parameter behaviors providing importance rankings. Indeed, only three parameters (temperature, atmospheric pressure, and carbon monoxide) were responsible for most of the total prediction accuracy. Conclusions: Data-driven and statistical tools, like the feature importance measure, are promising for discriminating the role of environmental and climatic factors in predicting the risk related to cardiovascular and respiratory diseases. Our results reveal the potential of employing these tools in public health policy applications for the development of early warning systems that address health risks associated with climate change, and improving disease prevention strategies.

Miniaturized frequency comb sources across hard-to-access spectral regions, i.e. mid- and far-infrared, have long been sought. Four-wave-mixing based Quantum Cascade Laser combs (QCL-combs) are ideal candidates, in this respect, due to the unique possibility to tailor their spectral emission by proper nanoscale design of the quantum wells. We demonstrate full-phase-stabilization of a QCL-comb against the primary frequency standard, proving independent and simultaneous control of the two comb degrees of freedom (modes spacing and frequency offset) at a metrological level. Each emitted mode exhibits a sub-Hz relative frequency stability, while a correlation analysis on the modal phases confirms the high degree of coherence in the device emission, over different power-cycles and over different days. The achievement of fully controlled, phase-stabilized QCL-comb emitters proves that this technology is mature for metrological-grade uses, as well as for an increasing number of scientific and technological applications. Here, the authors demonstrate full stabilization and control of the two key parameters of a four-wavemixing-based quantum cascade laser comb with metrological precision. These fully-controlled, frequency scalable comb emitters will allow an increasing number of mid- and far-IR applications.

ObjectivesCardiac amyloidosis (CA) is a rare and underdiagnosed disease associated with a high mortality rate. Although, in the last decade, there has been increasing attention in the literature to the relationship between CA and psychological distress in patients, the evidence on this association has not yet been systematised. Therefore, this study aims to fill this gap.DesignFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review was conducted.Data sourcesPubMed, ScienceDirect, Scopus and Web of Science were searched, with the last update conducted on 23 September 2024, and no time restrictions were applied.Eligibility criteriaStudies had to meet the following inclusion criteria to be included: (1) original quantitative research; (2) published in peer-reviewed journals written in English; (3) explore and report the relationship between CA and psychological distress or compare a clinical group with a control group and (4) investigate psychological distress through reliable and validated measures.Data extraction and synthesisOne author extracted the data, which was then double-checked by another, and data were reported both in tabular and textual form. The included studies were critically evaluated using the Appraisal Tool for Cross-Sectional Studies.ResultsThrough the research process, a total of 14 articles were selected. The quality assessment scores ranged from 12 to 18 (M=16.21±1.42). Overall, the results underline a significant presence of psychological distress in patients with CA. Moreover, while disease severity was not found to be associated with psychological distress in CA patients in all studies considered, more heterogeneous results emerged regarding the association between the severity of cardiac symptoms and psychological distress.ConclusionsResults suggest that psychological distress is an important aspect to be considered when dealing with CA patients. Integrating psychological assessment and support may improve patient outcomes by reducing disease burden and enhancing treatment adherence.PROSPERO registration numberCRD42023446913.

This study introduces a hybrid methodological approach for personalised clinical decision support, integrating SHACL-based deterministic constraints with Bayesian probabilistic models. The primary goal is to validate the model and demonstrate the benefits of combining encoded clinical knowledge with probabilistic uncertainties in managing complex therapeutic scenarios. The framework was applied to recurrent urinary tract infections (UTIs) in postmenopausal patients, a clinical context marked by high frequency, treatment challenges, and potential conflicts among therapeutic guidelines. Realistic simulated case studies were developed, encompassing both simple clinical profiles and complex situations, such as patients with antibiotic resistance. Each profile was modelled in RDF/Turtle, enabling semantic representation of clinical features and therapeutic rules. The system automatically calculates success and failure probabilities for different therapeutic scenarios, dynamically adapting them based on follow-up data. This allows clinicians to assess not only the initial therapy choice (Case study no. 1) but also the potential addition of supplementary interventions during treatment (Case study no. 2). Results highlight that the proposed hybrid SHACL–Bayesian framework enables tightly coupled deterministic–probabilistic reasoning, where SHACL constraints define the admissible clinical decisions and Bayesian inference operates within this validated space. Compared to deterministic or probabilistic approaches, the combined framework more effectively handles uncertainty, guideline conflicts, and temporal updates. The scientific contribution lies in showing that this integration enhances decision support for recurrent UTIs in postmenopausal patients, providing clinically consistent, transparent, and adaptive therapeutic recommendations aligned with the patient’s evolving condition.

Quantum cascade lasers (QCLs) are becoming a key tool for plenty of applications, from the mid-infrared (mid-IR) to the THz range. Progress in related areas, such as the development of ultra-low-loss crystalline microresonators, optical frequency standards, and optical fiber networks for time and frequency dissemination, is paving the way for unprecedented applications in many fields. For most demanding applications, a thorough control of QCLs emission must be achieved. In the last few years, QCLs’ unique spectral features have been unveiled, while multifrequency QCLs have been demonstrated. Ultra-narrow frequency linewidths are necessary for metrological applications, ranging from cold molecules interaction and ultra-high sensitivity spectroscopy to infrared/THz metrology. A review of the present status of research in this field is presented, with a view of perspectives and future applications.

Heart failure (HF) with mid-range ejection fraction (HFmrEF) has been conceptualized by the European Society of Cardiology guidelines with the aim of stimulating research to fill a gap in knowledge: whether such a condition exists as a distinct pathophysiological and clinical entity, or it is just a residual category of ejection fraction indeed is still a matter of debate. Current evidence suggests that HFmrEF represents up to one fifth of patients with HF, who may ultimately result in an intermediate clinical phenotype, as for age and gender, with an intermediate prevalence of comorbidities. Nevertheless, a strong connection exists with HF with reduced ejection fraction, since ischemic aetiology is common in both categories, conveying relevant implications for prognosis and therapeutic response. Little is known about its pathophysiology: mild systolic impairment may be not enough and advocating diastolic dysfunction may be an oversimplification. An increasing amount of data is clarifying how many of HFmrEF patients are the results of deteriorating or recovering hearts, thus underscoring that aetiology may be, more than EF, the key to understand this new category. Sparse evidence points toward a potential benefit of common HF therapies in those patients, but further research is still needed.

Aims Recognition of transthyretin amyloid cardiomyopathy is increasing due to advances in cardiac imaging and diagnostic strategies, but questions remain regarding disease frequency and characteristics. We examined the prevalence and characteristics of transthyretin amyloid cardiomyopathy in older patients with hypertrophic cardiomyopathy of unascertained aetiology. Methods and results TTRACK was a multicentre, non‐interventional, cross‐sectional epidemiologic study funded by Pfizer and conducted in 20 hospitals and medical centres in 11 countries (NCT03842163). Eligible patients were aged ≥50 years, had hypertrophic cardiomyopathy (maximal end‐diastolic left ventricular wall thickness ≥15 mm on echocardiogram) without an identified genetic or alternative origin at study enrolment, and underwent 99mTechnetium bone scintigraphy, with or without single photon emission computed tomography (SPECT). Cardiac‐versus‐bone uptake on scans was visually scored from 0 to 3 (Perugini scoring). Patients with grades 1–3 underwent monoclonal protein and laboratory testing and transthyretin (TTR) gene sequencing. Of 766 eligible patients, 691 (90.2%) had scintigraphy alone and 75 (9.8%) scintigraphy plus SPECT. Two hundred and eight patients (27.2%) had grade 2 or 3 cardiac uptake on scintigraphy; 144 (18.8%) had grade 2 or 3 cardiac uptake and no evidence of plasma cell dyscrasia and were diagnosed with transthyretin amyloid cardiomyopathy. Of patients with transthyretin amyloid cardiomyopathy, 11 (7.6%) had a pathogenic TTR gene variant and 34 (23.8%), 74 (51.7%), and 35 (24.5%) had New York Heart Association class I, II, and III/IV heart failure (HF) symptoms, respectively. Clinical and laboratory diagnostic characteristics were observed in ≥90% of patients with transthyretin amyloid cardiomyopathy. The characteristics most strongly associated with transthyretin amyloid cardiomyopathy on multivariable analysis were carpal tunnel syndrome (odds ratio [OR] 54.3; P < 0.0001) and male sex (OR 7.9; P < 0.0001). Conclusions In the TTRACK study, almost one in five patients ≥50 years of age with hypertrophic cardiomyopathy had transthyretin amyloid cardiomyopathy. Greater awareness of the frequency and characteristics of transthyretin amyloid cardiomyopathy in older patients with hypertrophic cardiomyopathy are needed to help improve early detection of this debilitating but treatable disease.

Four-wave-mixing-based quantum cascade laser frequency combs (QCL-FC) are a powerful photonic tool, driving a recent revolution in major molecular fingerprint regions, i.e. mid- and far-infrared domains. Their compact and frequency-agile design, together with their high optical power and spectral purity, promise to deliver an all-in-one source for the most challenging spectroscopic applications. Here, we demonstrate a metrological-grade hybrid dual comb spectrometer, combining the advantages of a THz QCL-FC with the accuracy and absolute frequency referencing provided by a free-standing, optically-rectified THz frequency comb. A proof-of-principle application to methanol molecular transitions is presented. The multi-heterodyne molecular spectra retrieved provide state-of-the-art results in line-center determination, achieving the same precision as currently available molecular databases. The devised setup provides a solid platform for a new generation of THz spectrometers, paving the way to more refined and sophisticated systems exploiting full phase control of QCL-FCs, or Doppler-free spectroscopic schemes. THz dual comb spectroscopy may be performed using down-converted or quantum cascade laser systems, forcing a choice between absolute frequency referencing and high sensitivity. Here, these strengths are combined in a hybrid, dual frequency comb spectrometer, capable of high-accuracy measurements on molecular transitions.

Since the beginning of this millennium, frequency comb generators have reshaped frequency metrology and related areas. After more than two decades since their first realization, several other ways to generate frequency combs, in any spectral region, have been demonstrated, each way with its peculiar features. This trend has triggered the need to quantitatively assess how close the new comb realizations are to an ideal comb, a feature that will be called combness throughout this paper. We will briefly review the very dynamic area of novel frequency comb sources and we will describe the techniques that have been recently developed to quantitatively assess the key parameters of old and new frequency combs, in view of the specific applications. Finally, we will try to sketch future steps in this recently born research area.