Multiparameter immunoprofiling for the diagnosis and differentiation of progressive versus nonprogressive nontuberculous mycobacterial lung disease-A pilot study.

Clinical prediction of nontuberculous mycobacteria lung disease (NTM-LD) progression remains challenging. We aimed to evaluate antigen-specific immunoprofiling utilizing flow cytometry (FC) of activation-induced markers (AIM) and IFN-γ enzyme-linked immune absorbent spot assay (ELISpot) accurately identifies patients with NTM-LD, and differentiate those with progressive from nonprogressive NTM-LD. A Prospective, single-center, and laboratory technician-blinded pilot study was conducted to evaluate the FC and ELISpot based immunoprofiling in patients with NTM-LD (n = 18) and controls (n = 22). Among 18 NTM-LD patients, 10 NTM-LD patients were classified into nonprogressive, and 8 as progressive NTM-LD based on clinical and radiological features. Peripheral blood mononuclear cells were collected from patients with NTM-LD and control subjects with negative QuantiFERON results. After stimulation with purified protein derivative (PPD), mycobacteria-specific peptide pools (MTB300, RD1-peptides), and control antigens, we performed IFN-γ ELISpot and FC AIM assays to access their diagnostic accuracies by receiver operating curve (ROC) analysis across study groups. Patients with NTM-LD had significantly higher percentage of CD4+/CD8+ T-cells co-expressing CD25+CD134+ in response to PPD stimulation, differentiating between NTM-LD and controls. Among patients with NTM-LD, there was a significant difference in CD25+CD134+ co-expression in MTB300-stimulated CD8+ T-cells (p <0.05; AUC-ROC = 0.831; Sensitivity = 75% [95% CI: 34.9-96.8]; Specificity = 90% [95% CI: 55.5-99.7]) between progressors and nonprogressors. Significant differences in the ratios of antigen-specific IFN-γ ELISpot responses were also seen for RD1-nil/PPD-nil and RD1-nil/anti-CD3-nil between patients with nonprogressive vs. progressive NTM-LD. Our results suggest that multiparameter immunoprofiling can accurately identify patients with NTM-LD and may identify patients at risk of disease progression. A larger longitudinal study is needed to further evaluate this novel immunoprofiling approach.

N-terminal pro-B-type natriuretic peptide post-discharge monitoring in the management of patients with heart failure and preserved ejection fraction - a randomized trial: The NICE study.

AIMS: There is a lack of specific studies assessing the impact of natriuretic peptide monitoring in the post-discharge management of patients with heart failure (HF) and preserved ejection fraction (HFpEF), throughout the vulnerable phase following acute HF hospitalization. The NICE study aims to assess the clinical benefit of incorporating N-terminal pro-B-type natriuretic peptide (NT-proBNP) into the post-discharge management of HFpEF patients. METHODS AND RESULTS: Individuals admitted with HFpEF (left ventricular ejection fraction >50%) were included in a multicentre randomized controlled study employing an open-label design with event blinding (NCT02807168). Upon discharge, 157 patients were randomly allocated to either NT-proBNP monitoring (n = 79) or no access to NT-proBNP (control group, n = 78) during pre-scheduled visits at 2, 4 and 12 weeks. Clinical endpoints were evaluated at 6 months. The primary endpoint of HF rehospitalizations occurred in 12.1% patients, without significant differences observed between the NT-proBNP monitoring group (12.8%) and the control group (11.4%) (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.47-2.81, p = 0.760). Regarding secondary endpoints, the NT-proBNP monitoring group demonstrated a significantly lower risk of death (1.3% vs. 10.1%; HR 0.12, 95% CI 0.02-0.09), whereas non-HF hospitalizations (12.8% vs. 19.0%, p = 0.171) and any adverse clinical event (26.9% vs. 36.7%, p = 0.17) did not reach statistical significance. Awareness of NT-proBNP levels were associated with higher doses of diuretics and renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers) in the NT-proBNP monitoring group. CONCLUSIONS: Post-discharge monitoring of NT-proBNP in HFpEF patients did not exhibit an association with reduced rates of HF hospitalization in this study. Nonetheless, it appears to enhance global clinical management by optimizing medical therapies and contributing to improved overall survival.

Cardiovascular effect of preeclampsia upon offspring development: Are (Pro) renin-renin receptor ((P)RR) and gender related?

Objectives: Preeclampsia (PE) is a complication of pregnancy that might increase progeny risk of cardiovascular and metabolic problems, mainly in males. Renin angiotensin aldosterone system is known to be involved. (Pro) renin/renin receptor ((P)RR) has been shown to participate in cardiovascular pathology. The aim of this work was to evaluate (P)RR expression and function upon cardiovascular and renal tissues from PE dams' offspring. Materials and Methods: We used offspring from normal pregnant and preeclamptic rats, evaluating body, heart, aorta and kidney weight, length, and blood pressure along 3 months after birth. Subsets of animals received handle region peptide (HRP) (0.2 mg/Kg, sc). Another group received vehicle. Animals were sacrificed at first, second, and third months of age, tissues were extracted and processed for immunoblot to detect (P)RR, PLZF, ß-catenin, DVL-1, and PKCα. (P)RR and PLZF were also measured by RT-PCR. Results: We found that offspring developed hypertension. Male descendants remained hypertensive throughout the whole experiment. Female animals tended to recover at second month and returned to normal blood pressure at third month. HRP treatment diminished hypertension in both male and female animals. Morphological evaluations showed changes in heart, aorta, and kidney weight, and HRP reverted this effect. Finally, we found that (P)RR, PLZF, and canonical WNT transduction pathway molecules were stimulated by PE, and HRP treatment abolished this increase. Conclusion: These findings suggest that PE can induce hypertension in offspring, and (P)RR seems to play an important role through the canonical WNT pathway and that gender seems to influence this response.

Preeclampsia as a possible risk factor for memory impairment, anxiety- and depressive-like behavior in offspring.

RATIONALE: Preeclampsia is a condition that can affect the health in offspring at adult life. The effect on several systems has been described, but less is known about its effect on neuropsychiatric disorders at early ages. OBJECTIVE: Evaluate the possible relationship of preeclampsia with development of anxiety- and depressive-like behavior, as well as memory impairments in male and female early adolescent offspring from preeclamptic mice. METHODS: Thirty pregnant females were divided into control group receiving vehicle, and preeclampsia group receiving L-NAME in drinking water at a dose of 60 mg/Kg from day 10 of pregnancy until delivery. Offspring was weaned and sexed at 4 weeks after birth. Each group was evaluated using the elevated plus maze test (anxiety- like response), tail suspension test (depressive-like behavior) and the recognition of novel objects test (recognition memory), in addition to the open field test was performance to corroborate their motor activity and validate our results. RESULTS: We found that preeclampsia produces behavioral alterations in offspring, and this effect is dependent on sex. The male offspring from preeclampsia showed an enhancement in the time that mice spend in the close arms in the elevated plus maze test, and longer immobility time in the tail suspension test, compared to the offspring from healthy pregnancies. On the other hand, female offspring from preeclampsia showed a lower percentage of recognition in the memory test compared to offspring from normal pregnancy. CONCLUSIONS: These results suggest that preeclampsia predisposes early adolescent young male offspring to develop anxiety- and depressive-like behavior as well as memory impairment in early adolescent young female offspring.

ECG-based data-driven solutions for diagnosis and prognosis of cardiovascular diseases: A systematic review.

Cardiovascular diseases (CVD) are a leading cause of death globally, and result in significant morbidity and reduced quality of life. The electrocardiogram (ECG) plays a crucial role in CVD diagnosis, prognosis, and prevention; however, different challenges still remain, such as an increasing unmet demand for skilled cardiologists capable of accurately interpreting ECG. This leads to higher workload and potential diagnostic inaccuracies. Data-driven approaches, such as machine learning (ML) and deep learning (DL) have emerged to improve existing computer-assisted solutions and enhance physicians' ECG interpretation of the complex mechanisms underlying CVD. However, many ML and DL models used to detect ECG-based CVD suffer from a lack of explainability, bias, as well as ethical, legal, and societal implications (ELSI). Despite the critical importance of these Trustworthy Artificial Intelligence (AI) aspects, there is a lack of comprehensive literature reviews that examine the current trends in ECG-based solutions for CVD diagnosis or prognosis that use ML and DL models and address the Trustworthy AI requirements. This review aims to bridge this knowledge gap by providing a systematic review to undertake a holistic analysis across multiple dimensions of these data-driven models such as type of CVD addressed, dataset characteristics, data input modalities, ML and DL algorithms (with a focus on DL), and aspects of Trustworthy AI like explainability, bias and ethical considerations. Additionally, within the analyzed dimensions, various challenges are identified. To these, we provide concrete recommendations, equipping other researchers with valuable insights to understand the current state of the field comprehensively.

Outcomes of a 24/7 service for urgent permanent pacemaker implantation.

INTRODUCTION AND OBJECTIVES: Most of the complications associated with acute and symptomatic bradyarrhythmia (ASB) occur in the time from diagnosis to permanent pacemaker implantation (PPI). We aimed to evaluate the outcomes of an urgent 24/7 PPI service (PPI-24/7) for patients with ASB. METHODS: A total of 664 patients undergoing first-time PPI for ASB were prospectively assessed during 2 periods of identical length (18 months): 341 patients who underwent the procedure during working hours only (PPI-WH), and 323 patients who underwent the procedure after the implementation of the PPI-24/7 service. The primary safety endpoint was established as the cumulative 180-day incidence of complications related to the index arrhythmia and device implant. The primary efficacy endpoint was determined as the average number of hospital stays per patient. RESULTS: The PPI-24/7 period was associated with a significant shortening of the time from diagnosis to implantation (median [interquartile range]): 3hours [2-6] vs 16 [5-21]). The cumulative incidence of patients with complications at 180 days was lower in the PPI-24/7 period: 9% vs 17% (adjusted odds ratio, 0.5; P=.002), due to a significant reduction in preimplant complications: 2.5% vs 12% (P <.001). The average number of hospital stays was reduced by 2 per patient in the PPI-24/7 period (nonparametric P <.001). PPI-24/7 implants performed outside working hours (n=178) were safe, with a 180-day cumulative incidence in procedure-related complications of 3.9%. CONCLUSIONS: Among patients with ASB, PPI-24/7 was associated with a significant reduction in patient morbidity and efficient hospital resource use.

Perinatal outcomes following fetoscopic laser surgery for early twin-to-twin transfusion syndrome: Systematic review and meta-analysis.

INTRODUCTION: Our objective was to investigate outcomes in twin-to-twin transfusion syndrome (TTTS) treated with fetoscopic laser surgery (FLS) at <18 weeks vs ≥18 weeks, and to conduct subgroup analysis of TTTS with FLS at <16 weeks vs 16-18 weeks. MATERIAL AND METHODS: PubMed, Scopus and Web of Science were searched systematically from inception until May 2023. Primary outcome was survival, and secondary outcomes included preterm premature rupture of membranes (PPROM), preterm birth and gestational age (GA) at delivery. RESULTS: Nine studies encompassing 1691 TTTS pregnancies were included. TTTS stage III was significantly more common in TTTS pregnancies treated with FLS at <18 weeks (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.24-6.54), and procedure duration was shorter at <18 weeks (MD -5.27 minutes, 95% CI -9.19 to -1.34). GA at delivery was significantly earlier in TTTS pregnancies treated with FLS at <18 weeks (MD -3.12 weeks, 95% CI -6.11 to -0.13). There were no significant differences in outcomes, including PPROM, PPROM at <7 days post-FLS, preterm birth at <28 and <32 weeks, delivery at <7 days post-FLS, and survival outcomes, including fetal demise, live birth and neonatal survival. Similarly, TTTS stage III was more common in TTTS with FLS at <16 weeks than at 16-18 weeks (OR 2.95, 95% CI 1.62-5.35), with no significant differences in the aforementioned outcomes. CONCLUSIONS: In early TTTS treated with FLS, outcomes were comparable between those treated at <18 weeks compared with ≥18 weeks except for GA at delivery, which was 3 weeks earlier. In the subset treated at <16 weeks vs 16-18 weeks, the procedure was feasible without an increased risk of very early preterm birth or perinatal mortality.

Internet interventions and therapies for addressing the negative impact of digital overuse: a focus on digital free tourism and economic sustainability.

BACKGROUND: The excessive use of information technologies (IT) and online digital devices are causing symptoms of burnout, anxiety, stress and dependency that affect the physical and mental health of our society, extending to leisure time and work relationships. Digital free tourism (DFT) is a phenomenon that emerges as a solution to technostress and pathologies derived from digital hyperconnection. The objective of this research is to advance the knowledge of new structures of motivational factors that can understand the decision of a tourist to make a DFT trip. To this end, it is investigated whether family and social engagement and health and relaxation have a positive impact on the behavioral intention of the potential tourist and whether this influences sustainability due to the importance of DFT in the new economic framework. METHODS: With a quantitative approach, the methodology used consisted of an online questionnaire among potential travelers. IBM SPSS Statistics 22.0 statistical software was used to evaluate the data obtained and confirm the relationships of the model and the research hypotheses. RESULTS: The results of the questionnaire assessed the contribution of each construct to the tourist's behavioral intention and the tourist's decision to make the decision to undertake a DFT experience. CONCLUSIONS: DFT can be a driver of economic sustainability and health therapy in tourism in the digital age. This study aims to expand the lines of research on DFT and determine the complex factors that can lead a tourist to participate in the DFT experience. The results obtained can help managers of companies in the sector to offer more efficient and sustainable services that contribute to the health and wellbeing of tourists as a differentiating factor.

Compositionally Equivariant Representation Learning.

Deep learning models often need sufficient supervision (i.e. labelled data) in order to be trained effectively. By contrast, humans can swiftly learn to identify important anatomy in medical images like MRI and CT scans, with minimal guidance. This recognition capability easily generalises to new images from different medical facilities and to new tasks in different settings. This rapid and generalisable learning ability is largely due to the compositional structure of image patterns in the human brain, which are not well represented in current medical models. In this paper, we study the utilisation of compositionality in learning more interpretable and generalisable representations for medical image segmentation. Overall, we propose that the underlying generative factors that are used to generate the medical images satisfy compositional equivariance property, where each factor is compositional (e.g. corresponds to human anatomy) and also equivariant to the task. Hence, a good representation that approximates well the ground truth factor has to be compositionally equivariant. By modelling the compositional representations with learnable von-Mises-Fisher (vMF) kernels, we explore how different design and learning biases can be used to enforce the representations to be more compositionally equivariant under un-, weakly-, and semi-supervised settings. Extensive results show that our methods achieve the best performance over several strong baselines on the task of semi-supervised domain-generalised medical image segmentation. Code will be made publicly available upon acceptance at https://github.com/vios-s.

Albumin Redox Modifications Promote Cell Calcification Reflecting the Impact of Oxidative Status on Aortic Valve Disease and Atherosclerosis.

Calcific aortic valve disease (CAVD) and coronary artery disease (CAD) are related cardiovascular diseases in which common mechanisms lead to tissue calcification. Oxidative stress plays a key role in these diseases and there is also evidence that the redox state of serum albumin exerts a significant influence on these conditions. To further explore this issue, we used multimarker scores (OxyScore and AntioxyScore) to assess the global oxidative status in patients with CAVD, with and without CAD, also evaluating their plasma thiol levels. In addition, valvular interstitial cells were treated with reduced, oxidized, and native albumin to study how this protein and its modifications affect cell calcification. The differences we found suggest that oxidative status is distinct in CAVD and CAD, with differences in redox markers and thiol levels. Importantly, the in vitro interstitial cell model revealed that modified albumin affects cell calcification, accelerating this process. Hence, we show here the importance of the redox system in the development of CAVD, emphasizing the relevance of multimarker scores, while also offering evidence of how the redox state of albumin influences vascular calcification. These data highlight the relevance of understanding the overall redox processes involved in these diseases, opening the door to new studies on antioxidants as potential therapies for these patients.

Early Estrogen Replacement Therapy Attenuates Cardiac Dysfunction Caused by Aging and Ovariectomy in Female Wistar Rats.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of women's mortality, linked to aging and reduced estrogen during menopause. Estrogen replacement therapy (ERT) is suggested for CVDs prevention. Yet, its timing initiation remains contentious. Thus, we aimed to evaluate the effect of early and late estrogen therapy on cardiac function and lipid metabolism in ovariectomized old female Wistar rats. METHODS: Fifty randomized female Wistar rats were included in 5 groups (n = 10, 18 months old): (1) Sham, (2) 10 weeks post ovariectomy (Ovx-10 w), (3) 10 weeks post Ovx + early estrogen replacement therapy (Ovx 10 w-early ERT), (4) 20 weeks post Ovx (Ovx-20 w) and (5) Ovx 20 w-late ERT. Three days (early ERT) or 10 weeks (late ERT) after surgery 17-ß estradiol was given (5 µg/kg/day), and 10 weeks after the start of ERT, we assessed cardiac function by echocardiography, electrocardiography, and cardiac catheterization. Estradiol, cholesterol, triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels were determined. Cardiac histology was performed with Masson's staining. RESULTS: Ovariectomy (Ovx) increases left ventricle internal systolic diameter (0.4 vs 0.3 cm, *p = 0.020) and decreases shortening fraction (40 vs 54 %, *p = 0.030) regardless of therapy. ERT prevents the increase in left ventricle mass after 10 weeks post-Ovx and the ejection fractionreduction after 20 weeks. Lower P wave amplitudes (18.8 vs 24.2 ms, *p = 0.013) were found in the Ovx-20 w group. A longer duration of the QRS complex after 20 weeks post-Ovx with and without ERT was found (32.5 and 32.1 vs 28.3 ms, *p = 0.003; *p = 0.007). Diastolic blood pressure was higher 20 weeks post-Ovx (86 vs 76 mmHg, *p = 0.047), regardless of ERT. The left ventricle (LV) -dP/dt was decreased in Ovx groups without ERT (-750 vs -1320 mmHg, *p = 0.034). An increase in LV collagen deposition was found in the Ovx 10 w group vs Sham (9.58 vs 4.54 %, *p = 0.028). Early ERT avoids the increase in body weight, cholesterol and LDL caused by Ovx. CONCLUSIONS: Ovariectomy causes time-dependent alterations in lipid metabolism, morphology, electrical activity, and heart contractile function. Early but not late ERT prevents some of these effects.

As We Were and as We Should Be, Combined Exercise Training in Adults with Schizophrenia: CORTEX-SP Study Part I.

INTRODUCTION: Given the health benefits and the role of exercise as an anti-inflammatory adjuvant program, this study aimed to determine the effectiveness of a combined exercise program on cardiorespiratory fitness (CRF), body composition, and biochemical levels in adults with schizophrenia (SZ) characterized at baseline as metabolically unhealthy overweight with low CRF. METHODS: Participants diagnosed with SZ ( n = 112, 41.3 ± 10.4 yr, 28.7% women) were randomly assigned into a treatment-as-usual control group ( n = 53) or a supervised exercise group ( n = 59, 3 d·wk -1 ). Each combined exercise session consisted of both a low-volume high-intensity interval training (<10 min of high-intensity time per session) and a resistance circuit-training program. All variables were assessed before and after the intervention (20 wk). For the assessment of CRF, a peak cardiopulmonary exercise test on a cycle ergometer was used. RESULTS: After the intervention, participants from the exercise group ( n = 51) showed increases in CRF ( P < 0.001) through peak oxygen uptake (L·min -1 ; Δ = 17.6%; mL·kg -1 ·min -1 , Δ = 19.6%) and the metabolic equivalent of task (Δ = 19%), with no significant changes ( P > 0.05) in body composition and biochemical variables. However, the treatment-as-usual group ( n = 38) did not show any significant change in the study variables ( P > 0.05). Between-group significant differences ( P ≤ 0.05) were observed in CRF, first ventilatory threshold, and heart rate peak after the intervention period, favoring the exercise group. CONCLUSIONS: This study demonstrated that a supervised combined exercise program in people with SZ helps to maintain body composition values and improve CRF levels. This could lead to an important clinical change in the characterization from metabolically unhealthy overweight to a metabolically healthy overweight population. Hence, exercise should be considered a co-adjuvant program in the treatment of the SZ population.

Assessing the relevance of mental health factors in fibromyalgia severity: A data-driven case study using explainable AI.

BACKGROUND AND OBJECTIVE: Fibromyalgia is a chronic disease that causes pain and affects patients' quality of life. Current treatments focus on pharmacological therapies for pain reduction. However, patients' psychological well-being is also affected, with depression and pain catastrophizing being common. This research addresses the clinicians' need to assess the influence of mental health factors on FM severity compared to pain factors. METHODS: A co-development study between FM clinicians and data scientists analyzed data from 166 FM-diagnosed patients to assess the influence of mental health factors on FM severity in comparison to pain factors. The study used the Polysymptomatic Distress Scale (PDS) and Fibromyalgia Impact Questionnaire (FIQ) as FM severity indicators and collected 15 variables including regarding demographics, pain intensity perceived, and mental health factors. The team used an author's developed framework to identify the optimal FM severity classifier and explainability by selecting a number of features that lead to obtaining the best classification result. Machine learning classifiers employed in the framework were: decision trees, logistic regression, support vector machines, random forests, AdaBoost, extra trees, and RUSBoost. Explainability analyses were conducted using the following explainable AI techniques: SHapley Additive exPlanations (SHAP), Partial Dependence Plot (PDP), and Mean Decrease Impurity (MDI). RESULTS: A balanced random forest with 6 features achieved the best performance with PDS (AUC_ROC, mean = 0.81, std = 0.07). Being FIQ the target variable, due to the imbalance in FM severity levels, a binary and a multiclass classification approaches were considered achieving the optimal performance, respectively, a logistic regression classifier (AUC_ROC, mean = 0.83, std = 0.08) with 6 selected features, and a random forest (AUC_ROC, mean = 0.91, std = 0.04) with 8 selected features. Next, the explainability analysis determined mental health factors were found to be more relevant than pain perceived factors for FM severity. CONCLUSIONS: This study's findings, validated by clinicians, are potentially aligned with FM international guidelines that promote non-pharmacological interventions such as promoting mental well-being of FM patients.

Neural networks memorise personal information from one sample.

Deep neural networks (DNNs) have achieved high accuracy in diagnosing multiple diseases/conditions at a large scale. However, a number of concerns have been raised about safeguarding data privacy and algorithmic bias of the neural network models. We demonstrate that unique features (UFs), such as names, IDs, or other patient information can be memorised (and eventually leaked) by neural networks even when it occurs on a single training data sample within the dataset. We explain this memorisation phenomenon by showing that it is more likely to occur when UFs are an instance of a rare concept. We propose methods to identify whether a given model does or does not memorise a given (known) feature. Importantly, our method does not require access to the training data and therefore can be deployed by an external entity. We conclude that memorisation does have implications on model robustness, but it can also pose a risk to the privacy of patients who consent to the use of their data for training models.

Controlling the coarsening dynamics of ferrogranular networks by means of a vertical magnetic field.

We are exploring in experiments the aggregation process in a shaken granular mixture of glass and magnetized steel beads, filled in a horizontal vessel, after the shaking amplitude is suddenly decreased. Then the magnetized beads form a transient network that coarsens in time into compact clusters, resembling a viscoelastic phase separation [Tanaka, J. Phys.: Condens. Matter 12, R207 (2000)0953-898410.1088/0953-8984/12/15/201], where attached beads represent the slow phase. Here we investigate how a homogeneous magnetic field oriented in vertical direction impedes the emergence and growth of the networks. With increasing field amplitude this phase is replaced by a fluctuating arrangement of repelling, isolated steel beads. The experimental results are compared with those of computer simulations. Coarse-grained molecular dynamics confirms the impact of an applied magnetic field on the structural transitions and allows us to investigate long-time regimes and magnetic response not yet accessible in the experiment. It turns out that an applied magnetic field has different impacts, depending on it strength. It can be used either to slow down the dynamics of the structural transitions without changing the type of the resulting phases and only affecting the amount and sizes of clusters, or to fully impede the formation of network-like and compact aggregates of steel beads.

Convalescent Adaptive Immunity Is Highly Heterogenous after SARS-CoV-2 Infection.

The optimal detection strategies for effective convalescent immunity after SARS-CoV-2 infection and vaccination remain unclear. The objective of this study was to characterize convalescent immunity targeting the SARS-CoV-2 spike protein using a multiparametric approach. At the beginning of the pandemic, we recruited 30 unvaccinated convalescent donors who had previously been infected with COVID-19 and 7 unexposed asymptomatic controls. Peripheral blood mononuclear cells (PBMCs) were obtained from leukapheresis cones. The humoral immune response was assessed by measuring serum anti-SARS-CoV-2 spike S1 subunit IgG via semiquantitative ELISA, and T-cell immunity against S1 and S2 subunits were studied via IFN-γ enzyme-linked immunosorbent spot (ELISpot) and flow cytometric (FC) activation-induced marker (AIM) assays and the assessment of cytotoxic CD8+ T-cell function (in the subset of HLA-A2-positive patients). No single immunoassay was sufficient in identifying anti-spike convalescent immunity among all patients. There was no consistent correlation between adaptive humoral and cellular anti-spike responses. Our data indicate that the magnitude of anti-spike convalescent humoral and cellular immunity is highly heterogeneous and highlights the need for using multiple assays to comprehensively measure SARS-CoV-2 convalescent immunity. These observations might have implications for COVID-19 surveillance, and the determination of optimal vaccination strategies for emerging variants. Further studies are needed to determine the optimal assessment of adaptive humoral and cellular immunity following SARS-CoV-2 infection, especially in the context of emerging variants and unclear vaccination schedules.

Timing Matters: Effects of Early and Late Estrogen Replacement Therapy on Glucose Metabolism and Vascular Reactivity in Ovariectomized Aged Wistar Rats.

Cardiovascular disease incidence increases after menopause due to the loss of estrogen cardioprotective effects. However, there are conflicting data regarding the timing of estrogen therapy (ERT) and its effect on vascular dysfunction associated with impaired glucose metabolism. The aim of this work was to evaluate the effect of early and late ERT on blood glucose/insulin balance and vascular reactivity in aged ovariectomized Wistar rats. Eighteen-month-old female Wistar rats were randomized as follows: (1) sham, (2) 10-week postovariectomy (10 w), (3) 10 w postovariectomy+early estradiol therapy (10 w-early E2), (4) 20-week postovariectomy (20 w), and (5) 20-week postovariectomy+late estradiol therapy (20 w-late E2). Early E2 was administered 3 days after ovariectomy and late therapy after 10 weeks, in both groups. 17ß-Estradiol (E2) was administered daily for 10 weeks (5 µg/kg/day). Concentration-response curves to angiotensin II, KCl, and acetylcholine (ACh) were performed. Heart rate (HR), diastolic and systolic blood pressure (DBP and SBP), glucose, insulin, HOMA-IR, and nitric oxide (NO) levels were determined. Higher glucose levels were found in all groups compared to the sham group, except the 20 w-late E2 group. Insulin was increased in all ovariectomized groups compared to sham. The HOMA-IR index showed insulin resistance in all ovariectomized groups, except for the 10 w-early E2 group. The 10 w-early E2 group increased NO levels vs. the 10 w group. After 10 w postovariectomy, the vascular response to KCl and Ach increases, despite early E2 administration. Early and late E2 treatment decreased vascular reactivity to Ang II. At 20-week postovariectomy, DBP increased, even with E2 administration, while SBP and HR remained unchanged. The effects of E2 therapy on blood glucose/insulin balance and vascular reactivity depend on the timing of therapy. Early ERT may provide some protective effects on insulin resistance and vascular function, whereas late ERT may not have the same benefits.

Relevancia del estudio genético de la amiloidosis cardíaca por transtiretina en el anciano / Importance of genetic study in elderly patients with transthyretin cardiac amyloidosis

Antecedentes y objetivo La amiloidosis cardiaca por transtiretina (AC-ATTR) es una enfermedad prevalente con la edad. Se recomienda realizar sistemáticamente un estudio genético incluso en los pacientes más añosos. Nuestro objetivo ha sido realizar un análisis de la prevalencia de amiloidosis por transtiretina hereditaria (ATTRv) en ancianos (≥75años) con AC-ATTR y sus implicaciones. Pacientes y método Estudio observacional retrospectivo de la cohorte de pacientes ancianos con AC-ATTR diagnosticados de acuerdo con el protocolo internacional. Analizamos los resultados de la secuenciación del gen TTR, las características diferenciales y sus implicaciones clínicas. Resultados Entre 2016 y 2022 se diagnosticaron 130 pacientes ancianos (89% cohorte) con AC-ATTR (85% varones). En 8 pacientes de los 123 con estudio genético se identificó una variante patogénica en TTR (6,5%), iniciándose tratamiento específico en 4 sujetos (50%). El estudio familiar identificó otro caso y 6 portadores asintomáticos. No hubo diferencias significativas entre características basales ni en los eventos clínicos. Conclusiones La prevalencia de ATTRv en ancianos con AC-ATTR fue del 6,5%, sin observarse características diferenciales que permitan guiar una indicación selectiva del análisis genético (AU)

Background and objective Cardiac transthyretin amyloidosis (CA-ATTR) is a prevalent disease with age. Genetic study is recommended, even in eldest patients. We aim to analyze the prevalence of hereditary transthyretin amyloidosis (ATTRv) in elderly patients (≥75years) with CA-ATTR and its implications. Patients and methodology Retrospective observational study of the cohort of elderly patients with CA-ATTR diagnosed according to the international recommended protocol. We analyze the results of sequencing TTR gene, the differential characteristics and their clinical implications. Results Between 2016 and 2022, 130 elderly patients (89% cohort) were diagnosed with CA-ATTR (85% male). In 8 of the 123 patients with a genetic study, a pathogenic variant in TTR was identified (6.5%), initiating specific treatment in 4 subjects (50%). The family study identified another case and 6 asymptomatic carriers. There were no significant differences between baseline characteristics or in clinical events. Conclusions The prevalence of ATTRv in elderly patients with CA-ATTR was 6.5% without observing differential characteristics that allow guiding a selective indication of genetic analysis (AU)

Predictive capacity of a genetic risk score for coronary artery disease in assessing recurrences and cardiovascular mortality among patients with myocardial infarction.

Aim: This study aimed to evaluate the capacity of a genetic risk score (GRS) for coronary artery disease (CAD) independent of classical cardiovascular risk factors to assess the risk of recurrence in patients with first myocardial infarction. The secondary aim was to determine the predictive value of this GRS. Methods: We performed a meta-analysis of individual data from three studies, namely, a prospective study including 75 patients aged <55 years, a prospective study including 184 patients with a mean age of 60.5 years, and a case-control study (77 cases and 160 controls) nested in a cohort of patients with first myocardial infarction. A GRS including 12 CAD genetic variants independent of classical cardiovascular risk factors was developed. The outcome was a composite of cardiovascular mortality and recurrent acute coronary syndrome. Results: The GRS was associated with a higher risk of recurrence [hazard ratio = 1.24; 95% confidence interval (CI): 1.04-1.47]. The inclusion of the GRS in the clinical model did not increase the model's discriminative capacity (change in C-statistic/area under the curve: 0.009; 95% CI: -0.007 to 0.025) but improved its reclassification (continuous net reclassification index: 0.29; 95% CI: 0.08-0.51). Conclusion: The GRS for CAD, independent of classical cardiovascular risk factors, was associated with a higher risk of recurrence in patients with first myocardial infarction. The predictive capacity of this GRS identified a subgroup of high-risk patients who could benefit from intensive preventive strategies.