COATi: Statistical Pairwise Alignment of Protein-Coding Sequences.

Sequence alignment is an essential method in bioinformatics and the basis of many analyses, including phylogenetic inference, ancestral sequence reconstruction, and gene annotation. Sequencing artifacts and errors made during genome assembly, such as abiological frameshifts and incorrect early stop codons, can impact downstream analyses leading to erroneous conclusions in comparative and functional genomic studies. More significantly, while indels can occur both within and between codons in natural sequences, most amino-acid- and codon-based aligners assume that indels only occur between codons. This mismatch between biology and alignment algorithms produces suboptimal alignments and errors in downstream analyses. To address these issues, we present COATi, a statistical, codon-aware pairwise aligner that supports complex insertion-deletion models and can handle artifacts present in genomic data. COATi allows users to reduce the amount of discarded data while generating more accurate sequence alignments. COATi can infer indels both within and between codons, leading to improved sequence alignments. We applied COATi to a dataset containing orthologous protein-coding sequences from humans and gorillas and conclude that 41% of indels occurred between codons, agreeing with previous work in other species. We also applied COATi to semiempirical benchmark alignments and find that it outperforms several popular alignment programs on several measures of alignment quality and accuracy.

Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).

When Does Primary Prevention Encroach on Secondary Prevention?

PURPOSE OF REVIEW: The risk of incident atherosclerotic cardiovascular disease (ASCVD) in primary prevention is typically lower than in secondary prevention. However, there is a spectrum of risk among individuals undergoing primary prevention with the risk in some individuals approaching those of secondary prevention. We review the clinical conditions wherein the risk in primary prevention is similar to that observed in secondary prevention. RECENT FINDINGS: Among individuals without established ASCVD, coronary artery calcium (CAC) scores ≥ 300 AU are associated with ASCVD event rates similar to secondary prevention populations. CAC score ≥ 1,000 AU are associated with an ASCVD risk seen in very high-risk secondary prevention populations. Interpretation of these observations must however consider differences in the risk reduction strategies. Current guidelines dichotomize ASCVD prevention into primary and secondary prevention, but certain primary prevention patients have an ASCVD risk equivalent to that of secondary prevention populations. Identifying higher risk primary prevention populations will allow for better risk mitigation strategies.

Infections in the first year after heart transplantation in a Latin American country.

BACKGROUND: Heart transplantation is the therapy of choice in patients with advanced heart failure refractory to other medical or surgical management. However, heart transplants are associated with complications that increase posttransplant morbidity and mortality. Infections are one of the most important complications after this procedure. Therefore, infections in the first year after heart transplantation were evaluated. METHODS: A retrospective cohort study of infections after heart transplants was conducted in a teaching hospital in Colombia between 2011 and 2019. Patients registered in the institutional heart transplant database (RETRAC) were included in the study. Microbiological isolates and infectious serological data were matched with the identities of heart transplant recipients and data from clinical records of individuals registered in the RETRAC were analyzed. The cumulative incidences of events according to the type of microorganism isolated were estimated using Kaplan-Meier survival analyses. RESULTS: Seventy-nine patients were included in the study. Median age was 49 years (37.4-56.3), and 26.58% of patients were women. Eighty-seven infections were documented, of which 55.17% (48) were bacterial, 22.99% (20) were viral, and 12.64% (11) were fungal. Bacterial infections predominated in the first month. In the first year, infections caused 38.96% of hospital admissions and were the second cause of death after heart transplants (25.0%). CONCLUSION: Posttransplant infections in the first year of follow-up were frequent. Bacterial infections predominated in the early posttransplant period. Infections, mainly bacterial, were the second most common cause of death and the most common cause of hospitalization in the first year after heart transplantation.

Adherence to Treatment Guidelines in Ambulatory Heart Failure Patients with Reduced Ejection Fraction in a Latin-American Country: Observational Study of the Colombian Heart Failure Registry (RECOLFACA).

INTRODUCTION: Although several guidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF) be treated with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs) or angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 inhibitor (SGLT2i), there are still several gaps in their prescription and dosage in Colombia. This study aimed to describe the use patterns of HFrEF treatments in the Colombian Heart Failure Registry (RECOLFACA). METHODS: Patients with HFrEF enrolled in RECOLFACA during 2017-2019 were included. Heart failure (HF) medication prescription and daily dose were assessed using absolute numbers and proportions. Therapeutic schemes of patients treated by internal medicine specialists were compared with those treated by cardiologists. RESULTS: Out of 2,528 patients in the registry, 1,384 (54.7%) had HFrEF. Among those individuals, 88.9% were prescribed beta-blockers, 72.3% with ACEI/ARBs, 67.9% with MRAs, and 13.1% with ARNIs. Moreover, less than a third of the total patients reached the target doses recommended by the European HF guidelines. No significant differences in the therapeutic schemes or target doses were observed between patients treated by internal medicine specialists or cardiologists. CONCLUSION: Prescription rates and target dose achievement are suboptimal in Colombia. Nevertheless, RECOLFACA had one of the highest prescription rates of beta-blockers and MRAs compared to some of the most recent HF registries. However, ARNIs remain underprescribed. Continuous registry updates can improve the identification of patients suitable for ARNI and SGLT2i therapy to promote their use in clinical practice.

Clinical Characteristics and Outcomes of Patients with Heart Failure of Hypertensive Etiology: Analysis of Colombian Heart Failure Registry (RECOLFACA).

INTRODUCTION: Arterial hypertension represents one of the main comorbidities observed in patients with heart failure (HF) and one of the main risk factors for its development. Despite this, studies assessing this hypertensive etiology are scarce in Latin America. Our objective was to analyze the prevalence of HF of hypertensive etiology and evaluate its prognosis in patients enrolled in the Colombian Heart Failure Registry (RECOLFACA by its Spanish acronym). METHODS: RECOLFACA recruited adult patients diagnosed with HF in 60 centers in Colombia between 2017 and 2019. The primary outcome was all-cause mortality. A Cox proportional hazards regression model was used to assess factors associated with primary outcomes in patients with hypertensive HF. A p value <0.05 was considered significant. All statistical tests were two-tailed. RESULTS: Out of the total number of patients evaluated in RECOLFACA (n = 2,514), 804 had a diagnosis of HF with hypertensive etiology (31.9%). These patients were less frequently males and had a significantly older age and lower prevalence of comorbidities than those with HF of other etiologies. Additionally, patients with hypertensive HF had a higher prevalence of HF with preserved ejection fraction (HFpEF) (34.1% vs. 28.3%; p = 0.004). Finally, type 2 diabetes mellitus, chronic obstructive pulmonary disease diagnosis, and NYHA class IV were classified as independent mortality risk factors. CONCLUSIONS: Hypertensive HF represents about one-third of the total number of patients with HF in RECOLFACA. Compared with HF of other etiologies, it presents a differential clinical profile - older age and a higher prevalence of HFpEF. RECOLFACA has become a useful tool to characterize patients with HF in Colombia, with which it has been possible to carry out a more specific search and reach the diagnosis of this pathology in our population, and it has served as an example to stimulate registries of patients with HF in other countries in the region.

Health insurance and clinical outcomes in patients with chronic heart failure in Latin America: an observational study of the Colombian Heart Failure Registry (RECOLFACA).

The effect of the health insurance type on the prognosis of heart failure (HF) patients in Colombia and Latin America is poorly known. We aimed to analyze the characteristics of HF patients that participated in the Colombian Heart Failure Registry (RECOLFACA) as stated by their health insurance type and their relationship with the immediate prognosis of these patients. Patients with HF diagnosis were included in the RECOLFACA registry between 2017-2019. The registry was conducted in 60 centers in Colombia. All-cause mortality was the principal outcome. To evaluate the impact of health insurance on mortality, a Cox proportional hazards regression model was used. The Kaplan-Meier analysis was performed to compare survival probabilities according to insurance type. All statistical analyses were two-tailed and were considered significant with a p value < 0.05. Of the 2,528 participants enrolled in the registry, 99% held details about their health insurance. Of those, 897 patients (35.6%) were covered by public insurance. These patients were significantly younger, with a lower proportion of men, more frequently from rural origin, and lower prevalence of most comorbidities (omitting hypertension, chronic obstructive pulmonary disease (COPD), and Chagas disease) than those with private insurance. Furthermore, patients with public insurance had a worse functional class, as well as a poorer quality of life, and lower frequency of use of implantable devices, while exhibiting similar prescription rates of triple medical therapy for HF. Finally, no differences in short-term mortality were observed between the two groups (HR 1.09; 95% CI 0.79, 1.51). The type of health insurance represents a condition related with relevant differences in the profile of patients with HF in Colombia. Despite this, no significant differences were detected in the short-term prognosis of these patients based on the type of health insurance.

The Role and Implications of COVID-19 in Incident and Prevalent Heart Failure.

PURPOSE OF REVIEW: This review examines the pathophysiological interactions between COVID-19 and heart failure, highlighting the exacerbation of heart failure in COVID-19 patients. It focuses on the complex mechanisms driving worse outcomes in these patients. RECENT FINDINGS: Patients with pre-existing heart failure experience more severe symptoms and higher mortality rates due to mechanisms such as cytokine storms, myocardial infarction, myocarditis, microvascular dysfunction, thrombosis, and stress cardiomyopathy. Elevated biomarkers like troponin and natriuretic peptides correlate with severe disease. Long-term cardiovascular risks for COVID-19 survivors include increased incidence of heart failure, non-ischemic cardiomyopathy, cardiac arrest, and cardiogenic shock. COVID-19 significantly impacts patients with pre-existing heart failure, leading to severe symptoms and higher mortality. Elevated cardiac biomarkers are indicators of severe disease. Acute and long-term cardiovascular complications are common, calling for ongoing research into targeted therapies and improved management strategies to better prevent, diagnose, and treat heart failure in the context of COVID-19.

Measurement of adherence and health-related quality of life during anticoagulation therapy in cancer-associated venous thromboembolism (VTE): a multicenter quantitative study.

PURPOSE: Therapy for cancer-associated venous thromboembolism (VTE) includes long-term anticoagulation, which may have substantial impact on the health-related quality of life (HRQL) of patients. We assessed patient-reported outcomes to characterize the HRQL associated with VTE treatment and to begin to examine those HRQL elements impacting anticoagulation adherence (AA). METHODS: Participants were adult cancer patients with confirmed symptomatic acute lower extremity deep venous thrombosis. Patients were excluded if there was an indication for anticoagulation other than VTE, ECOG performance status >3, or life expectancy < 3 months. Participants were assessed with a self-reported adherence tool. HRQL was measured with a 6-domain questionnaire using a seven-point Likert scale. Evaluations were performed at 30 days and 3 months after enrollment. For the primary objective, an overall adherence rate was calculated at each time point of evaluation. For the HRQL domains, non-parametric testing was used to compare results between subgroups. RESULTS: Seventy-four patients were enrolled. AA and HRQL at 30 days and 3 months were assessed in 50 and 36 participants, respectively. At 30 days the AA rate was 90%, and at 3 months it was 83%. In regard to HRQL, patients suffered frequent and moderate-severe distress in the domains of emotional and physical symptoms, sleep disturbance, and limitations to physical activity. An association between emotional or physical distress and AA was observed. CONCLUSION: Patients with VTE suffer a substantial impairment of their HRQL. Increased emotional distress correlated with better long-term AA. These results can be used to inform additional research aimed at developing novel strategies to improve AA.

Treatments for multi-system inflammatory syndrome in children - discharge, fever, and second-line therapies.

Scarce evidence exists about the best treatment for multi-system inflammatory syndrome (MIS-C). We analyzed the effects of steroids, intravenous immunoglobulin (IVIG), and their combination on the probability of discharge over time, the probability of switching to second-line treatment over time, and the persistence of fever 2 days after treatment. We did a retrospective study to investigate the effect of different treatments on children with MIS-C from 1 March 2020 to 1 June 2021. We estimated the time-to-event probability using a Cox model weighted by propensity score to balance the baseline characteristics. Thirty of 132 (22.7%) patients were initially treated with steroids alone, 29/132 (21.9%) with IVIG alone, and 73/132 (55%) with IVIG plus steroids. The probability of early discharge was higher with IVIG than with IVIG plus steroids (hazard ratio [HR] 1.65, 95% CI 1.11-2.45, p = 0.013), but with a higher probability of needing second-line therapy compared to IVIG plus steroids (HR 3.05, 95% CI 1.12-8.25, p = 0.028). Patients on IVIG had a higher likelihood of persistent fever than patients on steroids (odds ratio [OR] 4.23, 95% CI 1.43-13.5, p = 0.011) or on IVIG plus steroids (OR 4.4, 95% CI 2.05-9.82, p < 0.001). No differences were found for this endpoint between steroids or steroids plus IVIG.    Conclusions: The benefits of each approach may vary depending on the outcome assessed. IVIG seemed to increase the probability of earlier discharge over time but also of needing second-line treatment over time. Steroids seemed to reduce persistent fever, and combination therapy reduced the need for escalating treatment. What is Known: • Steroids plus intravenous immunoglobulin, compared with intravenous immunoglobulin alone for multi-system inflammatory syndrome (MIS-C) might reduce the need for hemodynamic support and the duration of fever, but the certainty of the evidence is low. What is New: • Intravenous immunoglobulin, steroids, and their combination for MIS-C may have different outcomes. • In this study, intravenous immunoglobulin increased the probability of discharge over time, steroids reduced persistent fever, while combination therapy reduced the need for second-line treatments.

A comprehensive approach for discrete resilience of complex networks.

The research and use of the term resilience in various types of technological, physiological, and socioeconomic systems has become very topical in recent years since this term has been applied in different fields with different meanings and connotations. One of the most common meanings of resilience is related to a positive idea that addresses recovery from failures. This study proposes to establish a theoretical and mathematical framework for discrete resilience that allows different systems to be quantitatively compared from this point of view. Also, a definition and a local view of the concept of resilience applicable to different characteristic measures in the field of complex networks is provided. Furthermore, several computational experiments are presented on the values of this new parameter in different types of synthetic and real-world networks, supplying a new set of conceptual tools for network science research.

Synthesis of a novel magnetic nanomaterial for the development of a multielemental speciation method of lead, mercury, and vanadium via HPLC-ICP MS.

A new magnetic functionalized material based on graphene oxide magnetic nanoparticles named by us, M@GO-TS, was designed and characterized in order to develop a magnetic solid-phase extraction method (MSPE) to enrich inorganic and organic species of lead, mercury, and vanadium. A flow injection (FI) system was used to preconcentrate the metallic and organometallic species simultaneously, while the ultra-trace separation and determination of the selected species were achieved by high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP MS). Therefore, preconcentration and separation/determination processes were automated and conducted separately. To the best of our knowledge, this is the first method combining an online MSPE and HPLC-ICP MS for multielemental speciation. Under the optimized conditions, the enrichment factor obtained for PbII, trimethyllead (TML), HgII, methylmercury (MetHg), and VV was 27. The calculated LOD for all studied species were as follows: 5 ng L-1, 20 ng L-1, 2 ng L-1, 10 ng L-1, and 0.4 ng L-1, respectively. The RSD values calculated with a solution containing 0.5 µg L-1 of all species were between 2.5 and 4.5%. The developed method was validated by analyzing Certified Reference Materials TMDA 64.3 for total concentration and also by recovery analysis of the species in human urine from volunteers and a seawater sample collected in Málaga. The t statistical test showed no significant differences between the certified and found values for TMDA 64.3. All the recoveries obtained from spiked human urine and seawater samples were close to 100%. All samples were analyzed using external calibration. The developed method is sensitive and promising for routine monitoring of the selected species in environmental waters and biological samples.

Combining Heart Rate Variability and Oximetry to Improve Apneic Event Screening in Non-Desaturating Patients.

In this paper, we thoroughly analyze the detection of sleep apnea events in the context of Obstructive Sleep Apnea (OSA), which is considered a public health problem because of its high prevalence and serious health implications. We especially evaluate patients who do not always show desaturations during apneic episodes (non-desaturating patients). For this purpose, we use a database (HuGCDN2014-OXI) that includes desaturating and non-desaturating patients, and we use the widely used Physionet Apnea Dataset for a meaningful comparison with prior work. Our system combines features extracted from the Heart-Rate Variability (HRV) and SpO2, and it explores their potential to characterize desaturating and non-desaturating events. The HRV-based features include spectral, cepstral, and nonlinear information (Detrended Fluctuation Analysis (DFA) and Recurrence Quantification Analysis (RQA)). SpO2-based features include temporal (variance) and spectral information. The features feed a Linear Discriminant Analysis (LDA) classifier. The goal is to evaluate the effect of using these features either individually or in combination, especially in non-desaturating patients. The main results for the detection of apneic events are: (a) Physionet success rate of 96.19%, sensitivity of 95.74% and specificity of 95.25% (Area Under Curve (AUC): 0.99); (b) HuGCDN2014-OXI of 87.32%, 83.81% and 88.55% (AUC: 0.934), respectively. The best results for the global diagnosis of OSA patients (HuGCDN2014-OXI) are: success rate of 95.74%, sensitivity of 100%, and specificity of 89.47%. We conclude that combining both features is the most accurate option, especially when there are non-desaturating patterns among the recordings under study.

Global Variations in Heart Failure Etiology, Management, and Outcomes.

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries. Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development. Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years. Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death. Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a ß-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies. Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

Control Theory and Systems Biology: Potential Applications in Neurodegeneration and Search for Therapeutic Targets.

Control theory, a well-established discipline in engineering and mathematics, has found novel applications in systems biology. This interdisciplinary approach leverages the principles of feedback control and regulation to gain insights into the complex dynamics of cellular and molecular networks underlying chronic diseases, including neurodegeneration. By modeling and analyzing these intricate systems, control theory provides a framework to understand the pathophysiology and identify potential therapeutic targets. Therefore, this review examines the most widely used control methods in conjunction with genomic-scale metabolic models in the steady state of the multi-omics type. According to our research, this approach involves integrating experimental data, mathematical modeling, and computational analyses to simulate and control complex biological systems. In this review, we find that the most significant application of this methodology is associated with cancer, leaving a lack of knowledge in neurodegenerative models. However, this methodology, mainly associated with the Minimal Dominant Set (MDS), has provided a starting point for identifying therapeutic targets for drug development and personalized treatment strategies, paving the way for more effective therapies.

Development and Evaluation of 99mTc Tricarbonyl Complexes Derived from Flutamide with Affinity for Androgen Receptor.

With the objective to develop a potential 99mTc radiopharmaceutical for imaging the androgen receptor (AR) in prostate cancer, four ligands bearing the same pharmacophore derived from the AR antagonist flutamide were prepared, labeled with 99mTc, and their structures corroborated via comparison with the corresponding stable rhenium analogs. All complexes were obtained with high radiochemical purity. Three of the complexes were highly stable, and, due to their favorable physicochemical properties, were further evaluated using AR-positive and AR-negative cells in culture. All complexes exhibited considerable uptake in AR-positive cells, which could be blocked by an excess of flutamide. The efflux from the cells was moderate. They also showed significantly lower uptakes in AR-negative cells, indicating interactions with the AR receptor. However, the binding affinities were considerably reduced by the coordination to 99mTc, and the complex that exhibited the best biological behavior did not show sufficient specificity towards AR-positive cells.

Medical decisions in organ donors and heart transplant candidates with history of COVID-19 infection: An international practice survey.

BACKGROUND: A growing proportion of transplant donors and recipients have a history of COVID-19 infection. This study sought to characterize clinical practice after recipient or donor COVID-19 infection. METHODS: An online survey was distributed to heart transplant clinicians through a professional society message board and social media. Responses were collected between September 29 and November 5, 2021. RESULTS: There were 222 health care professionals (68% transplant cardiologists, 22% transplant surgeons, 10% other) across diverse geographic regions who completed the survey. While there was significant variation in donor acceptance, as it relates to past and current COVID-19 infection, the respondents were fairly cautious: 28% would not typically accept a donor with a history of COVID-19 regardless of the infection course and > 80% would not accept donors who had evidence of myocardial dysfunction during past COVID-19 infection, or who died of COVID-19 or its complications. The timing of candidate reactivation on the waiting list after COVID-19 infection also varied and often diverged from scenarios addressed by social guidelines. Eighty-one percent of the respondents felt COVID-19 vaccine should be mandatory before transplant, but this rate varied by geographic region. CONCLUSION: Our results reflect evolving experience of the heart transplant field at a time of lack of high-quality evidence. In the absence of longer-term outcome data for donors and transplant candidates with history of COVID-19 infection, clinicians remain cautious; however, this approach will likely need to be refined as an increasing proportion of the population will continue to be infected with COVID-19.

Clinical spectrum of COVID-19 and risk factors associated with severity in Spanish children.

We aimed to identify the spectrum of disease in children with COVID-19, and the risk factors for admission in paediatric intensive care units (PICUs). We conducted a multicentre, prospective study of children with SARS-CoV-2 infection in 76 Spanish hospitals. We included children with COVID-19 or multi-inflammatory syndrome (MIS-C) younger than 18 years old, attended during the first year of the pandemic. We enrolled 1200 children. A total of 666 (55.5%) were hospitalised, and 123 (18.4%) required admission to PICU. Most frequent major clinical syndromes in the cohort were mild syndrome (including upper respiratory tract infection and flu-like syndrome, skin or mucosae problems and asymptomatic), 44.8%; bronchopulmonary syndrome (including pneumonia, bronchitis and asthma flare), 18.5%; fever without a source, 16.2%; MIS-C, 10.6%; and gastrointestinal syndrome, 10%. In hospitalised children, the proportions were 28.5%, 25.7%, 16.5%, 19.1% and 10.2%, respectively. Risk factors associated with PICU admission were age in months (OR: 1.007; 95% CI 1.004 to 1.01), MIS-C (OR: 14.4, 95% CI 8.9 to 23.8), chronic cardiac disease (OR: 4.8, 95% CI 1.8 to 13), asthma or recurrent wheezing (OR: 2.5, 95% CI 1.2 to 5.2) and after excluding MIS-C patients, moderate/severe liver disease (OR: 8.6, 95% CI 1.6 to 47.6). However, asthmatic children were admitted into the PICU due to MIS-C or pneumonia, not due to asthma flare.Conclusion: Hospitalised children with COVID-19 usually present as one of five major clinical phenotypes of decreasing severity. Risk factors for PICU include MIS-C, elevation of inflammation biomarkers, asthma, moderate or severe liver disease and cardiac disease. What is Known: • All studies suggest that children are less susceptible to serious SARS-CoV-2 infection when compared to adults. Most studies describe symptoms at presentation. However, it remains unclear how these symptoms group together into clinically identifiable syndromes and the severity associated with them. What is New: • We have gathered the primary diagnoses into five major syndromes of decreasing severity: MIS-C, bronchopulmonary syndrome, gastrointestinal syndrome, fever without a source and mild syndrome. Classification of the children in one of the syndromes is unique and helps to assess the risk of critical illness and to define the spectrum of the disease instead of just describing symptoms and signs.

Iboga Inspired N-Indolylethyl-Substituted Isoquinuclidines as a Bioactive Scaffold: Chemoenzymatic Synthesis and Characterization as GDNF Releasers and Antitrypanosoma Agents.

The first stage of the drug discovery process involves the identification of small compounds with biological activity. Iboga alkaloids are monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring. Both the natural products and the iboga-inspired synthetic analogs have shown a wide variety of biological activities. Herein, we describe the chemoenzymatic preparation of a small library of novel N-indolylethyl-substituted isoquinuclidines as iboga-inspired compounds, using toluene as a starting material and an imine Diels-Alder reaction as the key step in the synthesis. The new iboga series was investigated for its potential to promote the release of glial cell line-derived neurotrophic factor (GDNF) by C6 glioma cells, and to inhibit the growth of infective trypanosomes. GDNF is a neurotrophic factor widely recognized by its crucial role in development, survival, maintenance, and protection of dopaminergic neuronal circuitries affected in several neurological and psychiatric pathologies. Four compounds of the series showed promising activity as GDNF releasers, and a leading structure (compound 11) was identified for further studies. The same four compounds impaired the growth of bloodstream Trypanosoma brucei brucei (EC50 1-8 µM) and two of them (compounds 6 and 14) showed a good selectivity index.

Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure.

In this document, we propose a universal definition of heart failure (HF) as the following: HF is a clinical syndrome with symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and or objective evidence of pulmonary or systemic congestion. We propose revised stages of HF as follows. At-risk for HF (Stage A), for patients at risk for HF but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease. Pre-HF (stage B), for patients without current or prior symptoms or signs of HF, but evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels. HF (Stage C), for patients with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality. Advanced HF (Stage D), for patients with severe symptoms and/or signs of HF at rest, recurrent hospitalizations despite guideline-directed management and therapy (GDMT), refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care. Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). The classification includes HF with reduced EF (HFrEF): HF with an LVEF of ≤40%; HF with mildly reduced EF (HFmrEF): HF with an LVEF of 41% to 49%; HF with preserved EF (HFpEF): HF with an LVEF of ≥50%; and HF with improved EF (HFimpEF): HF with a baseline LVEF of ≤40%, a ≥10-point increase from baseline LVEF, and a second measurement of LVEF of >40%.