Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism.

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis, Leishmania donovani, and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery.

Activity of Oral Tebipenem-Avibactam in a Mouse Model of Mycobacterium abscessus Lung Infection.

The combination of the ß-lactam tebipenem and the ß-lactamase inhibitor avibactam shows potent bactericidal activity against Mycobacterium abscessus in vitro. Here, we report that the combination of the respective oral prodrugs tebipenem-pivoxil and avibactam ARX-1796 showed efficacy in a mouse model of M. abscessus lung infection. The results suggest that tebipenem-avibactam presents an attractive oral drug candidate pair for the treatment of M. abscessus pulmonary disease and could inform the design of clinical trials.

Phenotype of severe tricuspid regurgitation induced by intracardiac pacing devices. / Características de la insuficiencia tricúspide grave inducida por dispositivos de estimulación intracardiacos.

INTRODUCTION AND AIMS: Tricuspid regurgitation (TR) induced by the implantation of cardiac implantable electronic devices (CIED) is an increasingly common cause of severe TR. Our aim was to describe the echocardiographic phenotypic characteristics of CIED-induced severe TR. METHODS: Retrospective cohort study that included patients with severe TR related to CIED diagnosed in the cardiac imaging unit of a Spanish tertiary hospital. RESULTS: 37 patients with severe TR induced by lead/electrode interference formed our study group. TR was predominantly severe (68%), followed by massive (21%) and torrential (11%). The leaflet most affected by the interference was the septal. 58% of the sample presented severe dilatation of the right atrium (RA) (mean RA area 28cm2). Mean tricuspid annulus measurement was 42mm. The usual parameters for quantifying RV systolic function were on average within the normal range (TAPSE mean 19mm, S' wave 10mm, FAC 41%), while global RV strain (RVGLS -15%) and free wall strain (RVFWLS -19%) were found reduced. An incipient degree of ventricular/pulmonary arterial uncoupling was evident (mean TAPSE/PSAP 0.34, SGLVD/PSAP 0.27%/mmHg). CONCLUSIONS: Our patients with CIED-induced severe TR are characterized by a heterogeneous phenotype with a high prevalence of severe RA and tricuspid annulus dilatation. RVGLS, RVFWLS, and arterial ventricular coupling were the most sensitive parameters for early assessment of RV systolic dysfunction.

Prognostic Relevance of Gradient and Flow Status in Severe Aortic Stenosis.

Background: Severe aortic stenosis (AS) may present with different flow, gradient and left ventricular ejection fraction (LVEF) patterns. Paradoxical low-flow low-gradient (PLF-LG) severe AS has a specific clinical profile, but its prognosis and management remain controversial. Our aim is to evaluate the impact of different AS patterns in the incidence of major clinical events. Methods: A retrospective observational study was carried out on all the consecutive patients diagnosed with severe AS at our tertiary hospital centre in 2021. Echocardiographic measurements were carefully reviewed, and patients were classified following current guidelines into four categories: high gradient (HG), concordant low-flow low-gradient (CLF-LG), paradoxical low-flow low-gradient (PLF-LG) and normal-flow low-gradient (NF-LG). The baseline characteristics and clinical events (heart failure admission, intervention and death) at 1-year follow-up were collected from medical records. The association between categories and events was established using Student's t test or ANOVA as required. Results: 205 patients with severe AS were included in the study (81 ± 10 years old, 52.7% female). Category distribution was as follows: HG (138, 67.3%), PLF-LG (34, 19.8%), CLF-LG (21, 10.2%) and NF-LG (12, 5.9%). During the follow-up, 24.8% were admitted due to heart failure, 68.3% received valve replacement (51.7% TAVR) and 22% died. Severe tricuspid regurgitation was more frequent in patients with PLF-LG than in HG AS (14.7% vs. 2.2%; p < 0.01). Despite no differences in intervention rate, more patients with PLF-LG (32.4% vs. 15.9%; p = 0.049) died during the evolution. Conclusions: The PLF-LG pattern was the second most common pattern of severe AS in our cohort, and it was related to a higher mortality with no differences in intervention rate. Thus, this controversial category, rather than being underestimated, should be followed closely and considered for early intervention.

Superiority of 3D planimetry over pressure half-time method for the assessment of mitral valve area after percutaneous edge-to-edge mitral repair.

INTRODUCTION AND OBJECTIVES: There is limited evidence to identify the most accurate method for measuring the mitral valve area (MVA) after percutaneous edge-to-edge mitral repair. Our objective was to evaluate the optimal method in this context and its correlation with the mean transmitral gradient. METHODS: A registry of patients undergoing percutaneous mitral repair was conducted, analyzing different methods of measuring MVA and their correlation with the mean gradient. RESULTS: We analyzed data from 167 patients. The mean age was 76±10.3 years, 54% were men, and 46% were women. Etiology was degenerative in 45%, functional in 39%, and mixed in 16%. Postclip MVA measurements were 1.89±0.60 cm2 using pressure half-time (PHT), 2.87±0.83 cm2 using 3D planimetry, and the mean gradient was 3±1.19mmHg. MVA using 3D planimetry showed a stronger correlation with the mean gradient (r=0.46, P<.001) than MVA obtained by PHT (r=0.19, P=.048). Interobserver agreement was also higher with 3D planimetry than with PHT (intraclass correlation coefficient of 0.90 vs 0.81 and variation coefficient of 9.6 vs 19.7%, respectively). CONCLUSIONS: Our study demonstrates that the PHT method significantly underestimates MVA after clip implantation compared with direct measurement using transesophageal 3D planimetry. The latter method also correlates better with postimplantation gradients and has less interobserver variability. These results suggest that 3D planimetry is a more appropriate method for assessing postclip mitral stenosis.

Aortic Stenosis and the Evolution of Cardiac Damage after Transcatheter Aortic Valve Replacement.

Background/Objectives: Severe aortic stenosis (AS) is the most frequent valvular heart disease. Models for stratifying cardiac damage associated with aortic stenosis have been developed to predict outcomes following valve replacement. However, evidence regarding morphological and functional evolution, as well as potential changes in the degree of cardiac damage, is limited. We aim to provide information on the evolution of cardiac morphology and the function of patients undergoing transcatheter aortic valve replacement (TAVR) who have been classified using a cardiac damage staging system. Methods: In total, 496 patients were included in the analysis, and were classified into four stages based on the extent of cardiac damage as follows: Stage 0, no cardiac damage: left ventricle global longitudinal strain (LV-GLS) < -17%; right ventricular-arterial coupling (RVAc) ≥ 0.35), and absence of significant mitral regurgitation (MR). Stage 1, left-sided subclinical damage: LV-GLS ≥ -17%. Stage 2, left-sided damage: significant MR. Stage 3, right-sided damage: RVAc < 0.35. Results: The mean age was 82.1 ± 5.9 years, and 53.0% were female. In total, 24.5% of patients met the criteria for Stage 0, and Stage 1 included 42.8% of patients, Stage 2 included 16.5%, and Stage 3 comprised 16.2% of patients. Mortality was 8.4% for stage 0, 17.4% for stage 1, 25.6% for stage 2, and 28.6% for stage 3 patients (p = 0.004). Diabetes mellitus (DM) (p = 0.047) and chronic kidney disease (CKD) (p = 0.024) were the only clinical predictors of no change or worsening in the stage of cardiac damage. Regarding echocardiographic variables, concomitant tricuspid, and mitral regurgitation, ≥ 2 were both significantly associated with no change or worsening, also (p < 0.001). Conclusions: Cardiac damage that is secondary to severe aortic stenosis has morphological and functional repercussions that, even after valve replacement, persist and might worsen the prognosis.

Impact of a pulmonary embolism response team initiative on hospital mortality of patients with bilateral pulmonary embolism.

INTRODUCTION: Pulmonary embolism (PE) response teams (PERT) for the management of high-risk PE (HR-PE) and intermediate-high risk PE (IHR-PE) are encouraged in PE guidelines. We aimed to assess the impact of a PERT initiative on mortality in these groups of patients, compared with standard care. METHODS: We conducted a prospective, single-center registry, including consecutive patients with HR-PE and IHR-PE with PERT activation from February-2018 to December-2020 (PERT group, n=78 patients) and compared it with an historic cohort of patients admitted to our hospital in a previous 2-year period (2014-2016), managed with standard of care (SC-group, n=108 patients). RESULTS: Patients in the PERT group were younger and less comorbid. The risk profile at admission and the percentage of HR-PE was similar in both cohorts (13% in SC-group and 14% in PERT-group, p=0.82). Reperfusion therapy was more frequently indicated in PERT-group (24.4% vs 10.2%, p=0.01), with no differences in fibrinolysis treatment, while catheter-directed therapy (CDT) was more frequent in PERT group (16.7% vs 1.9%, p<0.001). Reperfusion and CDT were associated with lower in-hospital mortality (2.9% vs 15.1%, p=0.001 for reperfusion and 1.5% vs 16.5%, p=0.001 for CDT). The primary outcome, 12-month mortality, was lower in the PERT-group (9% vs 22.2%, p=0.02), There were no differences in 30-day readmissions. In multivariate analysis PERT activation was associated with lower mortality at 12 months (HR 0.25, 95% confidence interval 0.09-0.7, p=0.008). CONCLUSION: A PERT initiative in patients with HR-PE and IHR-PE was associated with a significant reduction in 12-month mortality compared with standard of care, and also with an increase in the use of reperfusion, especially catheter-directed therapies.

Comprehensive analysis of current epidemiology, clinical features and prognostic factors of puerperal endometritis: A retrospective cohort analysis.

Background: Puerperal endometritis has not been recently investigated. We aimed to describe the current dimension of the endometritis in the context of other causes of puerperal fever and investigate the microbiology and need for curettage in these patients. Methods: A retrospective cohort study was conducted based on a prospectively maintained database of patients with puerperal fever, (2014-2020) in which cases fulfilling criteria for endometritis were selected for further analysis. Description of clinical and microbiological features was performed and determination of the factors related with puerperal curettage requirement were studied using univariate and multivariate analysis through binary logistic regression. Results: From 428 patients with puerperal fever, endometritis was the main cause of puerperal fever (233 patients, 52.7 %). Curettage was required in 96 of them (41.2 %). Culture of endometrial samples were performed in 62 (64.5 %), of which 32 (51.6 %) yielded bacterial growth. Escherichia coli was the most common microorganism in curettage cultures (46.9 %). Multivariate analysis identified the following predictive factors for curettage: the presence of pattern compatible with retained products of conception (RPOC) in transvaginal ultrasonography (odds ratio [OR]: 17.6 [95 % confidence interval [CI]: 8.4-36.6]; P-value < 0.0001), fever during the first 14 days after delivery (OR:5.1; [95 % CI: 1.57-16.5]; P-value 0.007), abdominal pain (OR: 2.9; [95 % CI: 1.36-6.1]; P-value 0.012) and malodorous lochia (OR:3.5; [95 % CI: 1.25-9.9]; P-value 0.017). Scheduled cesarean delivery was protective (OR: 0.11 [95 % CI 0.01-1.2]; P-value 0.08). Conclusions: Endometritis is still the main cause of puerperal fever. Women requiring curettage typically presented with abdominal pain and foul-smelling lochia, an ultrasound image compatible with RPOC and fever in the first 14 days postpartum. Curettage culture is useful for the microbiological affiliation mostly yielding gram-negative enteric flora.

Current Usefulness of Transesophageal Echocardiography in Patients Undergoing Transcatheter Aortic Valve Replacement.

This review article describes in depth the current usefulness of transesophageal echocardiography in patients who undergo transcatheter aortic valve replacement. Pre-intervention, 3D-transesophageal echocardiography allows us to accurately evaluate the aortic valve morphology and to measure the valve annulus, helping us to choose the appropriate size of the prosthesis, especially useful in cases where the computed tomography is not of adequate quality. Although it is not currently used routinely during the intervention, it remains essential in those cases of greater complexity, such as for patients with greater calcification and bicuspid valve, mechanical mitral prosthesis, and "valve in valve" procedures. Three-dimensional transesophageal echocardiography is the best technique to detect and quantify paravalvular regurgitation, a fundamental aspect to decide whether immediate valve postdilation is needed. It also allows to detect early any immediate complications such as cardiac tamponade, aortic hematoma or dissection, migration of the prosthesis, malfunction of the prosthetic leaflets, or the appearance of segmental contractility disorders due to compromise of the coronary arteries ostium. Transesophageal echocardiography is also very useful in follow-up, to check the proper functioning of the prosthesis and to rule out complications such as thrombosis of the leaflets, endocarditis, or prosthetic degeneration.

The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis.

The sensitivity of Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis, which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.

Combined off-pump mitral repair and thoracoscopic maze surgery.

A 67-year-old man with severe mitral regurgitation and paroxysmal atrial fibrillation was admitted to our institution for surgical repair. The procedure was carried out off-pump. We first performed a totally thoracoscopic maze box lesion set with epicardial transmural radiofrequency, and clipped the left atrial appendage. The mitral valve prolapse was repaired by implanting three transapical neochordae. Six months later, the patient was in sinus rhythm with minimal residual mitral regurgitation on echocardiography. This novel approach is less invasive than the standard surgical correction and should ensure a faster recovery with similar safety and efficacy in selected cases.

Severe Acute Respiratory Syndrome Coronavirus 2 Vertical Transmission from an Asymptomatic Mother.

In utero transmission of severe acute respiratory syndrome coronavirus 2 infection is a point of debate. We report a case of severe acute respiratory syndrome coronavirus 2 vertical transmission from asymptomatic mother, with molecular detection in mother's blood at delivery and neonatal nasopharyngeal swabs at 5 and 28 hours of life and later IgG seroconversion. The newborn was asymptomatic.

Relationship between anthropometric variables and the cross-sectional area of the median nerve by ultrasound assessment in healthy subjects.

OBJECTIVE: Ultrasound study of the wrist in patients with suspected entrapment syndrome has severe limitations due to the variability of what is considered normal for the cross-sectional area of the median nerve and where to proceed to measure it. We aim to determine the extent to which different anthropometric variables influence the median nerve area in subjects without carpal tunnel syndrome. METHODS: We conducted an observational study based on a multivariate linear regression analysis using as a dependent variable the area of the median nerve cut at two specific points in the wrist of healthy subjects. The independent variables were sex, age, height, weight, body mass index, finger flexor strength, and carpal circumference. MAJOR RESULTS: The measurements of the median nerve cross-sectional area were normalized using a quadratic fixing procedure. Of all the variables included in the linear regression analysis, only carpal circumference and sex (0: female, 1: male) contributed significantly in the final model using the wrist crease as the measurement point (Constant B=-209.45, carpal circumference coefficient=21.07, sex coefficient 10.87). At four centimeters distal to the carpal fold, the model included the same variables (Constant B=-221.84, carpal circumference coefficient=24.01, and sex coefficient=11.41). CONCLUSION: Both the wrist circumference and the sex are variables that should be considered to determine cut-off points of normality in future validation studies about the cross-sectional area of the median nerve.

Update on cardiac imaging techniques 2014.

In this article, we review the contributions of the most important imaging techniques used in cardiology, reported in 2014. Echocardiography remains the cornerstone for diagnosing and monitoring valvular heart disease, and there has been a continuing effort to improve quantification of this condition and obtain prognostic parameters for follow-up. The study of regional myocardial function is anchored in the diagnosis of subclinical ventricular dysfunction, and 3-dimensional transesophageal echocardiography has become the perfect ally in interventional procedures for structural heart disease. Cardiac magnetic resonance imaging and cardiac computed tomography are the focus of most publications on cardiac imaging in ischemic heart disease, reflecting their consolidated use in clinical practice. Nuclear medicine excels in the study of myocardial viability after interventional treatment of acute coronary syndromes and its performance is validated in the diagnosis of ischemic heart disease.

Update on cardiac imaging techniques 2013.

Cardiac imaging is a cornerstone of diagnosis in heart conditions, and an essential tool for assessing prognosis and establishing treatment decisions. This year, echocardiography stands out as a guide in interventional procedures and in choosing the size of the prosthesis. It is also proving to be a valuable technique in low-flow, low-gradient aortic stenosis. Three-dimensional echocardiography is advancing our knowledge of cardiac anatomy and valvular measurements. The parameters indicating tissue deformation have predictive power in valve disease and in the follow-up of drug-induced cardiotoxicity. Single-photon emission computed tomography and positron emission tomography are proving useful in ischemic heart disease and in the diagnosis of cardiac inflammation and infections. The role of computed tomography has been strengthened in noninvasive coronary angiography, the emergency room management of chest pain, assessment of chronic occlusions, and morphologic study of coronary plaque. Cardiac magnetic resonance imaging remains the gold standard for tissue characterization in ischemic heart disease and cardiomyopathies, and is assuming a greater role in stress studies and in the assessment of myocardial viability.

Postcesarean Section Skin-to-Skin Contact of Mother and Child.

The first hour postpartum is critical for long-term, healthy development. At 12 de Octubre Hospital, Madrid, Spain, we developed and implemented a multidisciplinary strategy based on a consensual, participatory protocol for all health care professionals involved in cesarean deliveries. Our aims were 2-fold: the initiation of skin-to-skin (StS) contact with the newborn immediately after birth, regardless of the feeding method chosen, and the recognition of the importance of a companion present for support during the cesarean section (father or other designated by the mother). The objective of this article is to describe a policy developed to ensure timely postcesarean StS contact. Our protocol for neonatal StS contact with the mother is based on reported benefits found in literature, the World Health Organization's international recommendations, and deep respect for a process that is both natural and instinctive. We call it "humanizing the cesarean."

Hydroxychloroquine in obstetrics: New outlooks for therapy / La hidroxicloroquina en obstetricia. Nuevas perspectivas terapeuticas

Hydroxychloroquine is an antimalarial drug that is used to treat autoimmune diseases. It is safe in pregnancy and compatible with breastfeeding. Hydroxychloroquine is the drug of choice in pregnant women in need of treatment. Recently, it has proven useful for the treatment of refractory antiphospholipid syndrome and prevention of recurrence of congenital heart block in anti Ro/La-positive pregnant women. Two large prospective studies that will confirm the usefulness of this drug currently under way

La hidroxicloroquina es una droga antimalárica utilizada en enfermedades autoinmunes, segura en la gestación y en la lactancia, siendo la terapia de elección de mujeres gestantes que precisen tratamiento. Recientemente se ha visto su utilidad en el tratamiento del síndrome antifosfolipido refractario y en la prevención de la recurrencia del bloqueo cardiaco congénito en gestantes con anticuerpos antiRo/antiLa positivos. Están en marcha dos estudios prospectivos que confirmarán esta alternativa terapéutica

Impact of a pulmonary embolism response team initiative on hospital mortality of patients with bilateral pulmonary embolism / Impacto de una iniciativa de equipo de respuesta a la embolia pulmonar en la mortalidad hospitalaria de pacientes con embolia pulmonar bilateral

Introduction Pulmonary embolism (PE) response teams (PERT) for the management of high-risk PE (HR-PE) and intermediate-high risk PE (IHR-PE) are encouraged in PE guidelines. We aimed to assess the impact of a PERT initiative on mortality in these groups of patients, compared with standard care. Methods We conducted a prospective, single-center registry, including consecutive patients with HR-PE and IHR-PE with PERT activation from February-2018 to December-2020 (PERT group, n=78 patients) and compared it with an historic cohort of patients admitted to our hospital in a previous 2-year period (2014–2016), managed with standard of care (SC-group, n=108 patients). Results Patients in the PERT group were younger and less comorbid. The risk profile at admission and the percentage of HR-PE was similar in both cohorts (13% in SC-group and 14% in PERT-group, p=0.82). Reperfusion therapy was more frequently indicated in PERT-group (24.4% vs 10.2%, p=0.01), with no differences in fibrinolysis treatment, while catheter-directed therapy (CDT) was more frequent in PERT group (16.7% vs 1.9%, p<0.001). Reperfusion and CDT were associated with lower in-hospital mortality (2.9% vs 15.1%, p=0.001 for reperfusion and 1.5% vs 16.5%, p=0.001 for CDT). The primary outcome, 12-month mortality, was lower in the PERT-group (9% vs 22.2%, p=0.02), There were no differences in 30-day readmissions. In multivariate analysis PERT activation was associated with lower mortality at 12 months (HR 0.25, 95% confidence interval 0.09–0.7, p=0.008). Conclusion A PERT initiative in patients with HR-PE and IHR-PE was associated with a significant reduction in 12-month mortality compared with standard of care, and also with an increase in the use of reperfusion, especially catheter-directed therapies (AU)

Introducción Las guías de manejo de embolia pulmonar (EP) recomiendan organizar equipos de respuesta a la embolia pulmonar (PERT) para el manejo de la EP de riesgo intermedio-alto (EP-IAR) y de alto riesgo (EP-AR). Nuestro objetivo fue evaluar el impacto de una iniciativa PERT sobre la mortalidad en estos pacientes, en comparación con la atención estándar. Métodos Realizamos un registro prospectivo unicéntrico, incluyendo pacientes consecutivos con EP-IAR y EP-AR con activación del PERT desde febrero de 2018 hasta diciembre de 2020 (grupo PERT, n=78 pacientes) y lo comparamos con una cohorte histórica de pacientes ingresados en nuestro hospital en un período previo de 2 años (2014-2016), manejados con atención estándar (grupo SC, n=108 pacientes). Resultados Los pacientes del grupo PERT eran más jóvenes y con menos comorbilidades. El perfil de riesgo al ingreso y el porcentaje de EP-AR fue similar en ambas cohortes (13% en el grupo SC y 14% en el grupo PERT, p=0,82). La terapia de reperfusión fue más frecuentemente indicada en el grupo PERT (24,4% vs. 10,2%, p=0,01), sin diferencias en el uso de fibrinólisis, mientras que la terapia dirigida por catéter (CDT) fue más frecuente en el grupo PERT (16,7% vs. 1,9%, p<0,001). La reperfusión y la CDT se asociaron con una menor mortalidad hospitalaria (2,9% vs. 15,1%, p=0,001 para reperfusión y 1,5% vs. 16,5%, p=0,001 para CDT). El objetivo primario, la mortalidad a los 12 meses, fue menor en el grupo PERT (9% frente al 22,2%, p=0,02). No hubo diferencias en los reingresos a los 30 días. En el análisis multivariado la activación de PERT se asoció con una menor mortalidad a los 12 meses (hazard ratio 0,25, intervalo de confianza del 95%: 0,09-0,7, p=0,008)(AU)