Development of Corynebacterium glutamicum as a monoterpene production platform.

Monoterpenes are commonly known for their role in the flavors and fragrances industry and are also gaining attention for other uses like insect repellant and as potential renewable fuels for aviation. Corynebacterium glutamicum, a Generally Recognized as Safe microbe, has been a choice organism in industry for the annual million ton-scale bioproduction of amino acids for more than 50 years; however, efforts to produce monoterpenes in C. glutamicum have remained relatively limited. In this study, we report a further expansion of the C. glutamicum biosynthetic repertoire through the development and optimization of a mevalonate-based monoterpene platform. In the course of our plasmid design iterations, we increased flux through the mevalonate-based bypass pathway, measuring isoprenol production as a proxy for monoterpene precursor abundance and demonstrating the highest reported titers in C. glutamicum to date at 1504.6 mg/L. Our designs also evaluated the effects of backbone, promoter, and GPP synthase homolog origin on monoterpene product titers. Monoterpene production was further improved by disrupting competing pathways for isoprenoid precursor supply and by implementing a biphasic production system to prevent volatilization. With this platform, we achieved 321.1 mg/L of geranoids, 723.6 mg/L of 1,8-cineole, and 227.8 mg/L of linalool. Furthermore, we determined that C. glutamicum first oxidizes geraniol through an aldehyde intermediate before it is asymmetrically reduced to citronellol. Additionally, we demonstrate that the aldehyde reductase, AdhC, possesses additional substrate promiscuity for acyclic monoterpene aldehydes.

Cardiovascular Complications in Patients with Heart Failure and COVID-19: CARDIO COVID 19-20 Registry.

Since early 2020, different studies have shown an increased prevalence of COVID-19 and poorer prognosis in older adults with cardiovascular comorbidities. This study aimed to assess the impact of heart failure (HF) on cardiovascular complications, intensive care unit (ICU) admissions, and in-hospital mortality in patients hospitalized with COVID-19. The CARDIO COVID 19-20 registry includes 3260 hospitalized patients with a COVID-19 serological diagnosis between May 2020 and June 2021 from Latin American countries. A history of HF was identified in 182 patients (5.6%). In patients with and without previous HF, the incidence of supraventricular arrhythmia was 16.5% vs. 6.3%, respectively (p = 0.001), and that of acute coronary syndrome was 7.1% vs. 2.7%, respectively (p = 0.001). Patients with a history of HF had higher rates of ICU admission (61.5% vs. 53.1%, respectively; p = 0.031) and in-hospital mortality (41.8% vs. 24.5%, respectively; p = 0.001) than patients without HF. Cardiovascular mortality at discharge (42.1% vs. 18.5%, respectively; p < 0.001) and at 30 days post-discharge (66.7% vs. 18.0%, respectively) was higher for patients with a history of HF than for patients without HF. In patients hospitalized with COVID-19, previous history of HF was associated with a more severe cardiovascular profile, with increased risk of cardiovascular complications, and poor in-hospital and 30-day outcomes.

Morphology Determines an Efficient Coherent Electron Transport for Push-Pull Organic Semiconductors Based on Triphenylamine and Dicyanovinyl Groups.

The morphology of the active layer in organic solar cells is fundamental for achieving high power conversion efficiency. However, the morphological characteristics for optimal performance are still being investigated. An atomistic computational approach is required to determine the relationship between active layer morphology and performance. Since the organic solar cell has multiple phases and interfaces, the computational modeling of charge generation and transport is challenging. We then used a set of push-pull semiconductors to illustrate how the electronic transmission spectrum, derived from the Landauer-Büttiker formalism, can be used to investigate the efficiency of coherent charge transport across anisotropic organic solids. The electronic transmission spectrum was calculated from the electronic band structure obtained using the density-functional-based tight-binding method. We found that coherent charge transport was more efficient along the direction parallel with the interface between the electron-acceptor and electron-donor moieties for a herringbone morphology.

Latin-American Registry of Cardiovascular Disease and COVID-19: Final Results.

Background: Socioeconomic factors contribute to a more severe impact of COVID-19 in Latin American and Caribbean (LA&C) countries than in developed countries. Patients with a severe or critical illness can develop respiratory and cardiovascular complications. Objective: To describe a LA&C population with COVID-19 to provide information related to this disease, in-hospital cardiovascular complications, and in-hospital mortality. Methods: The CARDIO COVID-19-20 Registry is an observational, multicenter, prospective, and hospital-based registry of patients with confirmed COVID-19 infection that required in-hospital treatment in LA&C. Enrollment of patients started on May 01, 2020, and ended on June 30, 2021. Results: The CARDIO COVID-19-20 Registry included 3260 patients from 44 institutions of 14 LA&C countries. 63.2% patients were male and median age was 61.0 years old. Most common comorbidities were overweight/obesity (49.7%), hypertension (49.0%), and diabetes mellitus (26.7%). Most frequent cardiovascular complications during hospitalization or reported at discharge were cardiac arrhythmia (9.1%), decompensated heart failure (8.5%), and pulmonary embolism (3.9%). The number of patients admitted to the Intensive Care Unit (ICU) was 1745 (53.5%), and median length of their stay at the ICU was 10.0 days. Support required in ICU included invasive mechanical ventilation (34.2%), vasopressors (27.6%), inotropics (10.3%), and vasodilators (3.7%). Rehospitalization after 30-day post discharge was 7.3%. In-hospital mortality and 30-day post discharge were 25.5% and 2.6%, respectively. Conclusions: According to our findings, more than half of the LA&C population with COVID-19 assessed required management in ICU, with higher requirement of invasive mechanical ventilation and vasoactive support, resulting in a high in-hospital mortality and a considerable high 30-day post discharge rehospitalization and mortality.

Consensus document of the management of type 2 diabetes and heart failure: Consejo Interamericano de Falla Cardíaca e Hipertensión Pulmonar (CIFACAH) and Inter-American Society of Cardiology (IASC).

Heart failure (HF) syndrome is a global public health issue. On the other hand, type 2 diabetes is a risk factor associated with overweight/obesity and a sedentary lifestyle. This consensus aims to compile information available on the relationship between HF and type 2 diabetes and present, in a summarized and practical way, the management recommendations based on scientific evidence. The document includes the description of the epidemiology of HF and type 2 diabetes; pathophysiology of HF and type 2 diabetes; cardiovascular complications of type 2 diabetes; stages of HF; management of type 2 diabetes in patients with HF; and management of HF in patients with type 2 diabetes. Lastly, in the conclusions section, the growing trend of both events and the need to start preventive activities is presented, as well as the favorable role of antidiabetic drugs in the treatment of patients with HF.

El síndrome de insuficiencia cardíaca (IC) es un problema de salud pública global. Por su parte, la diabetes tipo 2 es un factor de riesgo asociado a sobrepeso/obesidad y sedentarismo. El presente consenso busca recopilar la información disponible sobre la relación entre la IC y la diabetes tipo 2, y presentar, de manera práctica y resumida, las recomendaciones de manejo basadas en la evidencia científica. El documento se estructura en la descripción de la epidemiología de la IC y la diabetes tipo 2; la fisiopatología de la IC y la diabetes tipo 2; las complicaciones cardiovasculares de la diabetes tipo 2; los estadios de la IC; el manejo de la diabetes tipo 2 en pacientes con IC; y el manejo de la IC en pacientes con diabetes tipo 2. Por último, en el apartado de conclusiones se presenta una clara tendencia creciente de ambos eventos y se señala la necesidad del inicio de actividades preventivas, así como también el papel favorable de los fármacos antidiabéticos en el tratamiento de los pacientes con IC.

Inter-American Society of Cardiology (CIFACAH-ELECTROSIAC) and Latin-American Heart Rhythm Society (LAHRS): multidisciplinary review on the appropriate use of implantable cardiodefibrillator in heart failure with reduced ejection fraction.

BACKGROUND: Our main objective was to present a multidisciplinary review on the epidemiology of sudden cardiac death (SCD) and the tools that could be used to identify malignant ventricular arrhythmias (VAs) and to perform risk stratification. In addition, indications and contraindications for the use of implantable cardioverter defibrillator (ICD) in general and in special populations including the elderly and patients with chronic kidney disease (CKD) are also given. METHODS: An expert group from the Inter American Society of Cardiology (IASC), through their HF Council (CIFACAH) and Electrocardiology Council (ElectroSIAC), together with the Latin American Heart Rhythm Society (LAHRS), reviewed and discussed the literature regarding the appropriate use of an ICD in people with heart failure (HF) with reduced ejection fraction (HFpEF). Indications and contraindications for the use of ICD are presented in this multidisciplinary review. RESULTS: Numerous clinical studies have demonstrated the usefulness of ICD in both primary and secondary prevention of SCD in HFpEF. There are currently precise indications and contraindications for the use of these devices. CONCLUSIONS: In some Latin American countries, a low rate of implantation is correlated with low incomes, but this is not the case for all Latin America. Determinants of the low rates of ICD implantation in many Latin American countries are still a matter of research. VA remains one of the most common causes of cardiovascular death associated with HFrEF and different tools are available for stratifying the risk of SCD in this population.

Consensus document on anemia and iron deficiency in heart failure: Consejo Interamericano de Falla Cardiaca e Hipertensión Pulmonar (CIFACAH) of the Interamerican Society of Cardiology (IASC).

Heart failure is a pathology that affects 1% of the population and is accompanied by iron deficiency as a comorbidity in 50% of cases. Anemia, meanwhile, is present between 22-37%. This is a consensus document that seeks to synthesize the information available on anemia and iron deficiency and its behavior in patients with HF, which is divided into pathophysiology, classification, clinical scenarios and algorithms (clinical pathways), treatment, and follow-up. This article integrates international recommendations based on evidence and presents a synthesis of management strategies.

La insuficiencia cardíaca (IC) es una patología que afecta al 1% de la población y se encuentra acompañada de deficiencia de hierro como comorbilidad en el 50% de los casos. La anemia, por su parte, está presente en el 22-37% de los casos de IC. Este es un documento de consenso que busca sintetizar la información disponible sobre la anemia y la deficiencia de hierro, y su comportamiento en pacientes con IC, que se divide en fisiopatología, clasificación, escenarios clínicos y algoritmos (rutas de manejo), tratamiento y seguimiento. Este artículo integra las recomendaciones internacionales basadas en la evidencia y se presenta una síntesis de las estrategias de manejo.

Short- and Long-Term Humoral and Cellular Immune Responses to SARS-CoV-2 Vaccination in Patients with Multiple Sclerosis Treated with Disease-Modifying Therapies.

BACKGROUND: This study aimed to evaluate short- and long-term humoral and T-cell-specific immune responses to SARS-CoV-2 vaccines in patients with multiple sclerosis (MS) treated with different disease-modifying therapies (DMTs). METHODS: Single-center observational longitudinal study including 102 patients with MS who consecutively received vaccination against SARS-CoV-2. Serum samples were collected at baseline and after receiving the second dose of the vaccine. Specific Th1 responses following in vitro stimulation with spike and nucleocapsid peptides were analyzed by quantifying levels of IFN-γ. Serum IgG-type antibodies against the spike region of SARS-CoV-2 were studied by chemiluminescent microparticle immunoassay. RESULTS: Patients undergoing fingolimod and anti-CD20 therapies had a markedly lower humoral response than those treated with other DMTs and untreated patients. Robust antigen-specific T-cell responses were detected in all patients except those treated with fingolimod, who had lower IFN-γ levels than those treated with other DMTs (25.8 pg/mL vs. 868.7 pg/mL, p = 0.011). At mid-term follow-up, a decrease in vaccine-induced anti-SARS-CoV-2 IgG antibodies was observed in all subgroups of patients receiving DMTs, although most patients receiving induction DMTs or natalizumab and non-treated patients remained protected. Cellular immunity was maintained above protective levels in all DMT subgroups except the fingolimod subgroup. CONCLUSIONS: SARS-CoV-2 vaccines induce robust and long-lasting humoral and cell-mediated specific immune responses in most patients with MS.

Blood CD8+ Naïve T-Cells Identify MS Patients with High Probability of Optimal Cellular Response to SARS-CoV-2 Vaccine.

This single-center study included 68 multiple sclerosis (MS) patients who received the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from one of several approved vaccine preparations in Spain. Blood samples were collected one to three months after the second dose of the vaccine had been administered. Cellular immune responses to the vaccine were assessed using QuantiFERON analysis, and peripheral blood mononuclear cell subsets were assayed using flow cytometry. Response associated with higher percentages of total lymphocytes, naïve CD4+ T-cells (p = 0.028), CD8+ T-cells (p = 0.013), and, mostly, naïve CD8+ T-cells (p = 0.0003). These results were confirmed by analyzing absolute numbers (p = 0.019; p = 0.002, and p = 0.0003, respectively). Naïve CD8 T-cell numbers higher than 17 cells/µL were closely associated with an optimal cellular response to SARS-CoV-2 vaccination (odds ratio: 24.0, confidence interval: 4.8-460.3; p = 0.0001). This finding clearly shows that independent of the treatment received, higher numbers of naïve CD8+ T-cells yield a strong cellular response to SARS-CoV-2 vaccines in MS patients. If this finding is validated with other viruses/vaccines, it could provide a good tool for identifying MS patients undergoing treatment who will develop strong cellular responses to anti-virus vaccines.

Effect of the acyl-group length on the chemoselectivity of the lipase-catalyzed acylation of propranolol-a computational study.

The selective N-acylation of 1,2-amino alcohols has been proposed to occur through the proton shuttle mechanism. However, the O-acetylation of propranolol catalyzed by Candida antarctica lipase B is an exception. We investigated the relation between the chemoselectivity of this reaction and the acyl group length. For this purpose, we compared the acyl groups: ethanoyl, butanoyl, octanoyl, and hexadecanoyl. We studied the Michaelis complexes between serine-acylated Candida antarctica lipase B and propranolol, employing a computational approach that involved sampling Michaelis complex conformations through ensemble docking plus consensus scoring and molecular dynamics simulations. The conformations were then classified as near attack conformations for acylation of the amino or hydroxy group. The relative populations of these two classes of conformations were found to be consistent with the experimentally observed chemoselective O-acetylation. We predict that increasing the length of the hydrocarbon chain of the acyl group will cause O-acylation to be unfavorable with respect to N-acylation. The nucleophilic attack of propranolol to the acylated lipase was found to be more favorable through the classical mechanism when compared with the proton shuttle mechanism.

Latin-American Registry of Cardiovascular Disease and COVID-19: Rationale and Design of the CARDIO COVID 19-20 Registry.

Background: Infection caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) exhibits a strong infectivity but less virulence compared to severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). In terms of cardiovascular morbidity, susceptible population include elderly and patients with certain cardiovascular conditions. This infection has been associated with cardiac injury, cardiovascular complications and higher mortality. Objectives: The main objective of the CARDIO COVID 19-20 Registry is to determine the presence of cardiovascular comorbidities and cardiovascular complications in COVID-19 infected patients that required in-hospital treatment in different Latin American institutions. Methods: The CARDIO COVID 19-20 Registry is an observational, multicenter, ambispective, and hospital-based registry of patients with confirmed COVID-19 infection who required in-hospital treatment in Latin America. Enrollment of patients started on May 01, 2020 and was initially planned to last three months; based on the progression of pandemic in Latin America, enrollment was extended until December 2020, and could be extended once again based on the pandemic course in our continent at that moment. Conclusions: The CARDIO COVID 19-20 Registry will characterize the in-hospital population diagnosed with COVID-19 in Latin America in order to identify risk factors for worsening of cardiovascular comorbidities or for the appearance of cardiovascular complications during hospitalization and during the 30-day follow up period.

Características cardiovasculares de pacientes con COVID-19 admitidos en el Hospital Santo Tomás durante la primera ola de casos en Panamá

Introducción: Múltiples ensayos clínicos realizados durante la pandemia por COVID-19 han demostrado el mayor compromiso clínico de los pacientes con riesgo cardiovascular conocido. Las complicaciones cardiovasculares durante la hospitalización de estos pacientes consituyen un campo de investigación activa. Objetivo: Determinar las características cardiovasculares de los pacientes con COVID-19 admitidos en el Hospital Santo Tomás durante la primera ola de casos en nuestro país. Método: Se realizó un estudio descriptivo retrospectivo tomando datos de la historia clínica de pacientes con diagnóstico de COVID-19 con prueba PCR confirmatoria admitidos en el Hospital Santo Tomás entre abril y junio del 2020. Resultados: 104 pacientes hospitalizados ingresaron al estudio. Existió predominio el sexo masculino. El 73,1% de los pacientes hospitalizados correspondieron a una edad > 40 años. La principal comorbilidad cardiovascular fue hipertensión arterial. La incidencia de complicaciones cardiovasculares durante hospitalización fue de 25%, siendo la más frecuente la falla cardiaca aguda. Una tercera parte de los pacientes hospitalizados necesitaron manejo en cuidados intensivos. La mortalidad global fue de 54.8%. La mortalidad de causa cardiovascular fue de 14%. De los pacientes con hipertensión arterial, el 40% requirió soporte ventilatorio mecánico invasivo. La mortalidad global de los pacientes con hipertensión arterial fue de 68.9%. Conclusiones: La hipertensión arterial fue la principal comorbilidad cardiovascular en los pacientes hospitalizados con COVID-19. La complicación cardiovascular más frecuente fue la falla cardiaca aguda. Los pacientes con hipertensión arterial presentaron mayor requerimiento de ventilación mecánica y mayor mortalidad global. (provisto por Infomedic International)

Introduction: Multiple clinical trials conducted during the COVID-19 pandemic have demonstrated the increased clinical involvement of patients with known cardiovascular risk. Cardiovascular complications during hospitalization of these patients constitute an active field of research. Objective: To determine the cardiovascular characteristics of patients with COVID-19 admitted to Hospital Santo Tomás during the first wave of cases in our country. Methods: A retrospective descriptive study was carried out taking data from the clinical history of patients diagnosed with COVID-19 with confirmatory PCR test admitted to the Hospital Santo Tomás between April and June 2020. Results: 104 hospitalized patients were admitted to the study. There was a predominance of male sex. Of the hospitalized patients, 73.1% were aged > 40 years. The main cardiovascular comorbidity was arterial hypertension. The incidence of cardiovascular complications during hospitalization was 25%, the most frequent being acute heart failure. One third of the hospitalized patients required intensive care management. Overall mortality was 54.8%. Cardiovascular mortality was 14%. Of the patients with arterial hypertension, 40% required invasive mechanical ventilatory support. The overall mortality of patients with arterial hypertension was 68.9%. Conclusions: Arterial hypertension was the main cardiovascular comorbidity in patients hospitalized with COVID-19. The most frequent cardiovascular complication was acute heart failure. Patients with arterial hypertension had a greater need for mechanical ventilation and higher overall mortality.   (provided by Infomedic International)

Impact of group purchasing in cooperative of hospital in Colombia, using a price index from 1999 to 2012 / Impacto del grupo de compra en la cooperativa de hospital en Colombia, con un índice de precios de 1999 a 2012

The application of price indices is useful to analyze the behavior of prices as an important component in patients´ access to essential medications over a period of time. The present work analyzed the variation in the prices of 303 medications sold by a cooperative of hospitals in central Colombia between 1999 and 2010 by applying inflation-adjusted price indices and Laspeyres-Paasche quantities by ABC groups and principal therapeuticals in the first and second ATC (anatomic, therapeutical, chemical) level, taking 1999 as the starting year. The medications of type A and B, as well as those belonging to the first four therapeutical groups in the first ATC level in cost and for seven groups in the second ATC level, registered a drop between 40 and 53% (P < 0.05) in the applied price indices. In addition, all the ABC and ATC groups showed increases between 9 and 12 times (P < 0.01) when applying the indices on units sold. The estimated net saving in 2010 at prices of 1999, went above $ 16.9 billion COP. This impact on prices has helped to expand the coverage in essential medications supplied to the public hospitals which are afterwards administered to the patients of this region of Colombia.

La aplicación de los índices de precios es útil para analizar el comportamiento de los precios como un componente importante en el acceso de los pacientes a los medicamentos esenciales en un determinado período de tiempo. El presente trabajo analiza la variación de los precios de 303 medicamentos comercializados por una cooperativa de hospitales en el centro de Colombia entre 1999 y 2010 mediante la aplicación de los índices de precios ajustados a la inflación, según las expresiones de Laspeyres y Paasche por grupos ABC y de principales agentes terapéuticos en el primer y segundo nivel ATC (anatómico, terapéutico, químico), tomando 1999 como año de partida. Los medicamentos de tipo A y B, así como los que pertenecen a los cuatro primeros grupos terapéuticos en el primer nivel de ATC en el costo, y considerando siete grupos en el segundo nivel de ATC, registraron una caída entre 40% y 53% (P < 0,05) en los índices de precios aplicados. Además, todos los grupos ABC y ATC mostraron aumentos entre 9 y 12 veces (P < 0,01) al aplicar los índices en las unidades vendidas. El ahorro neto estimado en 2010 a precios de 1999, pasó por encima de 16,9 mil millones de pesos colombianos. Este impacto en los precios ha contribuido a ampliar la cobertura en los medicamentos esenciales suministrados a los hospitales públicos, y que luego son administrados a los pacientes de esta región de Colombia.