Respiratory syncytial virus: A new era / Virus respiratorio sincitial: un nuevo tiempo

Respiratory syncytial virus (RSV) is a major public health problem that has undergone significant changes in recent years. First of all, it has become easier to diagnose with highly reliable and rapidly available confirmatory tests. This has led to a better understanding of its epidemiology and RSV has gone from being a disease of the pediatric age group, severe only in infants and immunosuppressed children, to being a common disease in people of all ages, particularly important in patients of advanced age or with immunosuppressive diseases. Recent therapeutic and prophylactic advances, both with long-lasting monoclonal antibodies and vaccines, are another reason for satisfaction. For these reasons, the COVID and Emerging Pathogens Committee of the Illustrious Official College of Physicians of Madrid (ICOMEM) has considered it pertinent to review this subject in the light of new knowledge and new resources for dealing with this infection. We have formulated a series of questions that we believe will be of interest not only to members of the College but also to any non-expert in this subject, with a particular focus on the situation of RSV infection in Spain. (AU)

El Virus Respiratorio Sincitial (VRS), es un problema de salud pública de primera magnitud que en años recientes ha experimentado cambios muy importantes. En primer lugar, se ha producido una mayor facilidad diagnóstica con pruebas confirmatorias altamente fiables y rápidamente disponibles. Esto ha permitido conocer mejor su epidemiología y VRS ha pasado de ser una enfermedad de la edad pediátrica, grave sólo en lactantes y niños inmunodeprimidos, a ser una enfermedad común en personas de toda edad, particularmente importante en pacientes de edades avanzadas o con enfermedades que inmunodeprimen. Los avances terapéuticos y profilácticos, recientes, tanto con anticuerpos monoclonales de larga duración como con vacunas, constituyen otro motivo de satisfacción. Por estos motivos, el Comité de COVID y de patógenos emergentes del Ilustre Colegio Oficial de Médicos de Madrid (ICOMEM) ha considerado pertinente revisar este tema, a la luz de los nuevos conocimientos y de los nuevos recursos para afrontar esta infección. Hemos formulado una serie de preguntas que creemos de interés no sólo para los colegiados si no para cualquier persona no experta en este tema, con una vista particular en la situación de la infección por VRS en España. (AU)

COVID -19: On the threshold of the fifth year. The situation in Spain / COVID-19: A las puertas del quinto año

Despite having emerged from pandemic status, the incidence of COVID-19 episodes has recently increased in Spain, including pediatric cases and admissions to Intensive Care Units. Several recombinant variants are circulating among us, particularly XBB arising from two Omicron BA.2 sublineages with mutations in the genes encoding the spicule proteins that could increase binding to the ACE2 receptor and be more prone to immune escape. Faced with these, 3 pharmaceutical companies have developed vaccines adapted to the XBB.1.5 sublineage that are already available for administration in our setting with risks that should not be different from those of previous mRNA vaccines and with clearly favorable benefit/risk ratios. They should be applied to patients with potential for poor COVID-19 evolution and to collectives that have a particular relationship of proximity with them. Their application should be understood not only from a perspective of individual convenience but also from that of collective responsibility. The most convenient seems to be a simultaneous immunization of COVID-19 and influenza in our environment. In the therapeutic aspect, there is little to expect right now from antisera, but the already known antiviral drugs are still available and indicated, although their efficacy will have to be reevaluated due to their impact on populations that are mostly immunized and with a better prognosis than in the past. In our opinion, it is necessary to continue to make a reasonable and timely use of masks and other non-pharmacological means of protection. (AU)

Pese a haber salido de la situación de pandemia, la incidencia de episodios de COVID-19 ha aumentado recientemente en España, incluidos los casos pediátricos y los ingresos en Unidades de Cuidados Intensivos. Circulan entre nosotros diversas variantes recombinantes, particularmente la XBB surgidas de dos sublinajes Omicron BA.2 con mutaciones en los genes que codifican las proteínas de la espícula y que pudieran aumentar la unión al receptor ACE2 y ser más propensas al escape inmune. Frente a ellas, 3 empresas farmacéuticas han elaborado vacunas adaptadas al sublinaje XBB.1.5 que ya se encuentran disponibles para su administración en nuestro medio con riesgos que no deben ser diferentes a los de las vacunas mRNA previas y con relaciones beneficio/riesgos claramente favorables. Deben aplicarse a pacientes con potencial de mala evolución de COVID-19 y a los colectivos que tienen una particular relación de proximidad con ellos. Su aplicación debe ser entendida no sólo desde una perspectiva de conveniencia individual sino desde la de la responsabilidad colectiva. Lo más conveniente parece hacer una inmunización simultánea de COVID-19 y gripe en nuestro medio. En el aspecto terapéutico hay poco que esperar ahora mismo de los antisueros pero siguen estando disponibles e indicados los fármacos antivirales ya conocidos aunque su eficacia tendrá que reevaluarse por su impacto en poblaciones mayoritariamente inmunizadas y con pronóstico mejor que las de tiempos pasados. A nuestro juicio, es necesario seguir haciendo un uso razonable y puntual de mascarillas y otros medios no farmacológicos de protección. (AU)

Tuberculosis in Spain: An opinion paper / Tuberculosis en España: Un documento de opinión

This document is the result of the deliberations of the Committee on Emerging Pathogens and COVID-19 of the Il lustrious Official College of Physicians of Madrid (ICOMEM) regarding the current situation of tuberculosis, particularly in Spain. We have reviewed aspects such as the evolution of its incidence, the populations currently most exposed and the health care circuits for the care of these patients in Spain. We have also discussed latent tuberculosis, the reality of extrapul monary disease in the XXI century and the means available in daily practice for the diagnosis of both latent and active forms. The contribution of molecular biology, which has changed the perspective of this disease, was another topic of discussion. The paper tries to put into perspective both the classical drugs and their resistance figures and the availability and indications of the new ones. In addition, the reality of direct observa tion in the administration of antituberculosis drugs has been discussed. All this revolution is making it possible to shorten the treatment time for tuberculosis, a subject that has also been reviewed. If everything is done well, the risk of relapse of tuberculosis is small but it exists. On the other hand, many special situations have been discussed in this paper, such as tuberculosis in pediatric age and tuberculosis as a cause for concern in surgery and intensive care. The status of the BCG vaccine and its present indications as well as the future of new vaccines to achieve the old dream of eradicating this disease have been discussed. Finally, the ethical and medicolegal impli cations of this disease are not a minor issue and our situation in this regard has been reviewed (AU)

El presente documento es el resultado de las deliberacio nes del Comité sobre Patógenos Emergentes y COVID-19 del Ilustre Colegio Oficial de Médicos de Madrid (ICOMEM) en re lación a la situación actual de la tuberculosis, particularmente en España. Hemos revisado aspectos tales como la evolución de su incidencia, las poblaciones actualmente más expuestas y los circuitos sanitarios para la atención a estos pacientes en España. Se ha discutido también la tuberculosis latente, la rea lidad de la enfermedad extrapulmonar en el siglo XXI y los me dios de que en la práctica diaria se dispone para el diagnóstico tanto de las formas latentes como de las activas. La aportación de la biología molecular que ha cambiado la perspectiva de es ta enfermedad ha constituido otro de los temas de debate. El documento trata de poner en perspectiva tanto los fármacos clásicos y sus cifras de resistencia como la disponibilidad e in dicaciones de los nuevos. Junto a esto, se ha discutido la rea lidad de la observación directa en la administración de fárma cos antituberculosos. Toda esta revolución está posibilitando el acortamiento del tiempo de tratamiento de la tuberculosis tema que ha sido igualmente revisado. Si todo se hace bien, el riesgo de recaída de la tuberculosis es pequeño pero existen te. Por otra parte, muchas situaciones especiales han merecido discusión en este documento como por ejemplo la tuberculosis en edad pediátrica y la tuberculosis como causa de preocupa ción en cirugía y cuidados intensivos. Se ha discutido tanto la situación de la vacuna BCG y sus indicaciones presentes, co mo el futuro de nuevas vacunas que permitan alcanzar el viejo sueño de erradicar esta enfermedad. Finalmente, las implica ciones éticas y medicolegales que esta enfermedad plantea no son un tema menor y se ha revisado nuestra situación en este particular (AU)

Sexually transmitted infections in Spain: Current status / Infecciones de transmisión sexual en España: Situación actual

Sexually Transmitted Infections (STI) are a major public health problem. The problems inherent to their diagnosis, treatment and prevention have to do not only with their nature, but also with organizational issues and overlapping competencies of the different health authorities in Spain. The real situation of STI in Spain, at present, is poorly known. For this reason, the Scientific Committee on COVID and Emerging Pathogens of the Illustrious Official College of Physicians of Madrid (ICOMEM) has formulated a series of questions on this subject which were distributed, not only among the members of the Committee, but also among experts outside it. The central health authorities provide very high and increasing figures for gonococcal infection, syphilis, Chlamydia trachomatis infection and lymphogranuloma venereum (LGV). Both HIV infection and Monkeypox are two important STI caused by viruses in our environment, to which it should be added, mainly, Herpes simplex virus (HSV) and Human papillomavirus (HPV) infections. Emerging microorganisms such as Mycoplasma genitalium pose not only pathogenic challenges but also therapeutic problems, as in the case of N. gonohrroeae. The pathways that patients with suspected STI follow until they are adequately diagnosed and treated are not well known in Spain. Experts understand that this problem is fundamentally managed in public health institutions, and that Primary Care and Hospital Emergency Services, together with some institutions that deal monographically with this problem, are the recipients of most of these patients (AU)

Las Infecciones de Transmisión Sexual (ITS) constituyen un problema de Salud Pública de primera magnitud. Los prob lemas inherentes a su diagnóstico, tratamiento y prevención tienen que ver no solo con la naturaleza de las mismas, sino también con problemas de organización y de solapamiento de competencias de las distintas autoridades sanitarias. La situación real de las ITS en España no se conoce bien en el momento actual. Por este motivo, el Comité Científico sobre COVID y Patógenos emergentes del Ilustre Colegio Ofi cial de Médicos de Madrid (ICOMEM) se ha formulado una se rie de preguntas sobre este tema que ha distribuido, no sólo entre los miembros del Comité, sino también entre expertos ajenos al mismo. Las autoridades ministeriales aportan cifras muy elevadas y crecientes de infección gonocócica, sífilis, in fección por Chlamydia trachomatis y Linfogranuloma venéreo. Tanto la infección por VIH como Monkeypox son en nuestro medio dos importantes ITS causadas por virus a las que deben añadirse, principalmente, las infecciones por el Virus herpes simplex (VHS) y el Virus del Papiloma Humano (HPV). Emer gen patógenos como Mycoplasma genitalium que plantean no sólo retos patogénicos si no también problemas terapéuticos, como ocurre en el caso de N. gonohrroeae. Los caminos que siguen los pacientes con sospecha de ITS hasta su adecuado diagnóstico y tratamiento no se conocen bien en España. Los expertos entienden que este problema es fundamentalmente manejado en instituciones sanitarias de titularidad pública, y que los servicios de Atención Primaria y de Urgencias Hospitalarias, junto con algunas instituciones monográficamente destinadas a este problema, son los re ceptores de la mayor parte de estas enfermedades. Una de las dificultades más serias de las ITS estriba en la disponibilidad de las pruebas microbiológicas necesarias para su diagnóstico, particularmente en esta época de externalización de servicios de Microbiología (AU)

Advantages and disadvantages of maintaining the mandatory use of masks in health centers and nursing homes in Spain. How and when is it justified to maintain it? / Ventajas e inconvenientes de mantener la obligatoriedad del uso de las mascarillas en centros sanitarios y sociosanitarios en España. ¿Cómo y cuándo está justificado mantenerla?

We address the advantages and disadvantages of main taining the mandatory use of masks in health centers and nursing homes in the current epidemiological situation in Spain and after the declaration of the World Health Organiza tion on May 5, 2023 of the end of COVID-19 as public health emergency. We advocate for prudence and flexibility, respect ing the individual decision to wear a mask and emphasizing the need for its use when symptoms suggestive of a respira tory infection appear, in situations of special vulnerability (such as immunosuppression), or when caring for patients with those infections. At present, given the observed low risk of se vere COVID-19 and the low transmission of other respiratory infections, we believe that it is disproportionate to maintain the mandatory use of masks in a general way in health centers and nursing homes. However, this could change depending on the results of epidemiological surveillance and it would be necessary to reconsider returning to the obligation in periods with a high incidence of respiratory infections (AU)

Abordamos las ventajas e inconvenientes de mantener la obligatoriedad del uso de las mascarillas en centros sani tarios y sociosanitarios en la situación epidemiológica actual de España y tras la declaración de la Organización Mundial de la Salud el 5 de mayo de 2023 del fin de la COVID-19 como emergencia de salud pública. Propugnamos prudencia y flexi bilidad, respetando la decisión individual de usar mascarilla y enfatizando la necesidad de su uso ante la aparición de sín tomas sugestivos de infección respiratoria, en situaciones de especial vulnerabilidad (como inmunodepresión) o al attender pacientes con dichas infecciones. En la actualidad, dado el ba jo riesgo observado de COVID-19 grave y la baja transmisión de otras infecciones respiratorias, creemos que es despropor cionado mantener el uso obligatorio de mascarillas de forma generalizada en centros sanitarios y sociosanitarios. No obs tante, esto podría cambiar en función de los resultados de la vigilancia epidemiológica y habría que reconsiderar volver a la obligatoriedad en periodos con alta incidencia de infecciones respiratorias (AU)

Risk of Ischemic Stroke Associated with Calcium Supplements and Interaction with Oral Bisphosphonates: A Nested Case-Control Study.

Conflicting results about the association of calcium supplements (CS) with ischemic stroke (IS) have been reported. We tested this hypothesis by differentiating between CS alone (CaM) and CS with vitamin D (CaD) and between cardioembolic and non-cardioembolic IS. We examined the potential interaction with oral bisphosphonates (oBs). A nested case-control study was carried out. We identified incident IS cases aged 40-90 and randomly sampled five controls per case matched by age, sex, and index date. Current users were compared to non-users. An adjusted odds ratios (AOR) and 95% CI were computed through conditional logistic regression. Only new users were considered. We included 13,267 cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls (20,147 and 41,231, respectively). CaM use was associated with an increased risk of cardioembolic IS (AOR = 1.88; 95% CI: 1.21-2.90) in a duration-dependent manner, while it showed no association with non-cardioembolic IS (AOR = 1.05; 95% CI: 0.74-1.50); its combination with oBs increased the risk of cardioembolic IS considerably (AOR = 2.54; 95% CI: 1.28-5.04), showing no effect on non-cardioembolic. CaD use was not associated with either cardioembolic (AOR = 1.08; 95% CI: 0.88-1.31) or non-cardioembolic IS (AOR = 0.98; 95% CI: 0.84-1.13) but showed a small association with cardioembolic IS when combined with oBs (AOR = 1.35; 95% CI: 1.03-1.76). The results support the hypothesis that CS increases the risk of cardioembolic IS, primarily when used concomitantly with oBs.

Effect of Primary Care Center Characteristics, Healthcare Worker Vaccination Status and Patient Economic Setting on Patient Influenza Vaccination Coverage Rates.

BACKGROUND: Reaching the public health organizations targets of influenza vaccination in at-risk patient groups remains a challenge worldwide. Recognizing the relationship between the healthcare system characteristics and the economic environment of the population with vaccination uptake can be of great importance to improve. METHODS: Several characteristics were correlated in this retrospective ecological study with data from 6.8 million citizens, 15,812 healthcare workers across 258 primary care health centers, and average income by area of the care center in Spain. RESULTS: No correlation between HCW vaccination status and patient vaccination was found. A weak negative significant correlation between the size of the population the care center covers and their vaccination status did exist (6 mo.-59 yr., r = 0.19, p = 0.002; 60-64 yr., r = 0.23, p < 0.001; ≥65 yr., r = 0.23, p ≥ 0.001). The primary care centers with fewer HCWs had better uptake in the at-risk groups in the age groups of 60-64 yr. (r = 0.20, p = 0.002) and ≥65 (r = 0.023, p ≥ 0.001). A negative correlation was found regarding workload in the 6 mo.-59 yr. age group (r = 0.18, p = 0.004), which showed the at-risk groups that lived in the most economically deprived areas were more likely to be vaccinated. CONCLUSIONS: This study reveals that the confounding variables that determine influenza vaccination in a population and in HCWs are complex. Future influenza campaigns should address these especially considering the possibility of combining influenza and SARS-CoV-2 vaccines each year.

Association of oral bisphosphonates with cardioembolic ischemic stroke: a nested case-control study.

Background: Bisphosphonates have been reported to increase the risk of atrial fibrillation. Therefore, it is conceivable that they may increase the risk of cardioembolic ischemic stroke (IS). However, most epidemiological studies carried out thus far have not shown an increased risk of IS, though none separated by the main pathophysiologic IS subtype (cardioembolic and non-cardioembolic) which may be crucial. In this study, we tested the hypothesis that the use of oral bisphosphonates increases specifically the risk of cardioembolic IS, and explored the effect of treatment duration, as well as the potential interaction between oral bisphosphonates and calcium supplements and anticoagulants. Methods: We performed a case-control study nested in a cohort of patients aged 40-99 years, using the Spanish primary healthcare database BIFAP, over the period 2002-2015. Incident cases of IS were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, matched for age, sex, and index date (first recording of IS) using an incidence-density sampling. The association of IS (overall and by subtype) with the use of oral bisphosphonates within the last year before index date was assessed by computing the adjusted odds ratios (AOR) and their 95% CI using a conditional logistic regression. Only initiators of oral bisphosphonates were considered. Results: A total of 13,781 incident cases of IS and 65,909 controls were included. The mean age was 74.5 (SD ± 12.4) years and 51.6% were male. Among cases, 3.15% were current users of oral bisphosphonates, while among controls they were 2.62%, yielding an AOR of 1.15 (95% CI:1.01-1.30). Of all cases, 4,568 (33.1%) were classified as cardioembolic IS (matched with 21,697 controls) and 9,213 (66.9%) as non-cardioembolic IS (matched with 44,212 controls) yielding an AOR of 1.35 (95% CI:1.10-1.66) and 1.03 (95% CI: 0.88-1.21), respectively. The association with cardioembolic IS was clearly duration-dependent (AOR≤1 year = 1.10; 95% CI:0.82-1.49; AOR>1-3 years = 1.41; 95% CI:1.01-1.97; AOR>3 years = 1.81; 95% CI:1.25-2.62; p for trend = 0.001) and completely blunted by anticoagulants, even in long-term users (AOR>1 year = 0.59; 0.30-1.16). An interaction between oral bisphosphonates and calcium supplements was suggested. Conclusion: The use of oral bisphosphonates increases specifically the odds of cardioembolic IS, in a duration-dependent manner, while leaves materially unaffected the odds of non-cardioembolic IS.

Status of Herpes Zoster and Herpes Zoster Vaccines in 2023: A position paper / Situación del herpes zóster y de las vacunas contra el mismo en 2023: Un documento de opinión

Herpes zoster infection (HZ) is an important public health problem due to its high incidence and frequent complications, especially post-herpetic neuropathy . The incidence of HZ increases with age and is more frequent in immunocompromised patients. It is estimated that at least 60,000 people develop HZ each year in Spain.The usual forms of HZ are so clinically characteristic that they do not usually require microbiological confirmation, which is reserved for cases without cutaneous manifestations or with atypical presentation.There are currently two vaccines approved by the regulatory agencies and marketed in Spain to prevent the onset of HZ and its complications. The first (Zostavax®) was marketed by the company MSD and licensed in Europe in 2006 and is a live attenuated virus vaccine that is administered in a single dose, while the second (Shingrix®) is a recombinant vaccine, marketed in 2017 and requires two doses. While the former cannot be administered to immunocompromised persons, the latter can be prescribed to any group of adults.The criteria for the indication and financing of these vaccines have not been uniform in the various autonomous communities of Spain.These and other aspects of HZ have been discussed by a group of experts from the Illustrious Official College of Physicians of Madrid (ICOMEM) whose criteria and opinions are included in this paper. (AU)

La infección por herpes zoster (HZ) es un importante problema de salud pública, por su elevada incidencia y frecuentes complicaciones; en especial la neuropatía post herpética. La incidencia de HZ aumenta con la edad y es más frecuente en inmunodeprimidos. Se calcula que, al menos, 60.000 personas desarrollan HZ cada año en España. Las formas habituales de HZ son tan características clínicamente que no suelen requerir confirmación microbiológica que se reserva para casos sin manifestaciones cutáneas o con manifestaciones atípicas En la actualidad, existen en España dos vacunas aprobadas por las agencias reguladoras y comercializadas para prevenir la aparición de HZ y sus complicaciones. La primera (Zostavax®) fue comercializada por la compañía MSD y autorizada en Europa en 2006 y es una vacuna de virus vivos atenuados que se administra en dosis única, mientras que la segunda (Shingrix®) es una vacuna recombinante, comercializada en 2017 y requiere dos dosis. Mientras la primera no puede ser administrada a inmunodeprimidos, la segunda puede administrarse a cualquier grupo de personas. Los criterios de indicación y de financiación de estas vacunas no han sido uniformes en las diversas comunidades autónomas de España. Estos y otros aspectos sobre HZ han sido discutidos por un grupo de expertos del Ilustre Colegio Oficial de Médicos de Madrid (ICOMEM) cuyo criterio y opinión recogemos en este trabajo. (AU)

Insights for COVID-19 in 2023 / Perspectivas de COVID-19 para 2023

Predictions for a near end of the pandemic by the World Health Organization should be interpreted with caution. Current evidence indicates that the efficacy of a fourth dose of classical mRNA vaccines (BT162b2 or mRNA-1273) is low and short-lived in preventing SARS-CoV-2 infection in its predominant variant (Omicron). However, its efficacy is high against severe symptomatic infection, hospitalization and death. The new vaccines being introduced are bivalent and active against the Omicron variants. Potential new vaccines to be introduced in the coming year include a vaccine based on a recombinant protein that emulates the receptor binding domain of the Spike protein under development by the Spanish company Hipra, as well as vaccines for nasal or oral administration. Available information suggests that vaccines against COVID-19 can be administered in association with influenza vaccination without particular complications. New drugs against COVID-19, both antiviral and anti-inflammatory, are under investigation, but this does not seem to be the case with monoclonal antibodies. The indication to use masks in some circumstances will be maintained next year in view of the accumulation of scientific data on their efficacy. Finally, the long COVID or Post-COVID syndrome may continue to affect a very high proportion of patients who have had the disease, requiring combined diagnostic and therapeutic resources. (AU)

Las predicciones para un próximo fin de la pandemia de la Organización Mundial de la Salud deben interpretarse con precaución. La evidencia actual indica que la eficacia de una cuarta dosis de las vacunas clásicas ARNm (BNT162b2 o mRNA-1273) es baja y de corta duración para prevenir la infección de SARS-CoV-2 en su variante predominante (Omicron). No obstante, su eficacia es alta frente a la infección sintomática grave, hospitalización y muerte. Las nuevas vacunas que están siendo introducidas son bivalentes y activas frente a las variantes Omicron. Entre las potenciales nuevas vacunas que se introducirán en el próximo año, se encuentra una vacuna basada en una proteína recombinante que emula el dominio de unión al receptor de la proteína Spike en desarrollo por la compañía española Hipra, así como vacunas de administración nasal u oral. La información disponible apunta a que las vacunas frente al COVID-19 podrán administrarse asociadas a la vacunación antigripal sin particulares complicaciones. Se encuentran en investigación nuevos fármacos frente a COVID-19 tanto antivirales como anti-inflamatorios pero no parece ocurrir lo mismo con los anticuerpos monoclonales. La indicación de utilizar mascarillas en algunas circunstancias se mantendrá el próximo año en vista a la acumulación de datos científicos sobre su eficacia. Finalmente, el síndrome del COVID largo o Post-COVID puede que siga afectando a una proporción muy elevada de los pacientes que sufrieron la enfermedad, requiriendo recursos diagnósticos y terapéuticos combinados. (AU)

Comprehensive Assessment of Myocardial Ischemia Mechanisms in the Catheterization Laboratory: Design and Rationale of the Advanced Invasive Diagnosis Strategy for Patients with Stable Coronary Syndromes Undergoing Coronary ANGIOgraphy - the AID-ANGIO Study.

BACKGROUND: The diagnostic yield of invasive coronary angiography (ICA) to identify obstructive coronary artery disease in the context of chronic coronary syndromes (CCS) is very low. Furthermore, myocardial ischemia may have a non-obstructive origin, which cannot be detected by ICA. METHODS: AID-ANGIO is an observational, prospective, single-cohort, multicenter study, intended to evaluate the diagnostic yield of adopting a hierarchical strategy to assess obstructive and non-obstructive causes of myocardial ischemia in an all-comers population of patients with CCS at the time of ICA. The primary endpoint will investigate the additional diagnostic value of such strategy over angiography alone regarding the identification of ischemia-generating mechanisms. SUMMARY: An estimated sample of consecutive 260 patients with CCS referred by their clinicians to ICA, will be enrolled. In a stepwise manner, a conventional ICA will be performed as the initial diagnostic tool. Those patients with severe-grade stenosis will not undergo further assessment and an obstructive origin for myocardial ischemia will be assumed. Subsequently, the remainder with intermediate-grade stenosis will be assessed with pressure guidewires. Those with a negative result from physiological evaluation and those without epicardial coronary stenosis will be further studied for ischemia of non-obstructive origin, including microvascular dysfunction and vasomotor disorders. The study will be conducted in two steps. Firstly, ICA images will be displayed to patient's referring clinicians, who will be asked to identify the existent epicardial stenosis, their angiographic severity and probable physiological relevance, together with a tentative therapeutic approach. Then, the diagnostic algorithm will continue to be applied and, considering the whole gathered information, a definite therapeutic plan will be consensually established by the interventional cardiologist and patient's referring clinicians. CONCLUSION: The AID-ANGIO study will assess the additional diagnostic yield of a hierarchical strategy over ICA alone to identify ischemia-generating mechanisms in patients with CCS and its impact on therapeutic approach. Positive results of the study might support a streamlined invasive diagnostic process for patients with CCS.

Increasing Influenza Vaccination in Primary Healthcare Workers Using Solidary Incentives: Analysis of Efficacy and Costs.

INTRODUCTION: Influenza vaccination campaigns have difficulty in reaching the 75% uptake in healthcare workers (HCWs) that public health organizations target. This study runs a campaign across 42 primary care centers (PCCs) where for every HCW vaccinated against influenza, a polio vaccine is donated through UNICEF for children in developing nations. It also analyses the efficacy and cost of the campaign. METHOD: This observational prospective non-randomized cohort study was conducted across 262 PCCs and 15.812 HCWs. A total of 42 PCCs were delivered the full campaign, 114 were used as the control group, and 106 were excluded. The vaccine uptake in HCWs within each of those PCCs was registered. The cost analysis assumes that campaign costs remain stable year to year, and the only added cost would be the polio vaccines (0.59€). RESULTS: We found statistically significant differences between both groups. A total of 1423 (59.02%) HCWs got vaccinated in the intervention group and 3768 (55.76%) in the control group OR 1.14, CI 95% (1.04-1.26). In this scenario, each additional HCW vaccinated in the intervention group costs 10.67€. Assuming all 262 PCCs had joined the campaign and reached 59.02% uptake, the cost of running this incentive would have been 5506€. The potential cost of increasing uptake in HCWs by 1% across all PCC (n = 8816) would be 1683€, and across all healthcare providers, 8862€ (n = 83.226). CONCLUSIONS: This study reveals that influenza vaccination uptake can be innovative by including solidary incentives and be successful in increasing uptake in HCWs. The cost of running a campaign such as this one is low.

Irregular Expression of Cellular Stress Response Markers in the Placenta of Women with Chronic Venous Disease.

Pregnancy comprises a period in a woman's life in which the circulatory system is subjected to hemodynamical and biochemical changes. During this period, while restructuring blood vessels and exchanging maternal-fetal products there is an increased risk of developing chronic venous disease (CVD), which may have an echo in life after childbirth for both mother and child. Previously, we investigated that pregnancy-associated CVD involves changes in placental architecture at angiogenesis, lymphangiogenesis and villi morphology compared with healthy controls (HC) with no history of CVD. We aimed to more deeply investigate the oxidative stress response in placenta from women with CVD versus HC through several markers (NRF2, KEAP1, CUL3, GSK-3ß). An observational, analytical, and prospective cohort study was conducted on 114 women in their third trimester of pregnancy (32 weeks). A total of 62 participants were clinically diagnosed with CVD. In parallel, 52 controls with no history of CVD (HC) were studied. Gene and protein expressions of NRF2, KEAP1, CUL3, GSK-3ß were analyzed by real-time polymerase chain reaction (RT-qPCR) and immunohistochemistry. Nrf2 gene and protein expression was significantly greater in placental villi of women with CVD, while Keap1, CUL-3 and GSK-3ß gene and protein expressions were significantly lower. Our results defined an aberrant gene and protein expression of Nrf2 and some of their main regulators Keap1, CUL-3 and GSK-3 ß in the placenta of women with CVD, which could be an indicator of an oxidative environment observed in this tissue.

Influenza Vaccination and Risk of Ischemic Stroke: A Population-Based Case-Control Study.

BACKGROUND AND OBJECTIVES: To assess the relationship between influenza vaccination in the general population and risk of a first ischemic stroke (IS) during pre-epidemic, epidemic and post-epidemic periods. METHODS: A nested case-control study was carried out in a Spanish primary care database over 2001-2015. Subjects aged 40-99 years with at-least 1-year registry and no history of stroke or cancer were selected to conform the source cohort, from which incident IS cases were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, individually matched with cases for exact age, sex and date of stroke diagnosis (index date). A patient was considered vaccinated when he/she had a recorded influenza vaccination at least 14 days before the index date within the same season. Adjusted odds ratios (AOR) and their respective 95% confidence intervals (CI) were computed through a conditional logistic regression. Pneumococcal vaccination was used as a negative control. RESULTS: From a cohort of 3,757,621 patients, we selected 14,322 incident IS cases (9,542 non-cardioembolic and 4,780 cardioembolic) and 71,610 matched controls. Of them, 41.4% and 40.5%, respectively, were vaccinated yielding a crude OR of 1.05(95%CI:1.01-1.10). Vaccinated subjects presented a higher prevalence of vascular risk factors, diseases and comedication than non-vaccinated and, after full adjustment, the association of influenza vaccination with IS yielded an AOR of 0.88(95%CI:0.84-0.92) was found, appearing early (AOR15-30 days=0.79;95%CI:0.69-0.92) and slightly declining over time (AOR>150 days=0.92;95%CI:0.87-0.98). A reduced risk of similar magnitude was observed with both types of IS, in the three epidemic periods and in all subgroups analyzed (men, women, subjects below and over 65 years of age, and subjects with intermediate and high vascular risk). By contrast, pneumococcal vaccination was not associated with a reduced risk of IS (AOR=1.08;95%CI:1.04-1.13). DISCUSSION: Results are compatible with a moderate protective effect of influenza vaccine on IS appearing early after vaccination. The finding that a reduced risk was also observed in pre-epidemic periods suggests that either the "protection" is not totally linked to prevention of influenza infection, or it may be partly explained by unmeasured confounding factors.

Risk of ischaemic stroke among new users of glucosamine and chondroitin sulphate: a nested case-control study.

Background: Several studies have reported that the use of chondroitin sulphate (CS) and glucosamine may reduce the risk of acute myocardial infarction. Although it is thought that this potential benefit could be extended to ischaemic stroke (IS), the evidence is scarce. Objective: To test the hypothesis that the use of prescription glucosamine or CS reduces the risk of IS. Design: Case-control study nested in an open cohort. Methods: Patients aged 40-99 years registered in a Spanish primary healthcare database (BIFAP) during the 2002-2015 study period. From this cohort, we identified incident cases of IS, applying a case-finding algorithm and specific validation procedures, and randomly sampled five controls per case, individually matched with cases by exact age, gender and index date. Adjusted odds ratios (AORs) and 95% confidence interval (CI) were computed through a conditional logistic regression. Only new users of glucosamine or CS were considered. Results: A total of 13,952 incident cases of IS and 69,199 controls were included. Of them, 106 cases (0.76%) and 803 controls (1.16%) were current users of glucosamine or CS at index date, yielding an AOR of 0.66 (95% CI: 0.54-0.82) (for glucosamine, AOR: 0.55; 95% CI: 0.39-0.77; and for CS, AOR: 0.77; 95% CI: 0.60-0.99). The reduced risk among current users was observed in both sexes (men, AOR: 0.69; 95% CI: 0.49-0.98; women, AOR: 0.65; 95% CI: 0.50-0.85), in individuals above and below 70 years of age (AOR: 0.69; 95% CI: 0.53-0.89 and AOR: 0.59; 95% CI: 0.41-0.85, respectively), in individuals with vascular risk factors (AOR: 0.53; 95% CI: 0.39-0.74) and among current/recent users of nonsteroidal anti-inflammatory drugs (NSAIDs) (AOR: 0.71; 95% CI: 0.55-0.92). Regarding duration, the reduced risk was observed in short-term users (<365 days, AOR: 0.61; 95% CI: 0.48-0.78) while faded and became nonsignificant in long-term users (>364 days AOR: 0.86; 95% CI: 0.57-1.31). Conclusions: Our results support a protective effect of prescription CS and glucosamine in IS, which was observed even in patients at vascular risk. Mini abstract: Our aim was to analyse whether the use of glucosamine or chondroitin sulphate (CS) reduces the risk of ischaemic stroke (IS). We detected a significant decrease.

Booster or additional vaccination doses in patients vaccinated against COVID-19 / Dosis vacunales de recuerdo o adicionales en pacientes vacunados frente a COVID-19

Several health organizations, mainly in Western countries, have recently authorized the use of a booster dose of the COVID-19 vaccine for patients previously vaccinated with mRNA vaccines, with criteria that do not always coincide. The COVID Scientific Committee of the Illustrious College of Physicians of Madrid (ICOMEM) has received and asked several questions about this situation, to which the group has tried to give answers, after deliberation and consensus. The efficacy of the vaccines administered so far is beyond doubt and they have managed to reduce, fundamentally, the severe forms of the disease. The duration of this protection is not well known, is different in different individuals and for different variants of the virus and is not easily predictable with laboratory tests. Data on the real impact of a supplementary or “booster” dose in the scientific literature are scarce for the moment and its application in large populations such as those in the state of Israel may be associated with a decrease in the risk of new and severe episodes in the short observation period available. We also lack sufficient data on the safety and potential adverse effects of these supplementary doses and we do not know the ideal time to administer them in different situations.In this state of affairs, it seems prudent to administer supplemental doses to those exposed to a higher risk, such as immunocompromised individuals and the elderly. On the other hand, we consider that this is not the time to accelerate, on the spur of the moment, a massive administration of a third dose to other population groups that are less exposed and at lower risk, without waiting for adequate scientific information, which will undoubtedly arrive gradually. We do not believe that this position is incompatible with the practical and ethical warnings made by the World Health Organization in this respect. (AU)

Varias organizaciones sanitarias, fundamentalmente de países occidentales, han autorizado recientemente el uso de una dosis de refuerzo de la vacuna frente al COVID-19 para pacientes previamente vacunados con vacunas mRNA, con criterios no siempre coincidentes. El Comité Científico de COVID, del Ilustre Colegio de Médicos de Madrid (ICOMEM) ha recibido y se ha formulado diversas preguntas sobre esta situación, a la que el grupo ha tratado de dar respuestas, tras deliberación y consenso. La eficacia de las vacunas administradas hasta el momento está fuera de toda duda y han logrado disminuir, fundamentalmente, las formas graves de enfermedad. La duración de esa protección no se conoce bien, es diferente en distintos individuos y para distintas variantes del virus y no es fácilmente predecible con pruebas de laboratorio. Los datos sobre el impacto real de una dosis complementaria o “booster” en la literatura científica son escasos por el momento y su aplicación en grandes poblaciones como las del estado de Israel pueden asociarse a una disminución del riesgo de nuevos episodios y episodios graves en el corto periodo de observación disponible. Carecemos también de datos suficientes sobre la seguridad y potenciales efectos adversos de estas dosis complementarias e ignoramos el momento idóneo de administrarlas en distintas situaciones. En este estado de cosas, parece prudente administrar dosis complementarias a aquellos expuestos a un mayor riesgo, como pueden ser los individuos inmunodeprimidos y las personas mayores. Por el contrario, consideramos que no es este el momento de acelerar improvisadamente una administración masiva de una tercera dosis a otros grupos de población menos expuesta y de menor riesgo, sin esperar la adecuada información científica, que sin duda irá llegando paulatinamente. No creemos que esta posición, sea incompatible con las advertencias prácticas y éticas que realiza la Organización Mundial de la Salud a este respecto. (AU)

Pharmacological treatment of COVID-19: an opinion paper / Tratamiento farmacológico del COVID-19: un documento de opinión

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation. (AU)

La precocidad y la eficacia de las vacunas desarrolladas hasta ahora frente al COVID-19, ha sido el avance más significativo y salvador frente a la pandemia. El desarrollo vacunal no ha impedido, durante todo el periodo de la pandemia, la búsqueda constante de remedios terapéuticos, tanto entre los medicamentos ya existentes y con indicaciones diversas, como en el desarrollo de nuevos fármacos. Sobre estos nuevos fármacos, sobre las novedades en la inmunoterapia y sobre lo aprendido de los moduladores de la respuesta inmune ya conocidos y que se han mostrado eficaces frente al virus, el Comité Científico del COVID-19 del Ilustre Colegio de Médicos de Madrid ha querido ofrecer una aproximación precoz, simplificada y critica que pueda ayudar a comprender la situación actual. (AU)

Statins and Colorectal Cancer Risk: A Population-Based Case-Control Study and Synthesis of the Epidemiological Evidence.

(1) Background: The pleiotropic effects of statins may explain a chemoprotective action against colorectal cancer (CRC). Many studies have tested this hypothesis, but results have been inconsistent so far. Moreover, few have examined statins individually which is important for determining whether there is a class effect and if lipophilicity and intensity may play a role. (2) Methods: From 2001-2014, we carried out a study comprised of 15,491 incident CRC cases and 60,000 matched controls extracted from the primary healthcare database BIFAP. We fit a logistic regression model to compute the adjusted-odds ratios (AOR) with their 95% confidence intervals (CIs). Additionally, we carried out a systematic review and meta-analysis. (3) Results: Current use of statins showed a reduced risk of CRC (AOR = 0.87; 95% CI: 0.83-0.91) not sustained after discontinuation. The association was time-dependent, starting early (AOR6months-1year = 0.85; 95% CI: 0.76-0.96) but weakened beyond 3-years. A class effect was suggested, although only significant for simvastatin and rosuvastatin. The risk reduction was more marked among individuals aged 70 or younger, and among moderate-high intensity users. Forty-eight studies were included in the meta-analysis (pooled-effect-size = 0.90; 95% CI: 0.86-0.93). (4) Conclusions: Results from the case-control study and the pooled evidence support a moderate chemoprotective effect of statins on CRC risk, modified by duration, intensity, and age.

Selective Serotonin Reuptake Inhibitors and Risk of Noncardioembolic Ischemic Stroke: A Nested Case-Control Study.

BACKGROUND: Multiple studies have reported that the use of selective serotonin reuptake inhibitors (SSRIs) is associated with an increased risk of ischemic stroke; however, this finding may be the result of a confounding by indication. We examined the association using different approaches to minimize such potential bias. METHODS: A nested case-control study was carried out in a Spanish primary health-care database over the study period 2001 to 2015. Cases were patients sustaining an ischemic stroke with no sign of cardioembolic or unusual cause. For each case, up to 5 matched controls (for exact age, sex, and index date) were randomly selected. Antidepressants were divided in 6 pharmacological subgroups according to their mechanism of action. The current use of SSRIs (use within a 30-day window before index date) was compared with nonuse, past use (beyond 365 days) and current use of other antidepressants through a conditional logistic regression model to obtain adjusted odds ratios and 95% CI. Only initiators of SSRIs and other antidepressants were considered. RESULTS: A total of 8296 cases and 37 272 matched controls were included. Of them, 255 (3.07%) were current users of SSRIs among cases and 834 (2.24%) among controls, yielding an adjusted odds ratio of 1.14 (95% CI, 0.97-1.34) as compared with nonusers, 0.94 (95% CI, 0.77-1.13) as compared with past-users and 0.74 (95% CI, 0.58-0.93) as compared with current users of other antidepressants. No relevant differences were found by duration (≤1, >1 year), sex, age (<70, ≥70 years old) and background vascular risk. CONCLUSIONS: The use of SSRIs was not associated with an increased risk of noncardioembolic ischemic stroke. On the contrary, as compared with other antidepressants, SSRIs appeared to be protective.

Persistence and viability of SARS-CoV-2 in primary infection and reinfections / Persistencia y viabilidad de SARS-CoV-2 en la primoinfección y reinfecciones

Since the beginning of the SARS-CoV-2 epidemic, virus isolation in the infected patient was only possible for a short period of time and it was striking that this occurred constantly and did not provide guidance on the clinical course. This fact led to confusion about the efficacy of some of the drugs initially used, which seemed to have a high efficiency in viral clearance and proved ineffective in modifying the course of the disease. The immune response also did not prove to be definitive in terms of evolution, although most of the patients with very mild disease had a weak or no antibody response,and the opposite was true for the most severe patients.With whatever the antibody response, few cases have been re-infected after a first infection and generally, those that have, have not reproduced a spectrum of disease similar to the first infection. Among those re-infected, a large number have been asymptomatic or with very few symptoms, others have had a moderate picture and very few have had a poor evolution.Despite this dynamic of rapid viral clearance, laboratory tests were still able to generate positive results in the recovery of genomic sequences and this occurred in patients who were already symptom-free, in others who were still ill and in those who were very seriously ill. There was also no good correlate.For this reason and with the perspective of this year and the half of pandemic, we compiled what the literature leaves us in these aspects and anticipating that, as always in biology, there are cases that jump the limits of the general behavior of the dynamics of infection in general. (AU)

Desde el inicio de la epidemia por SARS-CoV-2, el aislamiento del virus en el paciente infectado era posible solo durante un periodo corto de tiempo y llamaba la atención que esto ocurría de una manera constante y no orientaba sobre la evolución clínica. Este hecho, indujo a confusión sobre la eficacia de algunos de los fármacos utilizados inicialmente que parecían tener una gran eficiencia en el aclarado viral y que resultaron ineficaces para modificar el curso de la enfermedad. La respuesta inmune tampoco se mostraba definitiva para aventurar la evolución aunque la mayoría de los pacientes que tenían una enfermedad muy leve, tenían una débil o nula respuesta de anticuerpos y en los más graves pasaba lo contrario.Con cualquiera que haya sido la respuesta de anticuerpos, pocos casos han vuelto a infectarse tras una primo-infección y generalmente, los que lo han hecho, no han reproducido un espectro de enfermedad similar a la primera infección. Entre los re-infectados, gran parte han sido asintomáticos o con muy pocos síntomas, otros han tenido un cuadro moderado y muy pocos han tenido mala evolución.Pese a esa dinámica de rápido aclaramiento viral, las pruebas de laboratorio podían seguir siendo capaces de generar positivos en la recuperación de secuencias genómicas y esto ocurría en pacientes libres ya de síntomas, en otros que seguían enfermos y en los muy graves. Tampoco había un buen correlato.Por eso y con la perspectiva de este año y medio de pandemia recopilamos lo que nos deja la literatura en estos aspectos adelantando que, como siempre en biología, existen casos que saltan los límites del comportamiento general de la dinámica de la infección en general. (AU)