La infección activa (IA) por el CMV es frecuente en el paciente crítico sin inmunosupresión canónica (0-55% de los pacientes seropositivos para el CMV). Esta es comúnmente el resultado de la reactivación viral en el tracto respiratorio inferior, sin que pueda descartarse la reinfección como origen, en algunos casos. La IA por el CMV se ha asociado consistentemente con una mayor mortalidad, especialmente relacionada con el desarrollo de ALI/ARDS, una estancia en UCI más prolongada, una mayor duración del período de ventilación mecánica y un riesgo mayor de “superinfección” bacteriana y fúngica. No existen, sin embargo, vínculos incontestables de causalidad. Solo un ensayo clínico controlado puede precisar el papel del CMV como agente patogénico en este grupo de pacientes. En este seminario se tratarán los siguientes temas: (i) posible patogenia de la infección por el CMV en el paciente crítico; (ii) ensayos clínicos de tratamiento antiviral en marcha; (iii) factores biológicos (genómicos e inmunológicos) de riesgo para el desarrollo de IA en estos pacientes.
Febrile neutropenia - Infections in cancer patientsAli Musavi
This powerpoint provides a summary of infections in neutropenic patients and febrile neutropenia. It contains the definition, etiology, approach, treatments, and recommendations from ESMO and IDSA guidelines.
Maternal healthcare providers need to review how to diagnose sepsis and septic shock among pregnant patients from various infections during pregnancy and postpartum, so that we can intervene within 1 hour from diagnosis to impact prognosis and maternal survival. This is a lecture for the 1st online postgraduate course of the Philippine Obstetrical and Gynecological Society Cebu chapter and the Vicente Sotto Memorial Medical Center Department of Obstetrics and Gynecology on February 10, 2021 based on the Surviving Sepsis Campaign and the PSMID Clinical Practice Guidelines on Sepsis and Septic Shock.
I worked on this presentation in 2017, for the Infectious disease department. My sources are: UpToDate, IDSA guidelines. Please share & give me credit to my work.
Febrile neutropenia - Infections in cancer patientsAli Musavi
This powerpoint provides a summary of infections in neutropenic patients and febrile neutropenia. It contains the definition, etiology, approach, treatments, and recommendations from ESMO and IDSA guidelines.
Maternal healthcare providers need to review how to diagnose sepsis and septic shock among pregnant patients from various infections during pregnancy and postpartum, so that we can intervene within 1 hour from diagnosis to impact prognosis and maternal survival. This is a lecture for the 1st online postgraduate course of the Philippine Obstetrical and Gynecological Society Cebu chapter and the Vicente Sotto Memorial Medical Center Department of Obstetrics and Gynecology on February 10, 2021 based on the Surviving Sepsis Campaign and the PSMID Clinical Practice Guidelines on Sepsis and Septic Shock.
I worked on this presentation in 2017, for the Infectious disease department. My sources are: UpToDate, IDSA guidelines. Please share & give me credit to my work.
Es constata un increment de la incidència de sèpsia greu a Catalunya també observat en la majoria de països. L’envelliment de la població i el conseqüent augment de la pluripatologia podrien influir en aquesta tendència. Tot i això, la mortalitat disminueix, probablement per la millora de les tècniques assistencials a les unitats de cures intensives i la utilització de guies de pràctica clínica, entre d’altres factors.
Cal doncs, adreçar els esforços per a afavorir la detecció precoç de la sèpsia greu i la instauració, al més aviat possible, del tractament necessari en el lloc més adequat
La disponibilidad de un sistema de multiplicación del virus de la hepatitis C (VHC) infeccioso en cultivos celulares está permitiendo investigar nuevos factores de respuesta a tratamientos antivíricos en condiciones controladas. Se presentará evidencia de que el fitness vírico puede ser un factor de multiresistencia a inhibidores y quese pueden obtener eficientes reducciones de carga viral empleando diseños secuenciales de administración de inhibidores que incluyan ribavirina. Se discutirán posibilidades de aplicación clínica.
Here is the methodology and results of the 2013 Youth Count! conducted in Billings, Montana. This was the first ever survey of homeless youth in this community.
Seminar led by Rui Moreno, MD, PhD, from the Hospital de Santo António dos Capuchos Unidad de Cuidados Intensivos Polivalente Centro Hospitalar de Lisboa Central- Portugal.
Abstract: The impact of SSC 2012 on the planning and evaluation of my hospital's performance  The 2012 revision of the Surviving Sepsis Guidelines, together with the new sepsis bundles, will, have a profound impact on the evaluation of the performance of health care systems dealing with the recognition and early treatment of the patient with severe sepsis and septic shock.  With the application and evaluation of the new bundles (now at 3 hours and 6 hours after triage), most of the evaluation will focus in the very early stages of the process of care, when in a significant number of patients will be still in the Emergency Department (ED). This constitutes a major change when compared to the 2008 revision of the SSC, since at that time part of the evaluation was done after 24 hours of diagnosis, when most of the patients was already on the ICU.  An immediate consequence of this will be a major pressure on the ED and in the early connection of the ED with the ICU. This will can be done by creating dedicated admission pathways to patients with suspected severe sepsis and septic shock, to the presence of intensivists on the ED or even to the direct admission (by-passing the ED) to the ICU of theses patients. More than focusing in new therapies, the 2012 revision of the SSC will put the emphasis on the planning and creation of systems able to work fast and flexibly, delivering fast care where it is needed more. Only systems of care able to control and deal with these timing problems will be in condition to offer first quality care to the patient with severe sepsis and septic shock and consequently to have a good evaluation of their performance.
Presentation carried out by Xavier de la Cruz, head of the Translational Bioinformatics group at VHIR, at the course: Identification and analysis of sequence variants in sequencing projects: fundamentals and tools.
*Watch the video at the end of the presentation
Seminar led by Dr. Xavier de la Cruz, ICREA Research Professor. Head of the Translational Bioinformatics in Neuroscience group of VHIR, at VHIR (22nd November 2012).
Content: The need to identify the pathological character of mutations may arise in different contexts in biomedical research. However, the methods available to address this problem essentially depend on the number of cases under analysis. When we work with only a few mutations we can use an artisan-like approach, where all information available on protein sequence, structure and function is manually retrieved and studied. However, when we need to characterize many variants, as can be the case in exome projects, faster methods are required to assess their pathogenicity. In my talk I will illustrate the principles underlying these two approaches with examples from the study of Fabry disease mutations, resulting from our collaborative work at the VHIR.
C is known as first programming language for programers.As the time grows, many languages developed like C++, Java and many more.But still C is in demand and it is first programming language we learned in our school & college. So first should be easy to learn. In this book, I try to elaborate the C contents in a easy manner so it's make "C Is Easy" for begginner.
Presentation carried out by Sophia Derdak, from the Data Analysis Team at CNAG, at the course "Identification and analysis of sequence variants in sequencing projects: fundamentals and tools".
Francisco M. Marty, MD, and Kathleen Mullane, DO, PharmD, FIDSA, prepared useful Practice Aids pertaining to cytomegalovirus management for this CME activity titled "Refining the Management of CMV in HCT Recipients: What Does the Future Hold?" For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2uk5G0q. CME credit will be available until April 3, 2019.
The differences between a cow and a monkey are clear. It is easy to tell a moth from a mosquito. So why are there still scientific studies that mix them up? The answer is simple: hundreds of cell lines stored and used by modern laboratories have been wrongly identified. Some pig cells are labelled as coming from a chicken; cell lines advertised as human have been shown to contain material from hamsters, rats, mice and monkeys. Problems have already been found with more than 400 cell lines. (Cited from Nature 520 (2015)).
An increasing number of scientific publications (i.e. Nature journals) are now sistematically asking for cell line authentication at the moment of paper submission. To help researchers to meet this requirement, UAT is starting to offer a new service for human cell line authentication.
Se realiza una revisión sobre los diversos mecanismos neuroendocrinos que ocurren en la madre y en el recién nacido, y que están relacionados con el inicio y consolidación del apego entre ambos. Se expone el papel que diferentes hormonas y neurotransmisores juegan en la regulación del vínculo en relación con el parto, el postparto inmediato y la lactancia. La interferencia en el inicio del apego entre madre e hijo puede tener potenciales efectos a largo plazo en el comportamiento y en el afecto del recién nacido. La influencia que determinados aspectos relacionados con el parto (como la realización de una cesárea electiva, la administración de hormonas durante el parto, el nacimiento prematuro, la separación madre-hijo o la alimentación mediante biberón) puedan tener sobre el mecanismo neuroendocrino del vínculo y sus consecuencias son objeto de esta revisión
16/03/2015 Seminario VHIR
Dr. Sergio Sosa-Estani. Director del Instituto Nacional de Parasitología "Dr. Mario Fatala Chabén", investigador del Consejo Nacional de Investigaciones Científicas y Técnicas (Conicet). Buenos Aires, Argentina.
Director del Instituto Nacional de Parasitología-Dr. Mario Fatala Chaben en Argentina. El instituto está involucrado en un extenso programa de investigación, incluso como un referente regional en el diagnóstico, prevención y control de enfermedades prevalentes y emergentes en Argentina, tales como la enfermedad de Chagas, Leishmaniasis y otras.
Sosa-Estani desempeñó como director de la Unidad de Vector Borne de Control de Enfermedades del Ministerio de Salud de Argentina. Tiene más de 50 publicaciones a su nombre, y es el investigador principal o co-investigador en diez proyectos de investigación en curso o finalizados.
Presentation carried out by Casandra Riera, researcher from the Translational Bioinformatics group at VHIR, for the course "Identification and analysis of sequence variants in sequencing
projects: fundamentals and tools"
Presentation carried out by Sergi Beltran Agulló, from the CNAG, at the course: Identification and analysis of sequence variants in sequencing projects: fundamentals and tools .
Presentation carried out by CNAG's director, Ivo Gut, at the course: Identification and analysis of sequence variants in sequencing projects: fundamentals and tools.
Watch the video of the presentation on Youtube:https://www.youtube.com/watch?v=E6CmOWR8klI&feature=youtu.be
Seasonal influenza continues to cause yearly epidemics resulting in severe disease and a significant number of deaths despite available vaccines and antivirals. Even more concerning is the ability of influenza virus to cause pandemics every 10-50 years. In the last years, we and other have characterized several features associated with virus virulence and tropism. In addition, new developments suggest the possibility of universal influenza virus vaccines that induce protective antibodies against conserved regions.
La recerca bàsica i traslacional en malalties rares és fonamental per entendre la fisiologia humana i per desenvolupar teràpies innovadores sovint útils també per malalties molt més prevalents. L’anèmia de Fanconi, caracteritzada per disfunció de la medul·la òssia i predisposició tumoral, n’és un exemple edificant. El primer transplantament de cordó umbilical de la història de la medicina fou en un pacient Fanconi. El primer nen medicament va néixer per curar un pacient Fanconi. El primer cop que s’han generat teixits sans per auto-transplantament curant, desprogramant i re-diferenciant cèl·lules de la pell d’un malalt ha estat en anèmia de Fanconi. I els primers assajos clínics de teràpia gènica s’estan desenvolupat també en malalties de la sang com l’anèmia de Fanconi. Aquests són alguns exemples de com l’estudi de malalties rares por transcendir més enllà del pacient afecte en benefici de tota la societat.
Prof. Milan Macek. Professor of Medical and Molecular Genetics Chairman of Department of Biology and Medical Genetics Division of Clinical Molecular Genetics and the National Cystic Fibrosis Centre- University Hospital Motol and 2nd School of Medicine -Charles University Prague- Czech Republic.
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There is an increasing need to manage cost-effectiveness issues of novel or relatively expensive technologies that are currently in use or being proposed for the treatment of rare diseases. Cystic fibrosis (CF), where so called „CFTR modulating therapies“ rendered by several novel orphan medicinal products (e.g. ivacaftor, lumacaftor) are rapidly being introduced into clinical practice, will be used as a model. Health-economic evaluations of rising pharmacotherapeutic costs, as the major driver of overall cost, have to be part of the cost analysis of chronic and progressive (rare) diseases like CF that may require lifelong therapy. Total costs include not only direct healthcare costs but also the cost of lost productivity by both patients and family caregivers. When considering the results of cost-effectiveness analysis of new technologies associated with the management of CF, it is unreasonable to expect that the incremental cost-effectiveness ratio to be less than the generally applied thresholds (willingness to pay) for other common diseases. This issue is further compounded by mutation specific therapies for a subset of the overal cohort of CF patients. Therefore, when assessing CF and other rare diseases, such analyses should include complex health technology assessment approaches, which evaluate comparative treatment effectiveness (novel and established), as well as wider social benefits and ethical aspects. We will present the experience of the Prague CF center in terms of costs of illness studies and pharmacoeconomical approaches to studying children and adolescents with this disease.
The research interest of the investigator has focused on the molecular and cellular pathogenesis of sepsis. In particular, he has worked on soluble proteins involved in the innate recognition of bacteria such as soluble CD14 and MD-2, as well as in the Toll-like receptors activated by Gram-negative and Gram-positive bacteria. Another area of study is the molecular pathogenesis and cell signaling of ventilator-induced lung injury, and lung inflammation in the context of acute respiratory distress syndrome. He has also identified and tested biomarkers in the field of clinical sepsis.
Watch the presentation on Youtube: https://www.youtube.com/watch?v=CyWN7JlhlmI&
Enfermedad minoritaria, terapias nuevas. Una patología que afecta a menos de cinco personas por cada 10.000 habitantes es considerada una enfermedad rara o minoritaria. 35 millones de europeos se ven afectados por alguna de ellas. El 80% son de origen genético y conseguir un diagnóstico rápido es vital para asegurar la calidad de vida futura. La clave, una vez más, es apostar y potenciar la investigación biomédica. Se revisarán los resultados obtenidos los últimos 14 años, en el marco científico y regulador impulsado por la UE desde el año 2000. Sin embargo, se analizarán las dificultades y oportunidades para impulsar la investigación traslacional en estas enfermedades.
Sigue la presentación en Youtube: https://www.youtube.com/watch?v=d4U4a8xFCzA&
Seminario por el Sr. Juan Carrión: Presidente de la Federación Española de Enfermedades Raras (FEDER).
Desde FEDER se trabaja diariamente para promover y defender los derechos de 3 millones de personas con enfermedades raras. De esta forma, durante la ponencia trasladaremos las principales necesidades de las familias para lograr una adecuada atención social y sanitaria, así como cuáles son las líneas prioritarias que impulsamos desde FEDER en la búsqueda de soluciones ante los problemas que nos afectan.
Ver el vídeo del seminario aquí: https://www.youtube.com/watch?v=h091vwp40d0&feature=youtu.be
Watch the video of the presentation on Youtube: https://www.youtube.com/watch?v=WRegqg5yvRs
El Dr Welte té nombroses publicacions en àrees diverses relacionades amb el malalt crític. Particularment interessants són els seus estudis en relació al trasplantament pulmonar, així com els seus estudis sobre pneumònia i sèpsia. Així mateix, participa activament en la xarxa alemanya Capnetz, emprada per a l'elaboració d'estudis multicèntrics relacionats amb la pneumònia adquirida a la comunitat.
Rare diseases Conferences at Fundación ARECES-VHIR
Research in rare diseases is a very active and promising field. Nevertheless,even if it is not always obvious, requirements of the pharmaceutical regulations may be seen as a source of hurdles for a successful progress in medical science. The presentation will discuss how the regulatory framework can promote research and steer its translation into safe and efficacious products for rare diseases.
Watch the video of the seminar on Youtube: https://www.youtube.com/watch?v=dIYCC8cljt8
I will discuss the formation and subsequent growth of IRDiRC into an organization with nearly 40 public and private funder members who have collectively pledged over 1 billion euros for rare disease research. I will also present the goals of IRDiRC, the plan that has been developed to achieve them, and the progress that has been made thus far. Finally, I will explore how additional organizations can take part in this international collaborative effort
Over the last decades, more than 35 different definitions have been used to describe acute kidney injury (AKI). Multiple definitions for AKI have obviously led to a great disparity in the reported incidence and mortality of AKI making it difficult or even impossible to compare the various published studies focusing on AKI. Therefore, it became crucial to establish a consensual and accurate definition of AKI that could desirably be used worldwide. Recent consensus criteria for AKI definition and classification [the Risk Injury Failure Loss of kidney function End-stage kidney disease (RIFLE) and the Acute Kidney Injury Network (AKIN) classifications] have led to more consistent estimates of its epidemiology. This review will present and critically discuss current literature about AKI diagnosis and epidemiology.
Metagenomic projects provide a unique window into the genetic composition of microbial communities. To date, metagenomic analyses have focused primarily on studying the composition of microbial populations and inferring shared metabolic pathways. In this work we analyze how high-quality metagenomic data can be leveraged to infer the composition of transcriptional regulatory networks through a combination of in silico and in vitro methods. Using the SOS response as a case example, we analyze human gut microbiome data to determine the composition of the SOS meta-regulon in a natural context. Our analysis provides proof of concept that the existing knowledgebase on regulatory networks and reference genomes can be effectively leveraged to mine meta-genomic data and reconstruct multi-species regulatory networks. This approach allows us to identify de novo the core elements of the human gut SOS meta-regulon, highlighting the relevance of error-prone polymerases in this stress response, and identifies putative novel SOS protein clusters involved in cell wall biogenesis, chromosome partitioning and restriction modification. The methodology implemented in this work can be applied to other metagenomic datasets and transcriptional systems, potentially providing the means to compare regulatory networks across metagenomes. The use of metagenomic data to analyze transcriptional regulatory networks provides a realistic snapshot of these systems in their natural context and allows probing at their extended composition in non-culturable organisms, yielding insights into their interconnection and into the overall structure of transcriptional systems in microbiomes.
The discovery of the nuclear factor TDP-43 involvement in neurodegenerative disease has increased significantly the general interest on the characteristics of this protein. The aberrant localization and aggregation of TDP-43 in affected tissues coupled with the tight auto regulation of TDP 43 cellular levels has suggested novel pathways for neurodegeneration. TDP 43 is predominantly a nuclear protein that shuttles between nucleus and cytoplasm. In disease neurons TDP 43 mislocalize to cytoplasmic inclusions with devastating consequences on neuronal survival. These cytoplasmic aggregation disrupts the TDP-43 control of its own cellular level. In fact autoregulation is mediated byan unusual splicing event in the 3’UTR of its pre mRNA for which is essentiial the presence of TDP 43 in the nucleus. In addition animal models and highthroughput assays have recently highlighted the role played by this protein in the regulation of hundreds of nuclear and cytoplasmic RNA transcripts, many of them belonging to key genes for neuronal metabolism. A model has been developed to study the determinants of the aggregation process and the impact of the latter on neuronal function. Animal models of the disease have been developed in different species mainly mice and flies.
Durante los últimos años se han redoblado los esfuerzos de las agencias de investigación para financiar la creación, desarrollo y sostenibilidad de plataformas e infraestructuras de investigación. En Europa, el programa de infraestructuras europeas (EuropeanStrategyForumon Research Infrastructures -ESFRI) es un ejemplo de este tipo de acciones, que es apoyado desde los Estados Miembros.
Los registros de enfermedades raras constituyen sistemas de información estandarizada, que han sido tradicionalmente asociados a las administraciones sanitarias. Su uso, ha sido por tanto, restringido a la toma de decisiones de índole general sin aparente repercusión para las personas afectadas por una enfermedad. Más recientemente, los registros han ido tomando cada vez más importancia por su utilidad para la promoción de la investigación, ya que permiten tomar decisiones sobre la puesta en marcha de nuevas áreas de investigación, obtener datos válidos para la creación de buenas prácticas de utilidad directa para las personas enfermas y desarrollar estudios observacionales y experimentales a partir de la contribución de los sujetos que consientan la participación.
Los registros de enfermedades raras son particularmente necesarios tanto para la promoción de la investigación en este campo como para la toma de decisiones socio-sanitarias, debido a la baja prevalencia de estas enfermedades y a las dificultades que supone el encontrar casos suficientes de una misma enfermedad. El proyecto SpainRDR, del ISCIII, constituye un modelo cooperativo de registros de enfermedades raras en red para la investigación. También otros países europeos, los NIH, USA y la pro pia Comisión Europea están desarrollando modelos de registros basados en amplias colaboraciones y creación de plataformas.
More from Vall d'Hebron Institute of Research (VHIR) (20)
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Cytomegalovirus (CMV) in Intensive Care Unit (ICU) patients (David Navarro, PhD)
1. CMV in ICU
Cytomegalovirus (CMV) in Intensive Care Unit (ICU) patients
David Navarro, M.D., Ph.D.
Microbiology Service, University Clinic Hospital, Valencia, Spain
Department of Microbiology, School of Medicine, University of Valencia, Spain
Barcelona, 2013
3. UL1-146TLR 1-14 TRS1IRL/S
gpTLR11
gpUL16
gpUL18 gpUL27 gpUL33
gpUL40 gpUL83
gpUL111gpUL78 gpUL146
US1-34
gpUS2
gpUS3
gpUS6
gpUS10
gpUS11
Regulación
negativa
presentación
HLA I/II
Homólogo
receptor FcIII.
Inhibe ADCC
Bloquea
activación
vía NKG2D
Bloquea
activación
de NK
Liga LIR1
Bloquea
activación
de NK
Homólogos
receptores α-
quimioquinas
Quimioquina
homóloga IL-8Homólogo
IL-10.
Inhibe Th1
gpUS28
Inmunosupresor y pro-inflamatorio
Inhibe presentación
de IE-1
Homólogos
receptores
de β-quimioquinas y
fractalina
M θ (M1/M2)
IL-10
IL-18
vIL-10
IL-1
IL-6
TNF-α
NO
iNOS
COX-2
Inmunosupresión
Inflamación
DCs
Bloqueo
presentación
HLA I/II
CMV in ICU
Barcelona, 2013
4. Innate immunity
DC/MΦ
Adaptive immunity
Early control of CMV replication
Definitive control of CMV replication
IFNs (α,β,λ)
Antiviral cytokines
NK cells
TCD8+
TCD4+
Tregs
B cells
Complex
Hierarchical
Redundant
Neutralizing
ADCC
CMV in ICU
Barcelona, 2013
6. CMV in ICU
Clinical consequences of active CMV infection in ICU patients
• Longer stay in ICU (hospital)
• Longer time on mechanic ventilation
• Higher incidence of bacterial and fungal “superinfection”
•Higher mortality (raw)/ALI/ARDS
Domart et al., Chest, 1990
Cook et al., Am J Surg, 1998
Heininger et al., Crit Care Med, 2001
Cook et al., Crit Care Med, 2003
Von Müller et al., Emerg Infect Dis, 2004
Jaber et al., Chest, 2005
Ziemann et al., Crit Care Med, 2008
Limaye et al., JAMA, 2008
Chiche et al., Crit Care Med, 2009
Heininger et al., Crit Care, 2011
Coisel et al., PLOS one, 2012
Barcelona, 2013
7. Pooled odds ratio for all-cause mortality: 1.93 (95% C.I. 1.29-2.88; P=0.001)
•Clinical consequences of active CMV infection in ICU patients
CMV in ICU
Barcelona, 2013
9. Limaye et al., JAMA, 2008
CMV in ICU
plasma CMV DNA load (Q r-t PCR)
Barcelona, 2013
10. Randomized-controlled clinical trial of antiviral therapy
•CMV in critically ill patients: pathogen or bystander?
CMV in ICU
•Prospective or retrospective observational studies do not prove causality
Barcelona, 2013
11. CMV in ICU
• Real-time PCR for CMV monitoring
• Blood + Lower respiratory tract are screened
• Monitoring at least once a week
• CMV Surveillance for > 2 weeks
• CMV-seropositive (reactivation/reinfection)
• Burn and Surgical/Trauma ICUs
• Poor clinical scores at entry
0-55%
Barcelona, 2013
13. •Weekly virological monitoring in plasma and tracheal aspirates by Q-RT-PCR (L.O.D.=10
copies/mL)
No patient received antiviral therapy
53 patients undergoing mechanical ventilation
65% severe sepsis or septic shock
•Simultaneous screening of the LRT and the blood compartment for the
presence of CMV DNA is imperative for an optimal diagnosis of active CMV
infection in ICU patients
CMV in ICU
Barcelona, 2013
14. TA TA+PL PL (no TA specimens available)
Active CMV infection
•Dissociated episodes
Q-RT-PCR
(~10 copies/mL)
CMV in ICU
Chilet et al., J Med Virol, 2010
Barcelona, 2013
15. CMV in ICU
CMV DNA detected earlier in the LRT (11 days/16.5 days in plasma)
Longer time to resolution in the LRT (28 days/20 days in plasma)
Chilet et al., J Med Virol, 2010
Barcelona, 2013
16. TA TA+PL PL /leukocytes
(no TA specimens available in 9 patients)
Active CMV infection
Dissociated episodes
Qualitative PCR
(No defined L.O.D.)
Heininger et al., Critical Care, 2011
CMV in ICU
Barcelona, 2013
17. •Direct effect: Cytopathogenicity: High level virus replication
10-40% of patients with ALI/ARDS have histopathological evidences
of CMV pneumonitis
Papazian et al., Anesthesiology, 1998
Papazian et al., Crit Care Med, 2007
Chiche et al., Crir Care Med, 2009
•“Indirect effects”: Low level persistent virus replication
•CMV may increase lung inflammation (pro-inflammatory)
•CMV may increase the incidence of bacterial and fungal “superinfection”
•CMV may trigger immunopathogenic effects (CTLs) causing lung injury
•How may CMV injure immune competent hosts?
CMV in ICU
Barcelona, 2013
18. •Experimental mCMV model (sepsis/ileo-cecal puncture)
Pro-inflammatory status (SIRS)
CMV reactivation in LRT
TNF-α/IL-1β/LPS (systemic and LRT)
Pulmonar fibrosis
(ALI/ARDS)
TNF-α/IL-1β/
TGF-β
Infected alveolar macrophages
Activated CMV-specific CD8+/CD4+T cells
Viremia
Cook et al., 2002
Cook et al., 2006
Cook et al., 2007
Forster et al., 2010
•Pathogenesis of active CMV infection in ICU patients
CMV in ICU
Barcelona, 2013
19. CMV in ICU
Previous CMV infection increases pulmonary TNF-α response in sepsis
Cook and Trgovcich, 2011
•Experimental mCMV model of sepsis induced by ileo-cecal puncture
Barcelona, 2013
20. CMV in ICU
•Stronger rationale for the strategy of antiviral prophylaxis over pre-emptive therapy
•Exerts greater benefitial results on CMV-induced indirect effects in the SOT setting
Hodson et al. Lancet, 2005
Reischig et al. Am J Transplant ,2008
Kliem et al., Am J Transplant, 2008
•Data obtained in the murine model of sepsis-induced mCMV reactivation
Forster et al., Antiviral Res, 2010
Only a randomized-controlled clinical trial of antiviral therapy may reveal the
pathogenetic role, if any, of CMV in ICU patients
•When should antivirals be administered? Prophylactic vs. Pre-emptive
Barcelona, 2013
21. CMV mRNA in
Lung tissue
(Incidence)
Lung fibrosis
Gomori stain
(collagen)
(Severity)
Ganciclovir treatment
3 weeks following infection Forster et al., 2010
7 days (Pre-emptive)
7 days (Pre-emptive)
Ganciclovir treatment
•Experimental mCMV model (sepsis/ileo-cecal puncture)
CMV in ICUCMV in ICU
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Barcelona, 2013
22. CMV in ICU
•Efficacy of Ganciclovir/Valganciclovir for Prevention of Cytomegalovirus Reactivation
in Acute Injury of the Lung
•Funding: U.S.National Heart, Lung, & Blood Institute
•Fred Hutchinson Cancer Research Center, Seattle, WA
•Michael Boeckh, MD, Vaccine and Infectious Disease Division
Main inclusion criteria
•CMV IgG seropositive
•Intubated and requiring mechanical positive pressure ventilation
•Acute Lung Injury/ARDS
Main exclusion criteria
•Known or suspected immunosuppression
•Hospitalized for > 96 hours
Intervention
•Ganciclovir 5mg/kg iv, or valganciclovir 900 mg orally or placebo at entry
Multicenter randomized placebo-controlled double-blind trial
Barcelona, 2013
23. •Serum IL-6 level (predicts clinical outcome in ICU patients with ALI/ARDS)
•Change between baseline and 14 days post-randomization in placebo & ganciclovir groups
•Primary endpoint
•Secondary endpoints
•Incidence of CMV reactivation at 28 days
•Additional inflammatory cytokines
•Clinical outcomes
•Length of stay
•Incidence of CMV disease
•Safety
CMV in ICU
Barcelona, 2013
24. “Pre-emptive antiviral therapy of active
CMV infection in ICU patients with severe
sepsis, septic shock and mechanically
ventilated”
Número EudraCT: 2011-002603-15
Clinical trial code: GANCMV-2011
FIS de Investigación Clínica Independiente 2010.
Código: EC10-318
Randomized, unicentric, parallel group, double-blind placebo controlled phase II clinical‑ ‑
trial
CMV in ICU
Barcelona, 2013
25. •Primary Outcome Assessment:
Clearance of active CMV infection in LRT and blood (plasma)
The following virological parameters will be compared
between the groups:
Area under the curve (CMV DNA load in TA and plasma)
Peak viral load (in each compartment)
Time to CMV DNA load clearance
• Secondary outcome measurement: IL-6 in TA
and plasma (weekly monitorization).
CMV in ICU
Barcelona, 2013
26. •>18 years old
• No canonic immunosuppression
• CMV-seropositive
• Severe sepsis/septic shock
•Mechanical ventilation within 48 h. of admission
Inclusion criteria
Pre-emptive therapy
•Initiation: CMV DNA load >10 copies/mL in TA/plasma (or both)
•Discontinuation: Negative PCR in TA (BAS) and plasma
(treatment up to 14 days)
CMV surveillance
•Twice/week in TA and plasma
•Bronchoaspirates will be screened (once/week) if mechanical
ventilaton is discontinued
CMV in ICU
Barcelona, 2013
27. IV Ganciclovir/
Valganciclovir:
First 5 days : IV ganciclovir: 10 mg/kg daily,
given as 5 mg/kg every 12 hours (adjusted
for renal function). After first 5 days (for
a maximun of 14 days), either IV
ganciclovir 5 mg/kg QD or PO
valganciclovir 900 mg po QD (both
adjusted for renal function).
Placebo For the first 5 days, dosing of intravenous
placebo is daily, given every 12 hours.
After first 5 days (for at least 14 days),
either IV placebo QD or PO placebo QD. A
minimum interval of 6 hours is required
between the first and second dose. The
placebo is an IV solution or a PO tablet
that does not contain any active
medications.
CMV in ICU
Barcelona, 2013
28. • Clinical outcomes at 7, 14, 21 , 28, 60 , 90 days post-
randomization
Organ system failure at 14 and 28 days
Duration of mechanical ventilation
Lung injury score
Bacteremia and/or fungemia
Mortality
Composite of survival status, ventilation status, and IL-6 levels
• Length of stay
• CMV disease (biopsy-proven)
• Safety
Time to neutropenia ( <500/µL)
Use of G-CSF
Time to renal insufficiency (creatinine clearance < 60, < 30 ml/min)
Time to thrombocytopenia (platelet count < 50,000, < 20,000/µL)
CMV in ICU
Barcelona, 2013
29. CMV in ICU
•Only 1/3 of CMV-seropositive ICU patients will develop active CMV infection
•2/3 of CMV-seropositive ICU patients would be treated unnecessarily
It is unlikely that clinical studies will help to narrow the group at
highest risk for CMV reactivation
Looking for biological risk factors
•“Further studies must be conducted to identify subsets of patients who
are most at risk to develop active CMV infection”
Barcelona, 2013
30. •CMV-related risk factors
Latent CMV burden may determine
the risk of CMV reactivation
• CMV-specific IgG levels?
• Peripheral CMV-specific CD8+
T-cell levels?
Evaluation at the time of ICU admission
Inference by
CMV in ICU
Cook and Trgovcich, Antiviral Res, 2012
Is CMV DNA load in saliva predictive of the development
of LRT/systemic CMV reactivation?
Salivary glands are a major
site of chronic virus replication
mCMV murine model
Barcelona, 2013
31. CMV in ICU
•Host-related risk factors
•Genomic risk profile?
•Immune risk profile?
Evaluation at the time of ICU admission
Barcelona, 2013
32. IL 10 (2068) Intron - C/G
CCR5 (-2086) 5’ UTR - A/G
AA substitution
CCL2 (MCP1) (1543) 3´-UTR - C/T
IL-10
CCR5
MCP-1
CMV in ICU
•Genomic risk profile?
•Pairwise analysis
•Testing for a Dominant/Co-dominant/Recessive model
Bravo et al., manuscript in preparation, 2013
Barcelona, 2013
35. CMV in ICU
•Host-dependant risk factors
•Immune risk profile?
•CMV pp65 and IE-1 IFN-γ-producing CD8+
and CD4+
T cells protect against
the development of active CMV infection in the
Allo-SCT setting
Solano et al., Haematologica, 2008
Tormo et al., Bone Marrow Transplant, 2010
Tormo et al., Bone Marrow Transplant, 2011
Barcelona, 2013
36. pepmix pp65 and IE-1
(1 µg/mL/peptide)
+ CD28/CD49d moAbs
Brefeldin (at 2 h.)
6 h.
Lysis/Fixation
Permeabilization
Staining (CD3+
/CD4+
or
CD8+
/CD69+
/IFNγ)
BD Fastimmune
Solano et al., Haematologica, 2008
CMV in ICU
Flow cytometry for ICS
Barcelona, 2013
37. CMV in ICU
Active CMV Infection
T-cell subset
cells/µl
No YesNoYes
IFNγ CD8+ T cells IFNγ CD4+ T cells
•First immunological evaluation at the time ICU admission (median 2 days)
•Virological monitoring (TA+PLASMA) by real-time PCR
Clari et al. J Med Virol, 2013
•Immune risk profile? •32 patients
•80% Septic shock
Barcelona, 2013
38. CMV in ICU
•First immunological evaluation at the time of ICU admission (median 2days)
Ongoing episode (n=5)
During follow-up (n=5)
Ongoing episode (n=3)
During follow-up (n=2)
Ongoing episode (n=1)
During follow-up (n=1)
•Patients with active CMV infection (n=17)
Clari et al. J Med Virol, 2013
•Patients without active CMV infection (n=15)
Peak CMV DNA load:
2,830 copies/mL in TA and
100 copies/mL in plasma
Peak CMV DNA load: 230
copies/mL in TA and 100
copies/mL in plasma
•Enumeration of CMV p65 and IE-1-specific IFN-γ T cells at ICU admission may predict the risk of active CMV infection
and allow the inference of the level of CMV replication in the LRT within the episodes
Barcelona, 2013
39. CMV in ICU
•LPS (bacterial sepsis) induces a contraction of mCMV-specific
memory CD8+ T cells
Total CD8+
T cells
mCMV-specific CD8+
T cells
mCMV murine model
Barcelona, 2013
40. CMV in ICU
TLR4 -/- Knock-out mice
•Contraction of mCMV-specific CD8+ T cells after heterologous
antigenic stimulation (LPS) is driven by TLR-4
Barcelona, 2013
41. CMV in ICU
•Functional NK-cell deficit in ICU patients developing an episode of active CMV infection
•Immunological analyses
(at admission/days 7,14,21, 28,35)
15 cases and 15 controls
PBMCs
K562 cells (Direct)
P815 cells (ADCC)
ICS
IFN-γ
CD107b
•Virological monitoring: pp65 AG
Barcelona, 2013
42. CMV in ICU
Chiche et al., 2012
•Patients developing an episode of active CMV infection display an impaired functional NK-cell activity
(IFN-γ production) the week before diagnosis of active CMV infection but not at ICU admission
ADCC
ADCC
Direct
Direct
Barcelona, 2013
43. CMV in ICU
Chiche et al., 2012
•Immunological data on specimens
obtained the week right before detection of active CMV infection (pp65 AG)
•Expression of activating and inhibitory NK-cell receptors was comparable in cases and controls
Barcelona, 2013
44. CMV in ICU
•Functional NK-cell deficit mediated by IL-10 and IL-15
•Patients with an episode of active CMV infection displayed higher plasma IL-
10/IL-15 levels and lower plasma TGFβ2 levels than patients not developing it
Chiche et al., 2012
Barcelona, 2013
45. CMV in ICU
von Müller L et al. J Infect Dis. 2007;196:1288-1295
Active CMV infection (pp65 AG)
No active CMV infection (pp65 AG)
•Cytotoxic NK-cell activity is depressed in cases and controls
Barcelona, 2013
46. CMV in ICU
von Müller L et al. J Infect Dis.
2007;196:1288-1295
Active CMV infection (pp65 AG)
No active CMV infection (pp65 AG)
•An expansion of CMV-specific CD4+
and CD8+
T cells occurs in patients with active CMV infection
•Can we predict the outcome of active CMV infection in ICU
patients by measuring CMV-specific T-cell responses?
Chilet et al., 2010
Blanquer et al., 2011
Barcelona, 2013
47. CMV in ICU
0,0
0,1
0,2
0,3
0,4
0,5
0,6
cells/µl 0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
1,8
2,0
6,0
12,0
18,0
24,0
30,0
36,0
cells/μl
Baseline
•The magnitude of expansion of both T-cell subsets in patients with decreasing CMV DNA loads was not
significantly different from that seen in patients with increasing CMV DNA loads (P=0.72).
Baseline Peak level
Increasing CMV DNA loads
in plasma and/or LRT
Decreasing CMV DNA loads
in plasma and LRT
Clari et al. J Med Virol, 2013
pp65 and IE-1-specific CD8+
T cells pp65 and IE-1-specific CD8+
T cells
Peak level
•Monitoring of peripheral blood CMV-specific T-cell responses may no reflect the actual replicative state in the lungs
Barcelona, 2013
48. •IL-10 levels in LRT >blood (may impair CMV-specific T-cell functionality in the LRT)
•IL-10 levels correlate (P=0.001) with CMV DNA loads in LRT
CMV in ICU
•Monitoring of peripheral blood CMV-specific T-cell responses may no reflect the actual replicative state in the lungs
Barcelona, 2013
49. CMV in ICU
•Conclusions
•Active CMV infection is a frequent event in ICU patients without
canonical immunosuppression
•Screening of the LRT for the presence of CMV DNA is imperative for an optimal diagnosis of
active CMV infection
•Whether CMV is a truly pathogen in ICU patients or a mere by-stander
remains to be elucidated
•Further studies must be conducted to identify subsets of patients who are most
at risk to develop active CMV infection
•There might be a genotypic and an immunological risk profile for the development
of active CMV infection
• Monitoring of peripheral blood CMV-specific T cells may not reflect the actual
status of CMV replication in the LRT
Barcelona, 2013
50. CMV in ICU
Marifina Chilet
Dayana Bravo
M. Aª Clari
Elisa Costa
Beatriz Muñoz
Estela Giménez
Isabel Corrales
Gerardo Aguilar
Javier Belda
José Blanquer
José Carbonell
Liliana Henao
Microbiology ICU
Barcelona, 2013