The document summarizes a weekly presentation series on HIV, HBV, HCV, TB and other infectious diseases hosted by the UC San Diego AntiViral Research Center. The goal is to provide current research, clinical practices and treatment trends on these infectious diseases. The slides from an upcoming AIDS Clinical Rounds presentation on the impact of HCV on the brain are intended for educational purposes and may not be used without the presenter's permission.
The Prevalence and Prognostic Value of Neuroimaging Abnormalities in the Acut...CrimsonPublishersTNN
The Prevalence and Prognostic Value of Neuroimaging Abnormalities in the Acute Phase of Sepsis-Associated Encephalopathy by Keenan A Walker in Techniques in Neurosurgery & Neurology
The Prevalence and Prognostic Value of Neuroimaging Abnormalities in the Acut...CrimsonPublishersTNN
The Prevalence and Prognostic Value of Neuroimaging Abnormalities in the Acute Phase of Sepsis-Associated Encephalopathy by Keenan A Walker in Techniques in Neurosurgery & Neurology
Acyclovir Induced Acute Kidney Injury In Acute Meningitis Patient: A Case Rep...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Prediction of outcome of Multiple sclerosisAmr Hassan
Prediction of outcome of Multiple sclerosis
An understanding of the natural history of multiple sclerosis(MS) in a patient is important to begin proper treatment at the correct time, especially when there is a high risk for poor prognosis. Factors that predict unfavorable prognosis are a primary or secondary progressive course, older age at disease onset, short interval between first and second attacks, initial cerebellar or pyramidal symptoms, a large number of functional systems involved at onset, moderate to severe disability within the first 2 years, and the presence of typical plaques or greater lesion volume shown by magnetic resonance imaging results during the first 5 years. However, there are no established laboratory tests able to predict long-term prognosis.
Subacute sclerosing panencephalitis (SSPE) In Iraqiosrjce
IOSR Journal of Computer Engineering (IOSR-JCE) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of computer engineering and its applications. The journal welcomes publications of high quality papers on theoretical developments and practical applications in computer technology. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Acyclovir Induced Acute Kidney Injury In Acute Meningitis Patient: A Case Rep...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Prediction of outcome of Multiple sclerosisAmr Hassan
Prediction of outcome of Multiple sclerosis
An understanding of the natural history of multiple sclerosis(MS) in a patient is important to begin proper treatment at the correct time, especially when there is a high risk for poor prognosis. Factors that predict unfavorable prognosis are a primary or secondary progressive course, older age at disease onset, short interval between first and second attacks, initial cerebellar or pyramidal symptoms, a large number of functional systems involved at onset, moderate to severe disability within the first 2 years, and the presence of typical plaques or greater lesion volume shown by magnetic resonance imaging results during the first 5 years. However, there are no established laboratory tests able to predict long-term prognosis.
Subacute sclerosing panencephalitis (SSPE) In Iraqiosrjce
IOSR Journal of Computer Engineering (IOSR-JCE) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of computer engineering and its applications. The journal welcomes publications of high quality papers on theoretical developments and practical applications in computer technology. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Wesley Campbell, M.D., of U.S. Navy Medicine, presents "Neurocognitive Changes in Newly Diagnosed Patient with Low CD4: Implications for Prognosis and Employment"
Body Fluid reporting & interpretation has many inherent challenges right from sample collection, selection of tests, test method validation, appropriate reference intervals & clinical decision limits. Recent published articles & guidelines clarify most of the above mentioned concerns for all laboratory to adopt & implement.
Аллопуринол и прогрессирование ХБП и кардиоваскулярные события. РКИ / Allopur...hivlifeinfo
Allopurinol and Progression of CKD and Cardiovascular Events- Long-term Follow-up of a Randomized Clinical Trial.Am J Kidney Dis. 2015 Apr
Background:Asymptomatic hyperuricemia increases renal and cardiovascular (CV) risk. We previously
conducted a 2-year, single-blind, randomized, controlled trial of allopurinol treatment that showed improved
estimated glomerular filtration rate and reduced CV risk.
Study Design:Post hoc analysis of a long-term follow-up after completion of the 2-year trial.
Setting & Participants:113 participants (57 in the allopurinol group and 56 in the control group) initially
followed up for 2 years and 107 participants followed up to 5 additional years.
Intervention: Continuation of allopurinol treatment, 100 mg/d, or standard treatment.
Outcome:Renal event (defined as starting dialysis therapy and/or doubling serum creatinine and/or$50%
decrease in estimated estimated glomerular filtration rate) and CV events (defined as myocardial infarction,
coronary revascularization or angina pectoris, congestive heart failure, cerebrovascular disease, and peripheral vascular disease).
Results:During initial follow-up, there were 2 renal and 7 CV events in the allopurinol group compared with
6 renal and 15 CV events in the control group. In the long-term follow-up period, 12 of 56 participants taking
allopurinol stopped treatment and 10 of 51 control participants received allopurinol. During long-term follow-up,
an additional 7 and 9 participants in the allopurinol group experienced a renal or CV event, respectively, and an
additional 18 and 8 participants in the control group experienced a renal or CV event, respectively. Thus,
during the initial and long-term follow-up (median, 84 months), 9 patients in the allopurinol group had a
renal event compared with 24 patients in the control group (HR, 0.32; 95% CI, 0.15-0.69; P50.004;
adjusted for age, sex, baseline kidney function, uric acid level, and renin-angiotensin-aldosterone system
blockers). Overall, 16 patients treated with allopurinol experienced CV events compared with 23 in the
control group (HR, 0.43; 95% CI, 0.21-0.88;P50.02; adjusted for age, sex, and baseline kidney function).
Limitations:Small sample size, single center, not double blind, post hoc follow-up and analysis.
Conclusions: Long-term treatment with allopurinol may slow the rate of progression of kidney disease and
reduce CV risk.
Pancreas summary from 12th Banff Conference on Transplant Pathology from the meeting in Comandatuba-Bahia, Brazil on August 23rd, 2013 http://cybernephrology.ualberta.ca/banff/2013
Ledipasvir/sofosbuvir for 12 weeks in patients co-infected with HCV and HIV-1Илья Антипин
Naggie S. И др. (докладчик Cooper.) «Ledipasvir/sofosbuvir for 12 weeks in patients co-infected with HCV and HIV-1» 8th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Vancouver, 2015. TUAB0202.
Cathy Logan, MD, of the UC San Diego AntiViral Research Center, presents "Solid Organ Transplantation and HIV" at AIDS Clinical Rounds on August 29, 2014
Katherine Promer Flores, MD (she/her)
Staff Physician
Division of Infectious Diseases and Global Public Health
Department of Medicine
University of California San Diego
Daniel Lee, MD
Clinical Professor of Medicine
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Leandro Mena, MD, MPH
Chair and Professor of Population Health Science
Department of Population Health Science
University of Mississippi Medical Center
Maile Young Karris, MD
Associate Professor
Co-Director San Diego Center for AIDS Research Clinical Investigations Core
Divisions of Infectious Diseases & Global Public Health and Geriatrics & Gerontology
Department of Medicine
University of California San Diego
Edward Cachay, MD, MAS
Professor of Medicine
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Gabriel Wagner, MD
Associate Clinical Professor
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Jocelyn Keehner, MD
Infectious Disease Fellow
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Richard Garfein, PhD, MPH
Professor
Herbert Wertheim School of Public Health and Human Longevity Science
Adjunct Professor
Division of Infectious Disease and Global Public Health
Department of Medicine
University of California, San Diego
Laura Bamford, MD, MSCE
Associate Professor of Medicine
Medical Director, Owen Clinic
Division of Infectious Diseases and Global Public Health
Department of Medicine
University of California, San Diego
Davey Smith, MD, MAS
Professor of Medicine
Chief, Division of Infectious Diseases and Global Public Health
Co-Director, San Diego Center for AIDS Research (CFAR)
Department of Medicine
University of California, San Diego
Elliot Welford, MD
Infectious Diseases Fellow
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Darcy Wooten, MD
Assistant Professor of Medicine
Associate Program Director, Infectious Diseases Fellowship
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Amutha Rajagopal, MD
Associate Physician Diplomate
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
More from UC San Diego AntiViral Research Center (20)
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
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.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
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
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Title: Sense of Smell
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 primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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.
Are There Any Natural Remedies To Treat Syphilis.pdf
Impact of HCV on the Brain
1. AIDS CLINICAL ROUNDS
The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.
2. Impact of HCV on the Brain
A Brief Review
Scott Letendre, M.D.
3. Selected Questions Regarding Impact
of HCV on the Brain
Essential Questions Related Questions
• Does HCV affect the • What are the best
brain? methods to assess
• If so, how does HCV HCV’s impact on the
affect the brain? brain?
• Does HCV-related brain • Can HCV’s effects on
injury respond to the brain be reliably
therapy? distinguished from
• Does HCV infection of those of comorbidities,
the brain limit particularly HIV, liver
treatment success? disease, and drug and
alcohol use?
4.
5. Selected Questions Regarding Impact
of HCV on the Brain
Essential Questions Related Questions
• Does HCV affect the • What are the best
brain? methods to assess
• If so, how does HCV HCV’s impact on the
affect the brain? brain?
• Does HCV-related brain • Can HCV’s effects on
injury respond to the brain be reliably
therapy? distinguished from
• Does HCV infection of those of comorbidities,
the brain limit particularly HIV, liver
treatment success? disease, and drug and
alcohol use?
6. Author Journal Year Size Method People with HCV had…
HCV Serostatus
Clin Microbiol IHDS, Worse IHDS & trend toward worse executive
Thiyagarajan 2010 72
Inf CogState functioning
Hinkin J Addict Dis 2008 118 8 domains Worse learning and memory
Cherner Neurology 2005 430 14 tests Worse functioning in multiple domains
McAndrews Hepatology 2005 83 9 tests Worse learning
Morgello AIDS 2005 137 14 tests Worse executive functioning
Richardson AIDS 2005 220 8 tests More frequent global impairment
Ryan Neurology 2004 116 12 tests Worse executive functioning
Weissenborn J Hepatology 2004 45 10 tests Worse executive functioning and attention
Worse functioning associated with worse liver
Hilsabeck JINS 2003 21 4 tests
fibrosis
Computer- Worse concentration and speed of information
Forton Hepatology 2002 43
based processing
Kramer J Hepatology 2002 100 P300 ERPs Prolonged P300 latencies
HCV Viremia
In fully adjusted GLM, HCV viremia was not
Crystal JAIDS 2012 1338 4 tests
associated with scores on any of the cognitive tests
Clifford Neurology 2009 172 3 tests No difference based on HCV RNA
14. Selected Questions Regarding Impact
of HCV on the Brain
Essential Questions Related Questions
• Does HCV affect the • What are the best
brain? methods to assess
• If so, how does HCV HCV’s impact on the
affect the brain? brain?
• Does HCV-related brain • Can HCV’s effects on
injury respond to the brain be reliably
therapy? distinguished from
• Does HCV infection of those of comorbidities,
the brain limit particularly HIV, liver
treatment success? disease, and drug and
alcohol use?
15. HCV can Infect Cells that are
Relevant to CNS Pathogenesis
• Macrophages/Microglia or Astrocytes
– Letendre et al, J Infect Dis, 2007, 361: 70
– Wilkinson et al, J Virol 2009, 83(3): 1312-9
• Brain Microvascular Endothelial Cells
– Fletcher et al, Gastroenterology 2012, 142: 634-3
• Neuroblastoma and Neuroepithelioma Cells
– Fletcher et al, Gastroenterology 2010, 139: 1365-74
– Bürgel et al, J Viral Hepatitis 2011, 18: 562-70
• Peripheral Blood Mononuclear Cells
• No publications was identified in my non-
exhaustive literature search that demonstrated
infection of neurons
17. Autopsy Data Supports that HCV
can Infect Glial Cells
HCV antigens in brains by heparin columns by WB HCV antigens in astrocytes of HIV+ HCV+ cases
GFAP HCV
HCV-
HCV+
HCV+
Letendre, et al, J Infect Dis, 2007, 361: 70
Slide Courtesy Eliezer Masliah
18. Virologic Evidence that HCV Can
Adapt to the CNS Environment
Author Journal Year Size Finding
Brain HCV RNA found in 7. Brain HCV RNA sequences
Fishman J Infect Dis 2008 13
differed from liver and blood in 4 (57%)
HCV RNA was detected in 5 of 21; sequences in 2 of 5
Bagaglio AIDS 2005 21
differed from plasma and PBMCs
Sequences of brain-derived HCV RNA differed from
other tissues and clustered with lymph node
Forton J Virology 2004 2
sequences; Identified 2 unique brain-derived
mutations
HCV negative RNA strands were detected in brain
Radkowski J Virology 2002 6
tissue from 3 (50%)
HCV sequences were found in 8 CSF specimens and 4
Laskus J Virology 2002 13
of these exhibited differences from other tissues
HCV negative RNA strand sequences differed from
Vargas Liver Transpl 2002 2
consensus serum sequences in both
HCV RNA was detected in 5 of 19 and sequences did
Morsica J Med Virology 1997 19
not differ between CSF and serum
19. Other Mechanisms that May Contribute
to HCV-Associated CNS Injury
• Immune Response
• Glial Activation
– IDO-TRP-KYN-QUIN mediated neurotoxicity*
• Neurotoxic HCV-encoded Proteins
• Altered Blood-Brain Barrier Permeability
Others
• Past or Ongoing Neurotoxic Drug Use
• Liver Disease and Hepatic Encephalopathy
• Cryoglobulin-Associated Vasculitis
*IFN-α can also increase KYN production
20. Additional Relevant Findings
Paulino et al, J Neurovirol Letendre et al, 18th CROI
2011 17:327–340 2011, Abstract 408
23. IL28B and HCV
• Ge et al performed a GWAS predicting SVR in subjects from the
Initiating Dialysis Early and Late (IDEAL) study
• rs12979860 was the most strongly associated SNP in patients of
European ancestry
– 2.5-fold higher relative rate of response among non-Hispanic Caucasian
subjects carrying the C/C genotype. Also associated with better
treatment responses in Hispanics and in African Americans
• Suggested that IL28B variation may influence natural clearance of
HCV since the chronically infected cohort based had a lower
frequency of the C allele than ethnically matched population controls
• Other SNPs Identified:
– rs28416813, rs8103142 were strongly linked to rs12979860
– Another study found associations with rs8099917 and 5 others
Urban et al, Hepatology 2012, 56: 361-6
Ge et al, Nature 2009;461:399-401
24. IL28B and HCV
• IL28B encodes interferon-13, a type III (or λ) IFN, which
bind to a different receptor complex than IFN-α (type I
IFNs)
• IFN-λs have structural and functional similarity to both
interleukins (esp. IL-10) and IFN-αs
• Like other IFNs, IFN-λ activates ISGs via intracellular
signaling pathways but some are non-redundant with
other IFNs
• IFN-λ may result in relatively slower onset and more
prolonged ISG activation than IFN-α
• Expression of IFN-λ receptors appears to be more
restricted, with particularly high expression in the liver
Urban et al, Hepatology 2012, 56: 361-6
25. IL28B and Neurons
• Human neuronal cells expressed endogenous
IFN-λ1 but not IFN-λ2/3. Upon activation of
TLR-3 in the neuronal cells, both IFN-λ1 and
IFN-λ2/3 expression was significantly induced
• Human neurons also expressed functional IFN-
λ receptor complex, IL-28Rα and IL-10Rβ
Urban et al, Hepatology 2012, 56: 361-6
Zhou et al, Neuroscience 2009, 159: 629-37
28. Selected Questions Regarding Impact
of HCV on the Brain
Essential Questions Related Questions
• Does HCV affect the • What are the best
brain? methods to assess
• If so, how does HCV HCV’s impact on the
affect the brain? brain?
• Does HCV-related brain • Can HCV’s effects on
injury respond to the brain be reliably
therapy? distinguished from
• Does HCV infection of those of comorbidities,
the brain limit particularly HIV, liver
treatment success? disease, and drug and
alcohol use?
30. Treatment-Focused Investigations
Author Journal Year Size Finding
Reductions in basal ganglia Cho/Cr and basal ganglia MI/Cr were
Byrnes J Hepatology 2012 15
observed with SVR, but not in non-responders/relapsers
Pharmacologic KYN markedly rose during treatment, paralleled by a significant
Comai 2011 45
Research increase of the Kyn/Trp ratio, an index of IDO activity
MRS demonstrated lower NAA in the globus pallidus before
Pattullo Liver Intl 2011 40
treatment, which was unchanged with viral clearance
SVR was associated with significant improvements in some
Thein HIV Medicine 2007 34
measures of cognitive function, independent of HRQOL
After viral clearance, macrophage IDO activity, plasma TRP and
Zignego Dig Liver Dis 2007 89 KYN levels returned toward normal values and psychopathology
improved
IFN-α treatment was associated with significant activation in the
Capuron Biol Psychiatr 2005 10
dorsal part of the anterior cingulate cortex on functional MRI
31. UCSD IFN/RBV Project
• 40 HCV+ subjects starting IFN/RBV therapy
• Comprehensive medical, psychiatric, and cognitive
assessment before and 10, 24, 48, and 72 weeks after
treatment initiation
• After 10 weeks, neurocognitive impairment rose from 27.5%
to 47.5% (p < .05)
– Infection with genotype 1 was significantly (p < .05) associated
with decline
• After 72 weeks, 42.5% remained neurocognitively impaired
– Only initial 10-week neurocognitive decline predicted persistent
impairment
– Not viral clearance, severity of liver disease, or depressive
symptoms
Cattie et al, Submitted 2013
32. Demographic and Other Characteristics
Characteristic Mean (SD)
Age (years) 47.8 (8.5)
Education 12.9 (2.0)
Sex (#, % male) 20 (50.0)
N (%) Caucasian 28 (70.0)
Reading literacy (WRAT3) mean (SD) 96.0 (12.5)
Lifetime psychiatric/Substance Disorders
Major depressive disorder # (%) 13 (32.5)
Alcohol 15 (37.5)
Cannabis 15 (37.5)
Methamphetamine 17 (42.5)
Cocaine 16 (40.0)
Opioid 10 (25.0)
Any substance 25 (62.5)
Slide Courtesy Jordan Cattie
33. Baseline Medical Characteristics
Characteristic Mean (SD)
Hemoglobin 14.2 (1.6)
Platelet count 213.0 (77.2)
Albumin 4.0 (0.4)
ALT 85.2 (59.9)
AST 73.2 (48.7)
Bilirubin total 1.0 [0.2]
AST platelet ratio index (APRI) 0.78 (0.52)
log10 HCV RNA 5.8 (0.7)
HCV Genotype (n, %)
1 28 (70.0)
2 6 (15.0)
3 5 (12.5)
4 1 (2.5)
Slide Courtesy Jordan Cattie
35. Predictors of Neurocognitive Decline
at 10 Weeks
• Multivariable regression identified that worse neurocognitive
decline was associated with:
– Genotype 1
– Depressive symptoms at baseline or lifetime history of
major depression
• Predictors that failed to reach statistical significance:
– Baseline neurocognitive functioning
– Baseline APRI or fibrosis stage
36. Predictors of Neurocognitive Decline
at 72 Weeks
• Multivariable regression identified that worse neurocognitive
decline was associated with:
– Neurocognitive change from baseline to 10 weeks
• Predictors that failed to reach statistical significance:
– Early or Sustained Viral Response
– APRI or fibrosis stage
– Genotype
– Baseline cognitive status
– Current depression status
37. Selected Questions Regarding Impact
of HCV on the Brain
Essential Questions Related Questions
• Does HCV affect the • What are the best
brain? methods to assess
• If so, how does HCV HCV’s impact on the
affect the brain? brain?
• Does HCV-related brain • Can HCV’s effects on
injury respond to the brain be reliably
therapy? distinguished from
• Does HCV infection of those of comorbidities,
the brain limit particularly HIV, liver
treatment success? disease, and drug and
alcohol use?
38. Additional Research Questions
• How well do newer, direct-acting drugs
distribute into tissues other than the liver that
have HCV-infected cells?
• What are the CNS side effects of DAAs and
how can they be best managed?
• Does limited distribution of DAAs into the CNS
contribute to treatment failure?
• Does the blood-brain barrier and the CNS
normalize following successful treatment?
39. Acknowledgements
Study Volunteers
UCSD HNRC National Institutes
• Ronald J. Ellis Davey Smith of Health
• Igor Grant Tom Marcotte …Mental Health
• Allen McCutchan Cris Achim …Drug Abuse
• Bob Heaton Steven Woods …Neurological
• Edmund Capparelli Eliezer Masliah Disorders and Stroke
• Brookie Best
Industry
CHARTER and CIT2 Abbott Laboratories
• David Clifford Christina Marra GlaxoSmithKline
• Justin McArthur Susan Morgello Merck, Inc.
• Ned Sacktor David Simpson Janssen
• Ann Collier Ben Gelman Gilead Sciences
Biogen IDEC