Cryptococcal meningitis poses an ongoing public health burden in Africa, particularly among those with HIV/AIDS. New diagnostic tools like the lateral flow immunoassay for cryptococcal antigen detection in urine could enable earlier diagnosis and treatment. Ongoing clinical trials are evaluating shorter courses of amphotericin B combined with high-dose fluconazole as alternative treatment strategies that are more feasible and sustainable in resource-limited settings.
Professor Michael Levin's presentation at Meningitis Research Foundation's 2013 conference Meningitis & Septicaemia in Children & Adults www.meningitis.org/conference2013
Dr Marie-Pierre Preziosi's presentation at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults http://www.meningitis.org/conference2013
Emergence of a virulent new meningococcal W sequence type 11 in South America: experience, control measures and impact
http://www.meningitis.org/conference2015
Professor Michael Levin's presentation at Meningitis Research Foundation's 2013 conference Meningitis & Septicaemia in Children & Adults www.meningitis.org/conference2013
Dr Marie-Pierre Preziosi's presentation at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults http://www.meningitis.org/conference2013
Emergence of a virulent new meningococcal W sequence type 11 in South America: experience, control measures and impact
http://www.meningitis.org/conference2015
Current epidemiology of meningococcal disease in the African meningitis belt and new WHO outbreak response guidelines after the Meningitis Vaccine Project
http://www.meningitis.org/conference2015
Meningococcal carriage in the African meningitis belt and the impact of MenAfriVac: an overview of the MenAfriCar project
http://www.meningitis.org/conference2015
Meningococcal vaccination needed in india may 2017 chd revisedGaurav Gupta
Menactra, Sanofi Pasteur, latest data from India regarding Meningococcal disease, with information regarding need for vaccination in Indian situation for Pediatricians.
Presented in Chandigarh in May 2017
mpact of MenZB on the incidence of gonorrhoea and potential future implications for cost effectiveness of teenage meningococcal vaccination
https://www.meningitis.org/mrf-conference-2017
Current epidemiology of meningococcal disease in the African meningitis belt and new WHO outbreak response guidelines after the Meningitis Vaccine Project
http://www.meningitis.org/conference2015
Meningococcal carriage in the African meningitis belt and the impact of MenAfriVac: an overview of the MenAfriCar project
http://www.meningitis.org/conference2015
Meningococcal vaccination needed in india may 2017 chd revisedGaurav Gupta
Menactra, Sanofi Pasteur, latest data from India regarding Meningococcal disease, with information regarding need for vaccination in Indian situation for Pediatricians.
Presented in Chandigarh in May 2017
mpact of MenZB on the incidence of gonorrhoea and potential future implications for cost effectiveness of teenage meningococcal vaccination
https://www.meningitis.org/mrf-conference-2017
Современное лечение ВИЧ: модификация АРТ у пациентов с вирусологической супре...hivlifeinfo
Современное лечение ВИЧ: модификация АРТ у пациентов с вирусологической супрессией (2021) / Contemporary Management of HIV: Modifying ART in Virologically Suppressed Patients 2021
Современное лечение ВИЧ: новые подходы к оптимизации АРТ/Contemporary Managem...hivlifeinfo
Вопросы, связанные с АРТ первого ряда, смена арв-стратегии для пациентов с вирусной супрессией, акцентом на возрастающую роль новыхантиретровирусных стратегий.
Contemporary Management of HIV.How Common Comorbidities Affect ART Management...hivlifeinfo
In this downloadable slideset, expert faculty review key data and offer important guidance on managing HIV treatment in patients with frequently encountered comorbidities, including cardiovascular disease, osteopenia, and HCV coinfection.
Format: Microsoft PowerPoint (.ppt)
File size: 2.27 MB
Date posted: 2/12/2018
Современное лечение ВИЧ.Обобщённые данные с конференции CROI 2020 / Contempor...hivlifeinfo
Современное лечение ВИЧ.Обобощенные данные с конференции CROI 2020 / Contemporary Management of HIV.Integrating New Data From CROI 2020
Широкий спектр вопросов, включая стратегии АРТ на поздних стадихя заболевания, менеджмент ожирения, метаболические исходы АРТ, данные по АРТ во время беременности и пр
Format: Microsoft PowerPoint (.ppt)
File Size: 554 KB
Released: April 14, 2020
Clinical Impact of New Data From AIDS 2018hivlifeinfo
Clinical Impact of New Data From AIDS 2018
July 23-27, 2018; Amsterdam, The Netherlands
Expert faculty members summarize key studies from this important annual conference.
Fall 2014 HIV Update.Clinical Impact of New Data From ICAAC 2014, IDWeek 2014...Hivlife Info
In this downloadable slideset, Joseph J. Eron, Jr., MD and Jürgen K. Rockstroh, MD, review key HIV studies presented at the 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy, 2014 IDWeek, and 2014 HIV Drug Therapy Glasgow.
Format: Microsoft PowerPoint (.ppt)
File size: 1.70 MB
Similar to Confronting cryptococcal meningitis in Africa (20)
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
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
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
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Best Ayurvedic medicine for Gas and IndigestionSwastikAyurveda
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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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
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
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Colonic and anorectal physiology with surgical implications
Confronting cryptococcal meningitis in Africa
1. Confronting Cryptococcal meningitis in Africa:
New diagnostic, prevention and treatment strategies
to reduce disease burden
Tom Harrison
Meningitis Research Foundation
November 5th, 2013
2. Plan:
• Epidemiology
• ongoing burden HIV-associated CM (non HIV CM)
• Diagnostics
• New LF point-of-care dipstick test for CrAg
• Use in screening, early diagnosis
• Therapy
• Current options:
• Developed and Resource-limited settings
• Ongoing and future studies
• [Mnx of complications: CM-IRIS, timing ART (COAT study),
raised CSF pressure. Immunology of HIV-CM, virulence &
evolution C. neoformans]
3. HIV-associated cryptococcal infection:
• Accounts majority global burden of CM
• Cryptococcal meningitis: common in late stage HIV
• Treatment is poor – > 50% 10 wk mortality in Africa
• Common cause of death in HIV cohorts - around 15% all
HIV deaths S/E Africa
• At least 100,000 deaths/yr in SSA: CDC – CID 2009; 23:525
• Not decreasing yet with ART in most centres
• But ART means good long term prognosis if survive
acute infection
4. Aetiology of Adult Meningitis in S/E Africa
Cape Town, South Africa
Jarvis J et al. BMC Inf Dis 2010
Kampala, Uganda
Durski K et al. JAIDS 2013
5. S Africa: high CM burden despite ART rollout
Source: National Institute for Communicable Diseases, Johannesburg, SA
7. • Problem: Late presentation. Need: Earlier Diagnosis
• Early features – headache, fever v. non specific – patients
often not referred immediately to hospital for LP – by
which time may be too late for effective Rx
• Need Point-of-Care diagnostic test
• Polysaccharide capsule - major virulence factor but also
?Achilles heel of Cryptococcus
basis specific, early (subclinical stage) diagnostic test
(Latex agglutination assay CrAg)
• POC format
Immuno-Mycologics (Sean Baumann, CEO),
Tom Kozel (Univ. of Nevada at Reno):
8. LFI dipstick for GXM.
LFI was constructed
using a cocktail of
mAbs F12D2 and 339
KOZEL LAB.
The assay has a
sensitivity of 2-5
ng/ml for serotype A
GXM:
Jarvis et al CID
2011; 53:1019
Table 3. Sensitivity limits of a prototype LFI assay (constructed by IMMY) for
GXM of serotypes A, B, C and D compared with commercially available latex
agglutination assaysa
Immunoassay
Serotype Ab
Serotype B
Serotype C
Serotype D
CN6
MU-1
184
409
2406
6
KC
298
9375
127
Prototype LFI
assay
2.4
5.0
4.6
3.0
16
7.0
10
5.1
Commercial
latex
agglutinationc
250
500
500
250
8,000
4,000
1000
250
10. CrAg LFA test for serum, CSF (samples already approved
for latex agglutination test) approved in Europe, and now
by FDA
But, ideally need test using non-invasive sample, with no
processing
Urine
Drop whole blood
11. 106
Serum vs. plasma
104
Plasma vs. urine
104
105
103
103
104
102
Serum vs. urine
102
103
104
105
Serum (ng/ml)
106
R = 0.97
P < 0.0001
Slope = 0.097
101
100
100
10
1
10
2
10
3
10
4
Plasma (ng/ml)
10
5
Urine (ng/ml)
102
102
Urine (ng/ml)
R = 0.997
P < 0.0001
Slope = 0.85
103
10
6
R = 0.98
P < 0.0001
Slope = 0.083
101
100
100
101
102
103
Serum (ng/ml)
Concentration of GXM in paired serum, plasma and urine
from 25 subjects.
Blood and urine were collected from 25 patients in Cape
Town with culture proven cryptococcosis. Serum, plasma
and urine were evaluated by quantitative ELISA to assess
concentrations of GXM.
Jarvis et al CID 2011; 53:1019
104
105
106
12. Sensitivity of Urine vs Plasma/Serum LFA
in culture-confirmed cases CM - Cape Town
Retrospective Study:
Cryptococcus culture-confirmed paired serum, plasma and urine specimens
from 62 South African patients in Cape Town
Serum
Plasma
Urine
Crag LFA (+)
61
61
61
Crag LFA (+/-)
1
1
0
Crag LFA (-)
0
0
1
Crag LFA
Sensitivity
95% CI
Serum
Plasma
Urine
100%
100%
98%
94-100%
94-100%
91-100%
Jarvis et al CID 2011; 53:1019
13. • POC could be used:
• Facilitate earlier diagnosis (in primary care settings) and
treatment all symptomatic cases
• Prevention clinical CM by screening for subclinical
infection and pre-emptive treatment
• Targeted use pre-emptive fluconazole therapy for patients
with CD4<100 who are CrAg positive, after HIV diagnosis
and prior to starting ART:
an alternative strategy to primary “across-the-board”
fluconazole prophylaxis
Jarvis et al: Clin Infect Dis 2009; 48:856
14. • In South Africa
• 20-33% of cases now present after initiation of ART
• Over 70% present after a diagnosis of HIV
Bicanic CID 2007; 45:76 Jarvis CID 2010; 51:1463
• All these cases are potentially preventable
• Screening identifies those patients at risk :
Jarvis et al: Clin Infect Dis 2009; 48:856
Serum Antigen positive (approx 5-10% of CD4<100)
28% developed meningitis
Serum Antigen negative (90%+ of CD4<100)
0/660 patients developed meningitis
15. Current Gold Standard Therapy:
Amphotericin B plus Flucytosine
IDSA Perfect et al CID 2010 50:291-322,
WHO Rapid advice guideline, WHO November, 2011:
2 wks:
AmB 0.7-1 mg/kg/d plus flucytosine (5-FC) 100 mg/kg/d
Based on..Van der Horst et al NEJM 1997; 337:15
Supported by…Brouwer et al: Lancet 2004; 363:1764-67
Nailed by….Day et al NEJM 2013; 368:1291-302
16. • Vietnam trial, Day et al
Induction with:
•
AmB 1 mg/kg/d alone, 4 weeks
• Vs AmB 1 mg/kg/d alone plus 5FC 100 mg/kg/d, 2 weeks
• Vs AmB 1 mg/kg/d alone plus fluconazole 800 mg/d, 2
weeks
• To clinical endpoints [n=300]
• Results presented ICAAC last year, NEJM April 2013
17. Vietnam trial, Jeremy Day et al [ISRCTN95123928]
AmB+5FC
AmB
+flucon
AmB alone
Day J et al ICAAC 2011
18. Amphotericin B combinations
Given availability (low or no cost), safety fluconazole, but
current lack access 5FC
Important question for high burden countries in Africa in
particular is:
Is AmB plus fluconazole preferable to AmB alone?
20. Southern African J HIV Med 2013; 14:76
Vietnam trial plus
Pappas et al: CID 2009; 48 1775-83
in the absence of 5FC…
AmB 1 mg/kg/d plus fluconazole 800 mg/d
21. Antifungal therapy: New Paradigms in resource-restricted
settings
Problem
1. accepted gold standard 2 wks AmB+5FC not available,
feasible in many African centres
2. currently widely-used and available alternative oral
fluconazole - inadequate
22. F
S
C
Fluconazole 400 mg/d
l
m
/
U
F
C
Log CFU/ml CSF
7
6
5
4
3
g
2
o
L 1
0
0
2
4
6
8
Day
10 12 14
Amphotericin B 1 mg/kg/d
7
6
5
4
3
2
1
0
0
2
4
6
8
Day
Bicanic T et al, Clin Infect Dis 2007; 45:76-80.
10 12 14
23. Fluconazole 800
EFA -0.08 logCFU/d
Log CFU/ml CSF
7
No increased toxicity observed
– small numbers
6
5
4
Longley, Muzoora, et al
Clin Infect Dis 2008; 47 1556-61
3
2
1
2
4
6
10 12 14 16
Day
Fluconazole 1200
EFA -0.18 logCFU/d
7
Log CFU/ml CSF
8
6
5
0.5
Patients
from Cape
Town
0.0
4
3
2
-0.5
1
0
Rate of clearance (log CFU/d)
0
2
4
6
8
10 12 14 16
Day
400
800
1200
Fluconazole dose (mg/d)
25. 1 .0 0
0 .8 0
s u r v iv a l p r o b a b ilit y
0 .6 0
0 .4 0
0 .2 0
0 .0 0
F lu c o n a z o le m o n o t h e r a p y
F lu c o n a z o le / 5 F C c o m b in a t io n
0
2
4
6
8
n u m b e r o f w e e k s f o l lo w - u p
2 week mortality: HR 0.24 (0.05-1.16) p=0.05
Nussbaum et al. Clin Infect Dis 2010; 50:338-44
10
26. Alternative, resource-restricted centres:
Add Short course AmB (5-7 days)
Cohorts in Mbarara, Uganda (5 d) and Lilongwe, Malawi (7d)
(Muzoora et al J.Infect 2012, Jackson et al, AIDS 2012)
•Very large gain:
Tolerability
Feasibility, sustainability
•?Would efficacy be compromised?
Large initial reduction in organism load
Carries on through second week - with no flattening
?long half life AmB
Follow up therapy: high dose fluconazole
27. Muzoora et al: J Infect 2012; 64:76
30 patients Rx 1200 mg/d flucanozole plus AmB 1 mg/kg/d 5 days:
EFA -0.30 log CFU/d over 2 weeks, -0.31 over 7 days
28. Gain in tolerability::
Muzoora et al
Flu1200+ AmB1.0 5d
Laboratory parameter
Decrease in hemoglobin
level,
>2 g/d, (%)
Decrease in hemoglobin
level,
% change, mean
Creatinine level >2x
baseline level (%)
AmB 2 wks Bicanic
CID 2008; 47:123 -30
Day 14
Day 14
AmB 0.7
AmB 1.0
Day 7
Day 14
17
10
50
71
8
6
16
25
4
4.5
13
32
no grade III/IV anemia, ↑ALT,
no grade IV hypokalaemia, ↑creatinine
Trends in mortality: ↓ compared earlier Mbarara
cohorts: 2 and 10 wks: 23%, 28%
29. ACTA Trial: MRC funded: MLW Blantyre, UNC
Lilongwe, UTH Lusaka; ANRS: Cameroon
Strategy 1: Fluconazole 1200 mg /d plus flucytosine 25
mg/kg qds for 2weeks.
Strategy 2: Amphotericin B (AmB) 1 mg/kg/d +
fluconazole 1200 mg /d OR 5FC for 7 days
Strategy 3: Amphotericin B (AmB) 1 mg/kg/d +
fluconazole 1200 mg /d OR 5FC for 14 days
30. Potential Impact
Strategies 1, 2, much more readily, safely sustained than 3.
IF either shown to be as effective as 3, could result in a
reduction in the 10-week mortality in resource-limited
settings using fluconazole from around 50-60%
to the 30-35% seen with 2 wk AmB-combination treatment.
IF NOT as effective then substantial extra resources to
SAFELY deliver 2 wks AmB-combination Rx are justified
31. Other ongoing studies
Adjunctive Steroid study CRYPTODEX (Jeremy Day,
David Lalloo and colleagues)
ACTG 5225: Fluconazole dose escalation (1200g2000g/d) vs AmB. (Bob Larsen and colleagues)
32. Other planned / ongoing studies
Phase II: 3rd Strategy building on high dose fluconazole
backbone – adding
Intermittent high dose Ambisome – 1, 2, or 3 doses, vs
standard daily dosing Ambisome, with EFA endpoint.
Joe Jarvis, et al. Mwanza Tanzania.
33. CMAG - cryptococcal meningitis action group
Loyse A et al. Lancet Infect Dis. 2013 Jul;13(7):629-37
GAFFI – Global Action For Fungal Infections - David Denning
and colleagues
AmB and 5FC from 2013 on WHO
essential medicines list
34. St. George’s
Tihana Bicanic
Joe Jarvis
Angela Loyse
Nicky Longley
Sile Molloy
Annemarie Brouwer
Thailand
Nick White, Nick Day
Funders:
Wellcome Trust
MRC
USAID
DFID Malawi
British Infection Society
Lancet
ANRS
South Africa
Graeme Meintjes,
Linda-Gail Bekker, Robin Wood
Mbarara, Uganda
Conrad Muzoora, Kabanda Taseera
Lilongwe Malawi, UNC Project
Jesse Nussbaum, Charles Van der Horst, Dan
Namarika, Mina Hosseinipour
Blantyre, MLW, CoM: Rob Heyderman, David
Lalloo, Kate Gaskell
Lusaka UTH: Shabir Lakhi, Duncan Chanda
Cameroon: Charles Kuouanfack, Elvis Temfack
Pasteur Institute: Olivier Lortholary
London School Hygiene Tropical Medicine
Shabbar Jaffar, John Bradley
University Nevada, Reno: Tom Kozel
Immuno-Mycologics: Sean Baumann
Editor's Notes
Thank you Arturo
Happy to start off this mornings session focused on crypto dis
I wanted to give brief overview epidemiology ongoing burden of crypto dis
Causes mortality,
Discuss developments diagnostics
And in use current antifungals – point out lack novel anti CM drugs in clinical devlopment
Work recently completed and ongoing to try to reduce mortality and burden
AIM To provide current clinical context for discussion crypto dis this am - and discussion some novel approaches to development antifungal therapies later this am, and throughout the mycoses sessions
Efforts to reduce that disease burden thro..
And finally talk bit about lab based work on pathogen diversity and host defense and immunotherapy, and hope convince you of power of linking such lab studies to clinically based studies and detailed patient outcome data
ART coverage has climbed steeply since 2004 – almost 2 M in 2012 for entire SA
Incidence of cryptococcal meningitis although declining slowly, still remains high and above pre-ART incidence levels
Median CD4 at initiation ART 210 (2013) – partly because Cd4 threshold has shifted; large proportion start <200
being adopted in South Africa
potential to prevent HIV-associated cases that present after diagnosis of HIV
As suggested by original animal model work Bob Larsen
As suggested by original animal model work Bob Larsen
So issue is 30% reduction seen at 10 weeks in trial powered at 80% for 45% reduction in Mortality at 10 weeks – so that size effect altho important, v unlikely to be significant
Interesting to combine Pappas and Day data – I know Graeme has estimated
Also incidentally chosen DB and JD/DL as background regimens in their respective ART timing and Steroid trials
So data Ive shown data that forms basis of IDSA and WHO guidance in settings where 2 wks safe amb currently not possible – ie 1 wk better than none and flucon1200 / 5fc optimal oral regimen
And I think important in monitoring trial to look at the Art naïve and experienced patients separately
Which we hope may then take advantgae Giead openess to considering trying to make ambisome mreo available for crypto Rx, and define how it may be best used in CM
And I think important in monitoring trial to look at the Art naïve and experienced patients separately
Which we hope may then take advantgae Giead openess to considering trying to make ambisome mreo available for crypto Rx, and define how it may be best used in CM