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Question about Televison & Video
timer blinking contantly problem
mitsbishi model wd-52825
Posted by myong west on
thank your answer
but we need more detail solutions
you can find it please contact us
thank you
myong west
1.stand by power ok
tp30vs ok
tp12vs ok
tp6vs ok
tp+15v ok
tp-15v ok
2.main power no work
not coming power pulse from micon
you can find it please contact us
thank you
myong west
this tv is dlp tv
converzence circuit is not here
i checked A, door sensor,lamp,fan-ok
B,dc340v lamp ballast voltage not
come in(main power not work)
C,lamp,status led-off
D,timer(power)lamp blinking constant-
E,power dosent turn on
this tv is dlp tv ( not crt tv)
i replced 3300uf/16v 2pcs,thermal sensor is ok
this tv is mitsubishi dlp model wd-52825
this tv has signal,dm, fmt,power,terminal,hdd,lamp ballast,engine circuit (c board is not here)
Contact Mitsubishi customer relations and ask for a "one time consideration" for the service needed to correct this problem.
the part that commonly needs replacing is the chassis (part no. 955B298003). They might ask for that information.
Posted on Sep 18, 2008
The timer/standby indicator blinks for about 30 seconds then goes to the self-diagnosis function. Something is wrong with the video. Check video out, Q705, 732, 761 and other components on the C board, also check Q218, 219, 220 on the A board. Also unit be in IK blanking, try turning up screen slightly.
Posted on Sep 18, 2008
The timer/standby indicator blinks for
about 30 seconds then goes to the self-diagnosis function. Something is
wrong with the video. Check video out, Q705, 732, 761 and other components
on the C board, also check Q218, 219, 220 on the A board. Also unit be in
blanking, try turning up screen slightly.
Posted on Sep 18, 2008
Replace the two 3300uf caps on the PWB? how about the thermal sensor?
They have been made different colors so i cant say for sure, but thereare only two 3300 uf @16V caps on the PWB and you can get the thermalreistance if you need it at the following link but you would have toleave an email as they dont list alot of their little components. Justleave your model number and the name of the part your needing.
Posted on Sep 18, 2008
The fact that its making a chirping means the power supply is most likly ok. It probably the horizontal output transistor is shorted. Now the flyback transformer could be the cause of this or the small coil between the horizontal outut transistor Base and the horizontal driver transformer could need to be taken out and the leads scrapped of paint and resoldered or the the HI voltage caps in the horizontal section could be shorted or leaky. Most of the time when these are bad the caps are split or show burning. They are the 1.5kv disc caps Good Luck
Posted on Sep 10, 2008
Normally with DLP sets, the blinking lights will indicate a bad lamp or fan. If you have the owner's manual, the chapter on changing the lamp should be preceeded by a listing of the lamp indicators. Check also the lamp door and be sure that it is seated properly. There are a number of "safety" switches throughout the set that will cause this symptom if any of hte access doors are not closed properly.
If not the access doors or lamp, the ballast could be bad. It is important to look up the flashing code. Are there any other lights on the front? Temp? Power?
Posted on Sep 10, 2008
Could be anything if we don't know where to start, even the jungle chip that has blown.
Posted on Sep 06, 2008
Did you check the small fuses and resistors near to the convergence ICs? if they keep blowing there is a powering problem on the convergence board.
read this website, they are saying that it is a common fault on this model, that the part that commonly needs replacing is the chassis (part no. 955B298003).
They also say that Mitsubishi can cover out-of-warranty repair, try to give them a call, you find the number on the owner manual.
Well, the voltages are ok, this do not tell me anything.
More than voltages you should check if there is any error message.
Regarding: main power no work
not coming power pulse from micon.
If you can provide more details on this, it can reveal something.
If there is no power from power supply, tv won't startup, but you told me the led goes on.
See if the led blinks a certain number of times, if light flashes at intervals of three times, for example, you will need to replace the bulb. Test the bulb ion any case.
More than testing voltages out , see if you can spot any bad capacitor or resistor. Check the STKs on convergence board. Test high voltage board powering the lamp.
I have the service manual and schematics for Chassis V29-V30-V31
I put an upload here, you can download clicking here here.
Many boards and diagrams are the same as in your V28 chassis.
Rear projection TV have convergence STK ICs the same, only it works different, check the service manual.
SOURCE: I have freestanding Series 8 dishwasher. Lately during the filling cycle water hammer is occurring. How can this be resolved
a 6ya Technician can help you resolve that issue over the phone in a minute or two.
Best thing about this new service is that you are never placed on hold and get to talk to real repair professionals here in the US.
click here to Talk to a Technician (only for users in the US for now) and get all the help you need.
Posted on Jan 02, 2017
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New Delhi, May 19 (IBNS) Days after the Ladakh border standoff and visit of India's external affairs minister Salman Khurshid to China, the Chinese Premier, Li Keqiang, is arriving on a three-day visit to India from Sunday and is scheduled to hold talks with Prime Minister Manmohan Singh in the evening.
A border defence cooperation agreement with India proposed by China mooting freezing of troops level at the border will be discussed during the visit of Li Keqiang.
India´s Joint Secretary (East Asia) Gautam Bambawale said it is a subject which is being discussed between the two governments and it will continue to be discussed including during this visit.
"We are actually negotiating it with the Chinese and they are negotiating it with us," he said.
India´s external affairs ministry said Li Keqiang is arriving at 3:20 p.m. following which in the evening there is a restricted meeting with the Prime Minister.
Subsequently the Prime Minister is hosting a dinner for the Chinese Premier. On the next day, is the formal reception and welcome at the Rashtrapati Bhavan at 9 am. It is followed by the usual homage that visiting dignitaries pay to Mahatma Gandhi at 9:30 at Rajghat.
Premier Li Keqiang has decided to make India the first stop of the first foreign tour that he is embarking upon.
"We think very highly of this gesture because it is our view that high-level political exchanges between our two countries are an important aspect and vehicle for our expanded cooperation. The object of such visits and meetings is to enhance trust and understanding between our two governments and our peoples as well as to exhibit sensitivity to each other's concerns," said MEA spokesperson Syed Akbaruddin.
External Affairs Minister Salman Khurshid will call on the Chinese premier at 10:15 a.m. on Monday. After that at 11:30 there will be delegation-level talks at the Hyderabad House, following which some agreements will be signed.
After an event of media statements by the two leaders, the Prime Minister will host a banquet lunch for the visiting dignitary and his delegation and other important persons. In the afternoon, the Leader of Opposition (Sushma Swaraj) will call on the Chinese premier while the latter will also meet Chairperson of the ruling United Progressive Alliance (UPA) Sonia Gandhi and the Vice-President of India.
On the 21st, Li Keqiang will address university students at a function organised by the ICWA along with other collaborators. He will then will call on President Pranab Mukherjee at Rashtrapati Bhavan, and then depart for Mumbai.
In Mumbai he would be visiting the Tata Consultancy Services and will meet the relatives of Dr. Kotnis.
Li Keqiang will meet Maharashtra Chief Minister besides Chief Executives of leading Indian business houses at a function, and dinner which is being arranged by the ASSOCHAM, CII, FICCI, the three apex chambers of commerce.
He is leaving India on May 22.

subset: commoncrawl


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Goldmark: Candidates mustn't stay silent on NYC pension woes
One of the toughest problems staring at the next mayor of New York City is what to do about city pensions.
New York City today is nowhere near the kind of trouble Detroit is in. That city is bankrupt and no one knows how or even whether pensioners are going to be paid what they're owed. But New York City will be in exactly that kind of trouble if it keeps promising fat pensions for retiring workers but doesn't put up the money to pay for them.
Here's the problem in commonsense terms, without the numbing use of words like billion or trillion.
The city and its unions agreed on contracts that promised generous pensions and post-retirement health benefits to city workers: teachers, firefighters, police officers and others. To pay for those pensions, the city sets aside money in each year's budget. That money is invested and grows, and if everyone has done his or her job right, when a city worker retires there's a pile of money waiting big enough to pay the pension and some post-retirement health benefits till that worker dies.
But not all have been doing their jobs right.
The amount of money being put aside isn't enough to provide the future pensions workers are earning -- and expecting. The situation of New York State is even worse. For the past few years, the state has borrowed to pay the pension funds for those future pensions present workers are earning. And guess whom they borrowed from? From the pension funds themselves.
If you're gagging on that one, then you understand just how shortsighted that little maneuver is.
New York City's pension situation demands what in the financial world is called a workout. That's what you do when things get so far off the rails that no silver bullet, no immediate fix, can solve the problem, and you need a multiyear plan to work out of the mess one digestible bite at a time. We need a workout for the city pensions deficit.
What elements might go into such a workout? Everyone will have to give something. Options include higher payments by the city to cover past shortfalls; trimming health benefits for city workers already retired or who've yet to retire; shifting benefits for future employees from a promise of a fixed benefit to an amount that is purely the result of what the money invested earned; and asking present retirees to pay slightly more for their present benefits.
All these pieces wind up, in the inexorable logic of public finance, being paid for by some combination of taxpayers, present retirees and future retirees. So don't hold your breath to see if the candidates address this explosive problem during the campaign. And you can be equally sure that union leaders -- who ought to have an interest in a thoughtful solution, rather than driving their members right off a cliff, a la Detroit -- won't be seeking a public dialogue on this subject between now and Nov. 5.
So with this huge long-term problem staring us in the face -- and all the candidates focused 100 percent on saying the right things in the short term to win a primary in three weeks and a general election in two months -- what should we expect?
We should expect this: A serious candidate, who wants our trust and the votes of city taxpayers, should tell us we have to address this problem, and that he or she will appoint an independent commission to estimate roughly just how big the hole is and lay out the tough choices. That would be a serious first step.
Peter Goldmark, a former budget director of New York State and former publisher of the International Herald Tribune, headed the climate program at the Environmental Defense Fund.


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Covering the military, politics, terrorism, fitness, guns and anything else that catches my eye...
Sunday, August 30, 2015
15th MEU/SPMAGTF-Central Command combined arms exercise .... Photo by Cpl. Jonathan Boynes
This is interesting.
An MEU working with a SPMAGTF-CR? I am beyond confused by this duality in thinking.
On one hand we keep hearing about distributed operations, disaggregated MEUs and smaller forces becoming units of action (Company Landing Team). And on the other we see the Marine Expeditionary Brigade being re-emphasized, talk of combining MEUs on a regular basis and the need to preserve our forcible entry capability.
You can't have both.
Either the Marine Corps will remain a medium weight force in readiness, an excellent combined arms team without peer and having exceptional infantry or it will attempt to go Commando/SOCOM outer perimeter security/aviation mafia.
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So excited to be participating in this NEW vintage market in the Quad Cities.
Taking place October 25 & 26 at the River Center, Davenport, IA..... this promises to be an amazing venture!
Danielle Colby from "American Pickers" is hostess and coordinator.
All information here: American Vintage Market
Vintage Menswear & Gifts 2545 W. North Ave. Chicago, Il. 60647 Phone 773-943-0710 Email email@example.com
Wednesday, September 3, 2014
See RFF at the American Vintage Market in Davenport, IA October 25/26
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Have you observed the way in which celebs and supermodels have excellent the teeth? Do you consider they have got these excellent genes and were actually brought into this world doing this?
- Enamel shaping is really a procedure mostly employed when somebody has.
- I will assuredly explain to you these folks were not! Their the lord or goddess like pearly whites.
- Teeth whitening is one of the most widely used.
I will assuredly let you know these folks were not! Their the lord or goddess like pearly whites are a result of lots of money invested with a cosmetic dental care operating specialist.
The main objective of your own typical dental professional is ensuring the functionality of your own tooth along with the surrounding area all around them is nice. They analyze, analyze, and stop disorders and ailments of your respective periodontal and mouth tooth decay.
A plastic dental surgeon centers more about the visual part of your own the teeth. Their goal is to help make your look appear as pleasing and desirable as humanly possible. beverly hills aesthetic dentist
Beverly hills prosthodontist women's
How do they make this happen? The primary methods utilized include: teeth bleaching, enamel shaping, veneers, and chewing gum lifts.
Teeth whitening is among the most popular and least expensive strategies employed by these specialized medical doctors. Its fundamentally using a unique kind of chlorine bleach onto your the teeth which whitens them. Over time consuming soft drinks, gourmet coffee, and certain kinds of meals can mark your the teeth and this method means they are vibrant again. Although this process is not going to assist the form of your dentures it may help their coloration.
And this method means
Enamel shaping is really a treatment mostly used when a person has a nick with their teeth. It calls for eliminating a small portion of the outer top of the tooth to make a great easy physical appearance. Its pain-free and helps make the bottom part of your dentures appearance symmetrical.
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Laugh In
Veneers are thin porcelain laminates which actually review your teeth. This might be among the best techniques for getting best pearly whites without the need of receiving braces. Veneers are placed on top of a tooth, bonded directly to them, and loaded with a fabric within the back to avoid teeth cavities. This has become the most favorite surgical procedure of many cosmetic dental practitioners because its such as well as simple procedure and veneers are simple to change if chipped.
- Lightening is probably the most widely used and most affordable techniques applied by these specialized medical doctors. Its basically.
- The main focus of the typical dental professional is making sure the performance.
- A plastic dental care doctor concentrates more on the cosmetic side of.
- Enamel shaping is actually a procedure most frequently utilized.


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The Importance of Traveling
- Details
- Category: Volume 87 (Fall 2015 - Spring 2016)
- Published: 02 March 2016
Traveling is a great way to expand your view on the world, and if you have the opportunity to travel, you should take it.
Being at Monmouth, it's easy to forget that there's a whole other world outside of our little niche. The surroundings we're used to at Monmouth can feel like it has it all. There are shops, restaurants, and having our own beach doesn't hurt. Unfortunately, Monmouth doesn't have everything. There's a lot that you can learn when you're outside of your niche. It might not seem like it, but people who live even a few hours away live a different lifestyle than we do.
When you're traveling you're learning. When you visit new places, you're learning the history of them, which seems like a much better lesson than a history class. The lessons you learn when you travel are a whole different learning experience because you're making yourself familiar with a new environment.
Traveling is a good way to mature. You might find yourself in a new culture when you arrive in an unfamiliar place, and it is important to be respectful of these peoples' cultures.
When preparing to go somewhere, a lot of planning and coordination goes into your trip. Organizing a trip can help you learn new responsibilities because you're responsible for yourself and catering towards your own desires. If it's also a good way to test your responsibilities. You are out on your own, and you are totally responsible for yourself and all of your needs.
There's different concepts of traveling - local and distant. You shouldn't limit yourself to just one. Don't be afraid to travel to an unfamiliar place; broaden your experience. Sure, it'd be great to be able to travel all over the country, or the world for that matter, but can your average college student afford a bunch of trips like that? I wish, but probably not. There's so much you can do in a day trip. Not having to worry about paying for a hotel and pricey travel expenses, you're able to discover places around you that you might not have known existed. If you're bored of day trips, plan an exciting adventure with your friends.
I know when I have enough money saved, I'd rather spend it on an experience. There are so many places that I would love to travel to. I love that when traveling, I'm able learn about other cultures. I think the best way to learn is through experience. Some of the best times I've had is when I'm traveling with my friends. You can have fun and learn so much when you are exploring a new place. There are so many places I would not have even known existed if I didn't allow myself to go new places.
One special advantage we have here at Monmouth Univeristy is the option of studying abroad. They offer traveling to Spain, Australia, London, or Italy for either a whole semester or four weeks in the summer. It is the same tuition as a regular semester at Monmouth University which makes traveling and experience more affordable for people our age, rather then attempting to travel on your own. Study abroad also gives you more time to embrace the culture simply because you spend time living there, not just vacationing. It is definately something to look into.
The best part of traveling is the new experience. Some of the greatest moments of your life can happen when you're traveling to new places. Whether you're going around the world, across the country, or just around the block, there is always a good reason to travel.


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I can't found where my error is, can someone help me, please.That's my code:
/*var userChoice = prompt("Do you choose rock, paper or scissors?");var computerChoice = Math.random();if (computerChoice < 0.34) { computerChoice = "rock";} else if(computerChoice <= 0.67) { computerChoice = "paper";} else { computerChoice = "scissors";} console.log("Computer: " + computerChoice);*/var compare = function(choice1, choice2) { if (choice1 === choise2) { return "The result is a tie!"; }};
as an error I get:
Oops, try again. Did you create a function called compare?
First use this way to format your code:it is probably less work and is better readable as > is for indented text not code.
should probably be choice2 even though that doesn't seem to be related to the error.PS: Maybe the author was over thinking it and as he doesn't got the correct result from your code he anticipated that something is wrong with your function... Still not optimal.
So what I am supposed to do now ? ;d
you have a typo of choice2 in the compare section
OMG... Thanks a lot mate ;ddd


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Consonant and Vowel Sounds
The Montessori reading series is mostly focused on the phonetic aspect of language. The child will spend time learning the initial sounds. Next the focus is on identifying middle sounds of words (emphasizing short vowel sounds), and the ending sounds of words. He does a lot of matching and sorting activities. Objects and pictures are matched by their sounds.
Blending Sounds
Once the child has mastered the twenty-six basic sounds of the alphabet, the directress will then start blending sounds with the child. She may do this with sandpaper letters or the movable alphabet, and it is done quite literally. The directress will place the two letters at opposite sides of the workspace, then slowly say their sounds. As she continues to repeat the sounds, she will move them closer together and say the sounds faster, until visually the sounds are next to each other and orally they are blended. A third and final sound will then be added. Many times word families are introduced.
The child also can practice blending sounds with the movable alphabet. He will try to make up some of his own words, sounding out words that he knows.
Pink Series
The pink series focuses on words with three individual sounds. Most commonly they are consonant-vowel-consonant words, such as cat, rug, mat, etc. The child practices reading these words by labeling objects or pictures with cards. He practices spelling all of them with the movable alphabet. He also begins to learn sight words and starts work in appropriate phonetic readers.
Blue Series
In the blue series, short vowels are continued, but there are often more than three individual phonemes in the word. The child has to sound out consonant blends, which are when the two consonants keep their individual sounds. Initial consonant blends include bl, br, bl, cr, dr, fl, fr, gl, gr, pl, pr, sc, scr, sk, sp, spr, st, str, tr. Final consonant blends include ct, ft, lt, mt, nt, pt, st, lm, ln, lp, mp. Consonant digraphs are also introduced. These include ch, ph, sh, th, wh, kn. Words may be as short as raft and whip, or as long as infant and pumpkin.
Activities in this series again include object and picture labeling and movable alphabet practice. He can also use materials for sentences instead of words. Appropriate readers are slightly more advanced than those for the pink series.
Green Series
In the green series, the rest of the phonetic sounds are introduced. Long vowels are introduce with the "Silent E" for example. Vowels change their sound as r-controlled vowels: ar, er , ir, or, ur. Digraphs and diphthongs are also introduced as more phonograms (vowel/vowel and vowel/consonant combinations that make a unique sound when together).
Digraphs are two vowels that next to each other make on individual sound, such as ai and ea. Diphthongs are a pair of vowels that make two vowel sounds within the same syllable, such as oi, ou, oy. Again the child practices sorting, labeling, reading word lists, spelling with the movable alphabet, and reading more advanced books. As all of these phonograms are introduced, the potential length of the word is indefinite.
The Pink, Blue, and Green series facilitate the flow of the Montessori method in phonetic learning and in conjunction with foundation activities (like the sandpaper letters) are the basis of learning the structure of language.
Note: As much as Montessori is a method, it is also a philosophy. We suggest you consider familiarizing yourself with this by reading Montessori's books. When it is understood how the lessons relate to each other in this context one can achieve better outcomes


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What is it about this town that people feel so entitled that they refuse to use common sense and be respectable human beings? A free concert does not need to bring out the absolute worst in people but it sure seems to do that here.
Just follow a few basic rules, it is common courtesy and nothing more. Do NOT put tarps on the lawn, you kill it when you do that. Do NOT leave your trash in the park for someone else to pick up. Do NOT stay in the park after 10 PM, consider the people living around it and take your screaming kids and barking dogs home!


text: The Potential Role of Biomarkers in HIV Preventive Vaccine TrialsMacLachlan, Ellen PhD, MPH*; Mayer, Kenneth H MD†; Barnabas, Ruanne MBchB, DPhil*; Sanchez, Jorge MD, MPH‡; Koblin, Beryl PhD§; Duerr, Ann MD, PhD, MPH*JAIDS Journal of Acquired Immune Deficiency Syndromes: August 2009 - Volume 51 - Issue 5 - p 536-545 doi: 10.1097/QAI.0b013e3181adcbbe Critical Review: Clinical Science Abstract Author Information Article Outline Background: Successful conduct of HIV vaccine efficacy trials entails identification and enrollment of at-risk populations, assessment of appropriate end points as measures of vaccine efficacy for prevention of HIV acquisition, and amelioration of disease course among infected vaccinees, as well as identification of potential confounders or effect modifiers. Although not invariably useful and bringing their own cost in terms of measurement and validation, a variety of biomarkers may aid at each stage of trial conduct. Methods: A review of selected articles, chosen based on quality, relevance of the biomarker to HIV vaccine trials, and availability of the publication, was conducted. The authors also drew experience from current trials and other planned or ongoing trials. Conclusions: Biomarkers are available to assess HIV incidence in potential study populations, but care is needed in interpreting results of these assays. During trial conduct, sexually transmitted infections such as herpes simplex virus type 2 may act as effect modifiers on primary and secondary end points, including HIV incidence and set point viral load. The utility of sexually transmitted infection biomarkers will likely depend heavily on local epidemiology at clinical trial sites. Analyses from recent large HIV vaccine efficacy trials point to the complexities in interpreting trial results and underscore the potential utility of biomarkers in evaluating confounding and effect modification. From the *HIV Vaccine Trials Network (HVTN), Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA; †Fenway Community Health, Boston, MA; ‡IMPACTA Peru, Lima, Peru; and §New York Blood Center, New York, NY. Received for publication September 10, 2008; accepted February 23, 2009. The views presented in this article are those of the authors and do not necessarily reflect those of the US Department of Health and Human Services, National Institutes of Health, or any of the authors' employers, such as the HIV Vaccine Trials Network. Correspondence to: Kenneth H. Mayer, MD, Department of Medicine, Brown University/Miriam Hospital, 164 Summit Avenue, Providence, RI 02906 (e-mail: email@example.com). Abstract INTRODUCTION Trial Preparation and Enrollment Stages After Enrollment DISCUSSION REFERENCES Back to Top | Article Outline INTRODUCTION The HIV epidemic continues to spread worldwide. Even though strong HIV prevention programs, access to highly active antiretroviral therapy (ART), and the maturity of the epidemic are resulting in stabilization or even decreases in HIV incidence1-3 in 2007, there were approximately 2.5 million new HIV infections around the world.4 Most agree that, given the number of infections, the development of a safe and effective HIV vaccine is a global public health priority.5 Biomarkers could have multiple roles within HIV vaccine efficacy trials and could be used to answer key questions before, during, and after enrollment in trials.6 First, because the aim of most advanced HIV vaccine clinical trials is to enroll subjects at high HIV risk,7-10 biomarkers could serve the function of assessing and validating risk of exposure to HIV in the intended recruitment area. Second, biomarkers are routinely used in assessment of vaccine efficacy. For one, HIV vaccine trials focus on the ascertainment of HIV incidence to answer the primary question of vaccine efficacy.6,11-13 Also, the viral load set point, an early "stable" measure of plasma viremia, has been used as a surrogate end point biomarker14 to evaluate whether vaccine-induced immune response can ameliorate disease course in individuals who become HIV infected after vaccination-by enabling those who become infected to better control viral replication compared with those who received a placebo. Finally, biomarkers of disease, especially sexually transmitted infections (STIs), have been found to be intimately associated with HIV infectiousness, transmissibility, and disease progression.15-19 The measurement of STI biomarkers in HIV vaccine efficacy trials could provide valuable information about the main study outcomes of prevention of HIV infection or amelioration of disease progression or decreased HIV infectiousness. This is especially important if the STI is likely to serve as an effect modifier or a confounder in the analysis of vaccine efficacy or changes in disease progression. As thousands of individuals around the world continue to enter HIV vaccine trials, a critical review of some of the biomarkers to include in these trials is needed. In this article, we have reviewed the use of biomarkers already collected in HIV vaccine trials and evaluated others that, due to their relation to HIV infection, could be considered for inclusion in future trials. Also, the availability of a broader range of technologies to measure HIV infection (eg, use of antibody tests that provide some information on recency of infection) and other STIs may change the feasibility of using biomarkers in HIV vaccine trials. These technologies are reviewed here, with an emphasis on what potential additional information would be gained in a trial where these new technologies are employed. The intent of this review is to help clinical trial investigators in their considerations regarding HIV vaccine trial design in given target populations and sites. In this article, we use the official National Institutes of Health definition of a biomarker: "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention." Back to Top | Article Outline Trial Preparation and Enrollment Stages The global HIV epidemic ranges from generalized epidemics to concentrated HIV epidemics in subpopulations such as men who have sex with men (MSM), commercial sex workers, or injection drug users (IDUs).4 Before the initiation of an HIV vaccine efficacy trial, the most critical information investigators need is a reliable estimate of HIV incidence in specific populations. This is needed to develop a sample size estimate of the number of enrollees needed for the trial10 and to identify which populations are appropriate for enrollment into early phase or later phase trials. Ideally, if HIV incidence and behavioral data can be linked, risk factors can even be identified early on and used as entry criteria that will facilitate enrollment of persons at high risk of HIV acquisition. Unfortunately, HIV incidence has historically been difficult to estimate. HIV prevalence estimates can be obtained easily using rapid HIV antibody tests, with confirmation by Western blot or other specific techniques.20 The enzyme-linked immunosorbent assay (ELISA) assays in particular are widely available, very inexpensive, quick, and easy to use in regions where the highest prevalence subpopulations are found.21,22 However, these tests for current HIV infection do not provide information about the duration of infection in seropositive individuals. This HIV incidence information is exactly what is needed to plan for HIV vaccine efficacy trials, the number of new HIV infections in a population in a given period, although it is much harder to obtain. Because HIV incidence information is critical before initiation of HIV vaccine efficacy trials, better ways to inexpensively and quickly assess incidence in target populations are needed.23 The best and most precise incidence assessment is done by recruiting at-risk HIV-seronegative populations and prospectively following them over time. Another advantage of this approach is that the process of participant recruitment, risk assessment, and risk reduction counseling-and efforts to retain participants-are similar to the procedures involved in an actual vaccine trial. Thus, a prospective cohort study provides an opportunity to hone recruitment strategies, understand the target population, and implement operational processes. Such "vaccine preparedness" studies have in fact been carried out in several countries around the world, including the United States, and have been very helpful in understanding local HIV epidemiology in potential trial sites.7,24-26 As more HIV vaccine efficacy trials approach, this method for estimating incidence and gathering other epidemiological data could be advantageous to geographic areas or subpopulations with little to no epidemiological data. The major disadvantage of this approach is the time and expense involved in setting up the study, in the recruitment and retention of the cohort, and in following the cohort longitudinally. For example, in Africa, only a handful of such community-based prospective surveys have been undertaken so far.27 Furthermore, local HIV epidemiology may change by the time the longitudinal study is completed and an efficacy trial begins. Fortunately, some new methods for cheaply and easily obtaining HIV incidence have been developed in the last 10 years. One of the most recent approaches uses comparative antibody tests that take advantage of the evolution of anti-HIV antibodies that occurs in the months after HIV infection. These assays distinguish recent seroconverters from people with more established infection. One such assay is known as the "detuned" or a less sensitive enzyme immunoassay (LS-EIA), another is the immunoglobulin G (IgG) capture BED enzyme immunoassay (EIA) (BED) assay (Calypte Biomedical Corporation, Rockville, MD),28-32 and there are several others. These EIA assays have the advantage of being relatively inexpensive and rapid. They can theoretically be used to identify recent seroconverters and allow calculation of incidence using specimens derived from cross-sectional studies. Unfortunately, however, the detuned LS-EIA assay has never been optimized to precisely determine a narrow window of seroconversion (usually it is within the past 6 months) and thus may lead to unstable incidence estimates, especially if the sample size is small. This assay has also been found to miss acute HIV infections, and there is some evidence of confounding of the estimates by use of ART.33-36 In addition, results from LS-EIA seem to vary by subtype (eg, significantly different window periods were seen for HIV subtypes B- and E-infected populations from Thailand), and so it has not been widely implemented due to the difficulty of interpreting data from populations with multiple subtypes.37,38 The BED-EIA test may be more useful.31 This commercially available test indirectly measures the proportion of total IgG in a given specimen that is HIV-1 specific. Recent seroconverters have a lower proportion of HIV-specific IgG in the serum/plasma than those with long-standing infection. This assay was developed to address some of the shortcomings of the LS-EIA (eg, the difficulty of accurately making 1/20,000 dilution, assay variability, subtype-dependent performance) but has a similar mean window period as the LS-EIA, 160 days.23,28,37-39 In a recent publication using HIV-positive samples from Côte d'Ivoire, the BED-EIA had a sensitivity of 85.7% and a specificity of 77.1% in detecting recent infections.27 In a study among 26,548 volunteers screened for enrollment in a phase III HIV-1 vaccine trial in Thailand, 38 of the 415 HIV prevalent infections (9%) tested with BED-EIA were identified as recent seroconversions.38 It is impossible to measure the accuracy of the incidence rate reported, although the BED assay did seem to be a convenient and economic tool for identifying recent infections. The author notes that a threshold cutoff based on a calibrator specimen determines the classification of recent seroconversion, and so the assay protocol must be strictly adhered to for accurate, precise, and reproducible results.38 Other investigators have modified commercially available EIA tests such as the Vironostika HIV-1 EIA from BioMerieux (Craponne, France) and the Abbott HIV-1/2gO assay to detect recent infection.40-42 Another in-house test for recent infection with HIV-1 was developed by Barin et al,43 called the immunodominant epitope-V3 (IDE-V3) EIA. These 3 assays were compared with the BED-EIA in an incidence study, and all 4 showed mediocre performance at measuring recent infection in samples from individuals with known HIV infection dates (collected <180 days after infection).27 Using a longer window period and/or a different cutoff favoring better specificity may improve accuracy of the modified kits. In conclusion, these EIA methods (otherwise known as tests for recent infections or TRIs) for estimating HIV incidence are most appropriately used for population-level data. The window period for positivity in these assays is fairly broad (about 150-180 days) and varies considerably from person to person, so that incidence calculations, which use a single value for all individuals, should be interpreted carefully. Moreover, the assays have difficulties in identifying recent infections in persons with clades of HIV that are not B, E, or D clades and misclassify individuals with late-stage HIV disease, who lose antibodies as a result of immunodeficiency. In general, however, these tests will become more useful if future generations of tests can more accurately measure recent infection and adjust for individual-level variation in antibody kinetics. Comparisons to estimates from prospectively collected data and nucleic acid testing will aid assessments of the accuracy and advantages of different methods. Another method that has been used for pinpointing time of HIV infection has been the use of HIV RNA testing, or nucleic acid amplification testing (NAAT), to identify individuals who have been so recently infected that they have not had sufficient time to develop HIV antibodies. In the literature, these are referred to as acute HIV infections as opposed to the recent infections that incidence EIAs are designed to capture. Newer clinical testing algorithms suggest that pooling plasma specimens from high-risk persons who test antibody negative may result in cost-effective use of HIV NAAT screening; pooling algorithms using NAAT testing has been used to identify viremic individuals and to allow estimation of HIV incidence in high-risk groups.35,44 A hypothetical advantage of routinely screening for HIV RNA before enrollment into HIV vaccine trials is that acutely infected persons will not be enrolled. In addition, pooled samples showing incident infections might provide important information about where to target enrollment of at-risk populations. However, the narrow window period identified by NAAT testing confers a significant disadvantage-a few acute infections are detected. Specifically, the small number of infections identified-although important-limits the ability to identify risk factors associated with acute infection and may prevent intergroup incidence comparisons.35 Another major disadvantage of NAAT is that in regions of lower HIV prevalence, the number of false positives in RNA-positive/antibody-negative populations may exceed the number of acutely viremic persons. In addition, the cost implications of NAAT testing would need to be carefully evaluated. Many centers in the developing world may not be equipped to perform plasma pooling and HIV NAAT screening proficiently and in a cost-effective manner, although there are cases where NAAT is succeeding even in resource-constrained settings. For example, this has been demonstrated by CHAVI (Center for HIV-AIDS Vaccine Immunology) sites in Africa that perform NAAT pooling routinely and have already screened >10,000 high-risk individuals. In conclusion, the lack of more precise and cost-effective HIV incidence biomarkers can limit the information available to researchers. However, with the right laboratory evaluation method, HIV biomarkers may be used to refine the estimates of the prevalence and incidence of HIV in at-risk populations that are being considered for inclusion in vaccine trials.23 Two of these methods are the detuned EIA or BED capture assay and the NAAT-pooled screening methodology, each with certain limitations. These biomarkers may refine the determination of HIV incidence during the vaccine clinical trial, as described in the next section, by providing enhanced precision regarding the time of HIV acquisition by study participants. Finally, serologic testing for HIV incidence is faster than following cohorts prospectively but cannot replace the rich information provided by longitudinal cohorts. As stated earlier, such a cohort study may be critical in regions or subpopulations where little to no epidemiological information is available and can generate prospective biological and behavioral data in a way that can illuminate epidemic trends better than cross-sectional prevalence studies. Back to Top | Article Outline After Enrollment The most important biomarkers used during an HIV vaccine trial are HIV infection and HIV viral load, a surrogate marker of vaccine effect on disease progression. Commonly used biomarkers for this purpose are HIV seropositivity (by ELISA/Western blot) and set point viral load. Set point viral load is used as a surrogate for vaccine effects due to observations that lower set point viral load is correlated with a slower immunological decline in unvaccinated HIV-infected individuals.45 It has been proposed as a surrogate end point for trials of "T-cell vaccines" based on these observations and biologic plausibility, assuming that vaccine-induced immune responses will lead to control of viremia, which will be reflected in reduced viral load that will in turn lead to improved clinical course. It is also hypothesized that vaccine-induced decreases in plasma RNA viral load will result in reduced transmission of HIV to sexual partners. This is based on data from untreated unvaccinated individuals in a natural history study of discordant couples in the Rakai district of Uganda.46 For measurement of HIV acquisition in a trial, incident EIA testing would have limited utility during an HIV vaccine trial due to individual variation in the evolution of antibody response. This makes these tests more suitable for determining recency of infection on a population, rather than an individual, level. However, RNA tests are routinely used to test stored specimens to determine if an antibody-positive participant was viremic at a previous time point. BED-EIA, or other EIAs designed to capture recent HIV infection, might be used to narrow the "window" for a group of incident infections detected at a given visit. This would be most appropriate when study visits are far apart (eg, 1 year) because more frequent HIV testing (eg, every 6 months or every 3 months) would provide better discrimination of HIV incidence than would be provided by serologic testing for recency of infection. If these assays can help to better pinpoint the time of infection (eg, through routine NAAT testing to detect acute infections or if future generations of EIA tests can be used to identify very recent infections), they may aid in linking infection data with behavioral data obtained around the time of infection. This is a vast improvement over trying to link behavioral data with an infection date that is known very imprecisely. When a participant first tests positive for HIV serologically, stored specimens from the previous visit are routinely tested for HIV RNA as evidence of acute infection. NAAT testing is not routinely used for screening due to cost considerations, although specimens could be stored and then pooled and tested at a later date. However, if a substantial delay occurs in identifying acute infections, the advantages of the NAAT methodology over sequential serologic testing would likely be lost as participants would be well past the acute infection period when identified. Another major disadvantage of using these kinds of assays during an HIV vaccine efficacy trial is that they are expensive and not widely available outside the United States. There is also concern that they are not optimized for detection of infection with non-clade B HIV. Other important biomarkers to consider, as part of screening or after enrollment, are STI and other infectious disease biomarkers that may be cofactors for HIV acquisition or markers of risk. Biomarkers such as other STIs may be highly correlated with risk of HIV infection and, if they may possibly act as effect modifiers of vaccine efficacy, should be included in the final statistical analyses.13 The unexpected results seen in a recent test-of-concept trial of the Merck Ad5 HIV vaccine candidate and the observation of vaccine effects on HIV acquisition only in certain subgroups underscore the potential complexity of analysis of data from vaccine efficacy trials.47 These analyses may be aided by examination of additional biomarkers that can help elucidate, for example, HIV transmission dynamics for a given transmission modality or study site. Deciding on which STI biomarker to include is still very difficult, however, because the possible effect of STIs on the measurement of vaccine efficacy has not been documented and is mostly theoretical. The potential role of STIs in different trial scenarios is depicted in Table 1. In scenario B, where STIs are much less prominent in the placebo arm of the trial, the vaccine efficacy findings are biased toward the null. In scenario C, differential vaccine efficacy in STI arms of the trial also biases vaccine efficacy findings toward the null. As vaccines produce less and less modest effects, and fewer end points are available for analysis in STI subgroups, these effects may become more pronounced.48 Despite these possible effects, however, deciding whether or not to test for STIs or whether to alter trial design or sample size calculations based on these theoretical effects is not straightforward. When considering which STI to include in a trial, the overall epidemiological evidence for the STI as an HIV cofactor should be considered carefully, in addition to the epidemiological evidence for that importance of STI in a trial target population, such as MSM, or for a local community involved in the trial. Even so, the inclusion of STI biomarkers in HIV vaccine trials is controversial because of the lack of evidence that indeed these biomarkers will affect the results through confounding or effect modification. This in turn makes it very difficult to calculate parameters such as the sample size needed to conduct STI subgroup analyses because it is unknown what the potential size of the effect may be or even the direction of the effect. Certainly, trial sample sizes would need to increase to adequately perform STI subgroup analyses. TABLE 1 Proponents argue that STIs may affect estimates of vaccine efficacy because they influence HIV acquisition and HIV viral load,46,49,50 primary end points of HIV vaccine trials. Multiple well-designed cohort and nested case-control studies from 4 continents suggest that there is a 2-fold to 5-fold increased risk of HIV acquisition associated with intercurrent STDs and that genital ulcer diseases are generally associated with slightly higher risk estimates than discharge syndromes.51,52 For herpes simplex virus type 2 (HSV-2), a recent meta-analysis of longitudinal studies estimated that the risk of HIV-1 infection among HSV-2-infected individuals was 3 times that among HSV-2-uninfected individuals.53 This 3-fold increase in risk of HIV-1 acquisition suggests that in much of the developing world, where HSV-2 prevalence is high, a substantial proportion of HIV infection may be attributable to genital herpes. Thus, HSV-2 is the STI most often proposed as a possible HIV vaccine effect modifier, although it is possible that other STIs reviewed here could play a similar role. It is also possible, because of the 3-fold increased risk for HIV acquisition, that vaccine trials conducted in high prevalence HSV-2 settings will reach trial end points much more quickly. Logically, reducing HSV-2 using suppressive therapy would also reduce risk of HIV. However, a recent trial did not demonstrate efficacy of HSV-2 suppression treatment in preventing new HIV infections.54 Thus, exactly how these biological cofactors interact with candidate vaccines remains to be elucidated in clinical vaccine trials. In addition to the propensity of HSV-2 infection to increase susceptibility to HIV acquisition, it can affect HIV-1 viral load, particularly during acute HIV-1 infection, and may affect the HIV set point viral load in HSV-2-infected individuals. Studies suggest that, for HIV-1-infected individuals, the plasma HIV viral load is 0.33 to 1 log higher among HSV-positive persons compared with HSV-negative individuals.55-59 Several studies demonstrate that HSV-2 may directly increase the replication of HIV-1, explaining the higher HIV viral load seen in HSV-2-infected people.49 Again, such a role for HSV-2 could theoretically lead to vaccine effect modification in vaccine trials seeking to demonstrate reductions in viral load. Another example of potential effect modification is syphilis. Genital ulcers due to syphilis have been shown to be associated with increased HIV transmission and acquisition51,60,61 and with increases in HIV viral load.62,63 These associations could potentially have implications for HIV vaccine trials, especially in certain geographic areas and in key subpopulations such as MSM. MSM populations in cities in the United States and internationally have documented co-epidemics of syphilis and HIV, with HIV infection rates as high as 50%-60% among gay/bisexual men with early syphilis.64 We have discussed the use of biomarkers in assessing the primary end points in a vaccine trial and their potential role in explaining effect modification and confounding, using the examples of HSV-2 and syphilis. Although not directly related to the study question of vaccine efficacy, another approach to the use of STI biomarkers in an HIV vaccine trial may be the use of biomarkers as a screening tool. STI screening may be especially relevant to phase II/III trials that seek to enroll participants at highest risk of HIV into a trial, by helping to assess patterns of risk-taking behavior in specific populations (eg, commercial sex workers, IDUs, MSM, adolescents). In general, there is agreement that using STIs for this purpose is most beneficial at the population level (eg, to define STI epidemiological trends in key groups and thus identify groups or communities who may be at high risk of HIV) as opposed to the individual level, where concluding HIV risk based on STI infection can be very difficult. Non-disease biomarkers such as those used for semen are not included in this review, although they do exist. Although most researchers agree that there are several limitations to definitively linking STI infection to HIV risk behavior at the individual level,65,66 in general, high STI incidence and prevalence in a population or in target groups do help identify populations at risk for HIV due to unprotected sex.67 Thus, measuring incident STIs would be most useful in planning before opening an HIV vaccine trial or as a screening tool. If incident STI information was available at the clinic level, the occurrence would likely be rare and it would be difficult to validate sexual behavior or improve counseling based on STI outcomes. Nevertheless, STI outcomes could be used in this way. Syphilis and HSV-2 can again be used as examples. Because the risk behaviors are so similar to those for HIV, performing serologies for syphilis and HSV-2 could help clinic staff identify high-risk volunteers, validate reported behaviors, and provide appropriate counseling throughout a trial,68 especially in populations known to be at risk such as MSM.64,69-72 Fortunately, assays used to test for syphilis reactivity (rapid plasma reagin or VDRL), confirmed by fluorescent treponemal antibody or microhemagglutination assay (MHA-TP), are widely available and are fairly inexpensive.73 Also, for detection of HSV-2, newer antibody assays are becoming more widely available, cheaper, and quicker and have been shown to be more cost effective than traditional culture methods.74 Finally, HSV-2 rapid test kits and commercial ELISA HSV-2 tests are available.75 For HSV-2 EIA tests, it should be noted that gG2-based HSV-2 EIAs have performed poorly in many populations and is a potential drawback to HSV-2 testing.76 Other STIs that can be useful in patient management are bacterial STIs. Testing for gonorrhea and chlamydia has been made easier by use of polymerase chain reaction (PCR) testing of urine and self-administered vaginal swabs for women, even though sometimes the cost of PCR testing can be prohibitive and specimen collection can be logistically challenging in some settings.77 In addition, the association with HIV transmission and acquisition is not as strong as with syphilis and HSV-2, and the prevalence of bacterial STI is generally lower. It would thus be much harder to make a case that bacterial STIs may act as effect modifiers in an HIV vaccine trial, although the potential indirect benefits to the trial and to trial participants described earlier would still apply. To decrease the cost of testing, pooled testing with PCR or in-house PCR can be used.77-80 It is worth noting the unique case of gonorrhea and chlamydia in MSM because MSM are often important vaccine trial participants. Pharyngeal and rectal testing for gonorrhea and chlamydia by NAAT is not Food and Drug Administration approved. Pharyngeal testing may have limited utility as a marker of sexual risk behavior, whereas rectal gonorrhea and chlamydia in men have been shown to enhance susceptibility to HIV infection. Rectal infections would not be detected if only urethral screening was performed; in one study among MSM, 53% of chlamydial infections and 64% of gonococcal infections were at nonurethral sites. Up to 85% of rectal infections are asymptomatic.81 Increases in chlamydial and gonococcal infections in MSM in the United States and elsewhere may indicate a need to consider testing for these infections in MSM in HIV vaccine trials, both as an index of sexual risk behavior and as a possible confounder of HIV acquisition or viral load end points in a trial.82-85 Certain hepatitis infections may also be useful markers of HIV risk and can corroborate self-reported sexual risk behavior. For example, it may be helpful to assess hepatitis C serologies [hepatitis C virus (HCV)] in vaccine trials involving IDUs.86 Due to shared risk factors for transmission, coinfection with HIV and HCV is common, especially among IDUs and recipients of contaminated blood or products.87-89 In addition, studies of MSM in the United States and elsewhere have shown a higher prevalence of HCV than the general population and often a high correlation with HIV infection.90-92 For example, a survey of 183 MSM at a community health center in Boston found a prevalence of 11.5% for HCV; men with HCV were more likely than those not infected with HCV to have HIV infection (70% versus 29%; P < 001) or hepatitis B infection (47% versus 12%; P < 001).90 These results may indicate that the risk behaviors for HCV are aligned with HIV risk behavior (HCV seropositivity was significantly associated with an aggregate score representing high-risk sexual behavior in the past 6 months), although it remains unclear what role sexual behavior plays in HCV transmission. Finally, the potential role of hepatitis B screening should be considered mostly as a benefit to trial participants. In the United States, many people who may volunteer for HIV vaccine trials are not vaccinated against hepatitis B. This is especially true of the high-risk groups that are sought for HIV vaccine trials, such as high-risk MSM and heterosexual populations in sub-Saharan African countries with high prevalence of hepatitis B. Studies among high-risk women and MSM in the United States indicate low rates of hepatitis B virus vaccination in these groups.93-96 Clinical trial sites in areas of high hepatitis B prevalence could potentially test for hepatitis B and provide or refer study participants for vaccination. Authors have noted that hepatitis B vaccination could be used as an incentive to HIV vaccine trial participation, as could other STI testing and/or vaccinations noted in this review.97 Back to Top | Article Outline DISCUSSION The review of HIV biomarkers reveals a wide spectrum of utility and ease of implementation. EIA tests for recent HIV infection and NAAT tests for acute infection are best used for incidence studies done in preparation for HIV vaccine studies. Even though the richest incidence data from a population are obtained from prospective cohort studies, incident EIA testing and/or NAAT testing provide HIV incidence information in a more efficient and cost-effective manner than a cohort study. However, the ease of using these tests to obtain incidence estimates from cross-sectional specimen collections has a price. Estimates of incidence obtained in this manner may be less accurate than prospectively collected data, and cross-sectional studies using these methodologies (especially those using "waste" specimens collected for another purpose) often provide only limited information on sexual risk behavior or other cofactors for HIV infection. This may be a distinct disadvantage when identifying groups at high risk of HIV infection (eg, by ethnic group, sex, geographic location, or risk group) is a goal. EIA tests for recent HIV infection during a trial may be of use when there are long windows between testing (eg, annual testing) and an investigator would like to better pinpoint the actual infection date. For the most part, however, when a participant becomes HIV infected during a vaccine trial, earlier specimens are RNA tested to identify whether the person was acutely infected at the previous study visit. Using NAAT testing at screening into a trial is generally cost prohibitive based on the small number of acute infections that would be detected. EIA tests for recent infection and NAAT/RNA tests can aid with understanding of behavioral data by allowing linkages of behavioral data with a more accurate estimate of HIV infection date. Investigators in a vaccine trial who are contemplating the use of STI biomarkers should first consider whether the biomarker in question is of direct benefit to the overall trial or of indirect benefit, for example, including potential STI biomarkers in a clinical trial because the possibility of confounding and effect modification is of direct benefit to the primary scientific question and should be looked at closely by HIV vaccine trial teams. Other uses of biomarkers, such as to corroborate risk-taking behavior or identify groups at risk, are of indirect benefit. Also, in making decisions about including STI assessment in trials, local STI epidemiology should be carefully considered. STI prevalence will vary from site to site, and the unique contribution of specific STIs to each trial outcome may vary. Once an STI of importance has been identified, testing for such STIs could be of use before the trial, as a screening tool and as a baseline measurement, and perhaps also throughout an HIV vaccine efficacy trial. For the STI biomarkers reviewed, there are 2 important mechanisms through which STIs may theoretically modify candidate HIV vaccine efficacy. First, trial participants with intercurrent STIs may face a 2-fold to 5-fold increased risk of acquiring HIV, as has been demonstrated by multiple studies.51,52 Estimates of vaccine efficacy for HIV prevention may be affected if STIs occur more commonly in one arm of the trial or if STIs act as effect modifiers. Second, intercurrent STIs may affect HIV viral load, an important outcome in HIV vaccine trials. Neither of these concerns about STIs increasing HIV acquisition and viral load would apply if STIs are equally common in both arms and if the vaccine action was the same among participants with and without STIs, that is, the vaccine effect was not modified by intercurrent STIs. It is important to note again that such interactions are currently theoretical. What does STI evaluation mean practically in vaccine trials? In addition to the planning and analytical issues relating to STI testing in clinical protocols, the trial sites will face operational issues associated with counseling, testing, and treatment for STIs. Certainly, additional resources would be needed. Another key question to consider is whether treatment would be offered to symptomatic participants only or to all infected participants. For HSV-2, for example, providing treatment for symptomatic HSV-2 may reduce viral load preferentially in placebo recipients, potentially confounding the true vaccine effect. This effect may be even greater if asymptomatic participants are provided with therapy. It may be possible to control for this effect, as would be done for the effect of ART, if data on HSV infection and treatment are collected. Nevertheless, issues around counseling, testing, and treatment of any STI biomarker are complex and need to be considered carefully. The recent discontinuation of vaccinations in 2 large HIV vaccine trials in the Americas and South Africa and the complexity of the data from these trials underscore the potential utility of collecting more extensive biological and behavioral information. An HIV vaccine based on an Adenovirus serotype 5 (Ad5) vector with a clade B insert failed to protect against HIV acquisition and failed to reduce HIV set point viral load among individuals who became infected with HIV after vaccination.47 Among 2 subgroups-men with serologic evidence of prior exposure to Ad5 and uncircumcised men-those who received vaccine seemed more likely to acquire HIV infection. Whether this was due to a direct or indirect vaccine effect, chance, or behavioral differences between the vaccinees and placebo recipients is currently being investigated. A limited number of biomarkers (such as HSV-2 serology) are available and will be included in the multivariate analysis. Another feature of this study was the low incidence observed in women-those who received placebo and those who received vaccine. Although these women reported a large number of partners and many pregnancies were observed during the trial, it seems that their sexual networks were at low risk for HIV. It may be that in future trials in women additional biomarkers could be used to more completely assess women's risk of HIV and other STIs. In conclusion, this review has presented the rationale for the use of biomarkers before and after HIV vaccine trial cohort enrollment. It is clear that the final determination of the use of biomarkers in HIV vaccine trials needs to be based on a careful balancing of trial location, scientific rationale, costs, burden to clinical trials units, and ethical obligations and/or benefits to participants. We have summarized issues relating to the use of different biomarkers in Table 2. In this table, the biomarkers discussed in this review are displayed, along with a description of (1) what they could be used for in a trial, (2) the advantages of the biomarker, (3) the disadvantages of the biomarker, and (4) some examples of products commonly used to test for the biomarker. In the history of vaccine development, it has often been the case that a given vaccine shows dramatic effect although the underlying mechanisms are not well understood.98 This should tell us that in the end, if we do discover a partially effective HIV vaccine, we may end up relying heavily on the biological and behavioral information we collected during a trial to try and determine why it worked. TABLE 2 Back to Top | Article Outline REFERENCES1. Diop OM, Pison G, Diouf I, et al. Incidence of HIV-1 and HIV-2 infections in a rural community in southern Senegal. AIDS. 2000;14:1671-1672. Cited Here... 2. Gregson S, Garnett GP, Nyamukapa CA, et al. HIV decline associated with behavior change in eastern Zimbabwe. Science. 2006;311:664-666. Cited Here... 3. Msuya SE, Mbizvo EM, Stray-Pedersen B, et al. Decline in HIV prevalence among women of childbearing age in Moshi urban, Tanzania. Int J STD AIDS. 2007;18:680-687. Cited Here... 4. UNAIDS. AIDS Epidemic Update: December 2007. 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Duerr A, Wasserheit J, Corey L. HIV vaccines: new frontiers in vaccine development. Clin Infect Dis. 2006;43:500-511. Cited Here... 15. Greenblatt RM, Lukehart SA, Plummer FA, et al. Genital ulceration as a risk factor for human immunodeficiency virus infection. AIDS. 1988;2:47-50. Cited Here... 16. Mayer KH, Anderson DJ. Heterosexual HIV transmission. Infect Agents Dis. 1995;4:273-284. Cited Here... 17. Pao D, Fisher M, Hué S, et al. Transmission of HIV-1 during primary infection: relationship to sexual risk and sexually transmitted infections. AIDS. 2005;19:85-90. Cited Here... 18. Plummer FA, Simonsen JN, Cameron DW, et al. Cofactors in male-female sexual transmission of human immunodeficiency virus type 1. J Infect Dis. 1991;163:233-239. Cited Here... 19. Wasserheit JN. Epidemiological synergy. Interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sex Transm Dis. 1992;19:61-77. Cited Here... 20. 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Lama JR, Lucchetti A, Suarez L, et al; Peruvian HIV Sentinel Surveillance Working Group. Association of herpes simplex virus type 2 infection and syphilis with human immunodeficiency virus infection among men who have sex with men in Peru. J Infect Dis. 2006;194:1459-1466. Cited Here... 70. Nicoll A, Hamers FF. Are trends in HIV, gonorrhoea, and syphilis worsening in western Europe? BMJ. 2002;324:1324-1327. Cited Here... 71. Stolte IG, Dukers NH, de Wit JB, et al. Increase in sexually transmitted infections among homosexual men in Amsterdam in relation to HAART. Sex Transm Infect. 2001;77:184-186. Cited Here... 72. Tabet S, Sanchez J, Lama J, et al. HIV, syphilis and heterosexual bridging among Peruvian men who have sex with men. AIDS. 2002;16:1271-1277. Cited Here... 73. Goh BT. Syphilis in adults. Sex Transm Infect. 2005;81:448-452. Cited Here... 74. Ramaswamy M, McDonald C, Smith M, et al. Diagnosis of genital herpes by real time PCR in routine clinical practice. Sex Transm Infect. 2004;80:406-410. Cited Here... 75. Morrow RA, Friedrich D, Meier A, et al. Use of "biokit HSV-2 Rapid Assay" to improve the positive predictive value of Focus HerpeSelect HSV-2 ELISA. BMC Infect Dis. 2005;5:84. Cited Here... 76. Oladepo DK, Klapper PE, Percival D, et al. Serological diagnosis of varicella-zoster virus in sera with antibody-capture enzyme-linked immunosorbent assay of IgM. J Virol Methods. 2000;84:169-173. Cited Here... 77. Johnson RE, Newhall WJ. Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections-2002. MMWR Recomm Rep. 2002;51(RR-15):1-38. Cited Here... 78. Cook RL, Hutchison SL, Østergaard L, et al. Systematic review: noninvasive testing for Chlamydia trachomatis and Neisseria gonorrhoeae. Ann Intern Med. 2005;142:914-925. Cited Here... 79. Mania-Pramanik J, Potdar S, Kerkar S. Diagnosis of Chlamydia trachomatis infection. J Clin Lab Anal. 2006;20:8-14. Cited Here... 80. Tan HH, Chan R. 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Smith, who literally wrote the book on reputation management, penning Image, Media and the Law in his spare time, has amassed some stunning victories for his clients (see story).
In December he won an injunction against the publication of photos of Tiger Woods – photos that may not have even existed in the first place. It's like that picture of the hand drawing the other hand or a set of Esher stairs … mind boggling.
But, that said, there had been comments made by Smith of late that were difficult to reconcile with his firm's creed of 'reputation management'. In particular during his 17 December appearance on BBC Radio 5 to debate privacy.
Fellow panellist and Observer sports writer Will Buckley – himself a former lawyer – was shocked by one of Smith's comments about Tiger Woods:
"Smith saying 'obviously Tiger's got problems', doesn't really fit in with reputation management," argued Buckley.
But when asked about Smith's departure, Schillings business director Christopher Mills gave a quote befitting the firm's legendary renown for keeping the private just so.
"There were no problems," said Smith, "it was just that after 14 years with the firm he [Smith] decided to move on to some new challenges."
Now that's how you manage a reputation.
Also on TheLawyer.com: A&O and Latham tackle Man U bond; DLA Piper loses its spot on Virgin Group's panel; and ex-Hengeler partner quits Milbank after just ten days.


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Coral Announce Launch Of Win A Million Football Jackpot
Leading bookmaker Coral has announced the launch of "Football Jackpot" a unique pool bet which will give its customers a chance to become an instant millionaire for a £1 stake.
Ground breaking Football Jackpot will launch on Saturday and run every weekend throughout the 2013/14 football season. Coral customers can place their Football Jackpot bets via coupons available in Coral's 1800 shops, or online at coral.co.uk or via Coral's mobile app.
Each week Coral will provide the Football Jackpot coupon which will contain 15 football matches and customers will be asked to predict either a home win, draw or away win for a £1 stake. The first sole winner of Football Jackpot is guaranteed by Coral to win £1million, and there are also consolation prizes for customers who narrowly miss out. Customers who correctly predict 13 or 14 results will receive a consolation cash payment and depending on the size of the pool and the number of consolation winners, consolation payout could run into tens of thousands of pounds. Customers will also have the flexibility of either choosing a lucky dip or making their own selections.
Simon Clare, PR Director of Coral comments, "This is an historic day as we are the first British bookmaker on the high street to ever offer our own "football pool bet" and one with the potential to create millionaires."
Clare continues, "We are confident Football Jackpot will become a huge success and are investing a seven figure sum to launch and promote this exciting new bet on TV and in print advertising over the coming weeks and months. Football has a huge and growing following in Britain and by offering football fans a simple, Lottery-style, 'small-stake big-win' product we hope to attract thousands of new customers to our shops and online, as well as giving existing football punters a new and fun betting opportunity to try and win a life-changing sum of money"
The first match on the coupon will be at 3pm Saturday 17th August with the final game being the Monday night Premier League fixture on 19th August between Manchester City and Newcastle United. The structure of weekend fixtures means Coral will be able to tell if it has customers in with a chance of scooping the jackpot and will look to create interest via social media and in its chain of retail betting shops.
Clare adds, "The beauty of the Football Jackpot is that we will always know going into the last game every Monday or Sunday whether we have a customer in with a chance of becoming a millionaire and what results they need, enabling us to promote the thrill and excitement of the bet as it happens through social media and CoralTV in Coral betting shops"
The Football Jackpot win pool will rollover if there is no winner, and Coral predicts that there will be occasions during the season where customers will be in with a chance of winning well in excess of £1m.
Football Jackpot will be advertised on all the main TV channels from Saturday 10th August with a simple message to say you can "win a million". Coral have also partnered with The Sun newspaper featuring expert punditry from Terry Venable and the Football Jackpot coupon will be inserted in The Sun, The Daily Star, The Express, The Mirror and The Daily Record as well as additional activity within a selection of these newspapers.


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in the heart of
is designed to provide a broad introduction to the elements of filmmaking, completing the cycle with a third year of specialization in Producing where concentration is placed toward the student's third term project.
The International Department's Bachelors program is designed to give the student a thorough understanding of the aesthetic and technical aspects of filmmaking enabling the student to find employment in the various occupations of audio-visual industries including film, television and new media.
The filmmaking component begins with a concentration on storytelling for the documentary to develop the student's visual vocabulary through theoretical courses and practical exercises.
The student will distinguish and develop for their fiction cinema project, the techniques implied in each of the following specializations: producing, cinematography, directing, screenwriting and editing.
This second year gives the students the opportunity to discover and experience a wide spectrum of filmmaking disciplines before they choose and commit to the Producing major.
Students complete the cycle with a third year of specialization where concentration is placed on the third term project that is oriented toward the Producing major.
Students with a Major in Production are required to produce a minimum of 3 student productions in their final 3rd term. During the second term, in addition to the required BFA courses, students will have a series of specialized workshops, and intense one-to-one tutoring with professional producers.
The students' participation in student film exercises and productions other than their own, their ability to work as part of a team, and the quality of their contribution to each project are equally important factors in the final evaluation their overall performance in the BFA program.
► Download the Course description
The Bachelor of Fine Arts with a major in Producing aims to give students professional preparation for a career as a Producer in film, television and digital media.
EICAR graduate producers are more than prepared for the rigors of the professional world and work in a multitude of audio-visual related occupations including Film and Television Executive Producer, Co-Producer, Associate Producer, Line Producer, Production Manager, Production Assistant, Production Runner, Unit Production Manager, Music Video Producer.