An ongoing dialogue on HIV/AIDS, infectious diseases,
June 22nd, 2013
NEJM Group, Blog Freeze, and Puppy Brothers
It’s official — the various medical products of the Massachusetts Medical Society are now lumped under NEJM Group — including the flagship New England Journal of Medicine itself, the Journal Watches, even this site.
No surprise, therefore, that there will be a new web platform, with the launch slated for next week. I’ve been told this means a “blog freeze” — sounds like a summer ice cream treat — for at least June 24-25. During the freeze, there will be no new posts or comments.
Here then, to bide the time until we’re up and running again, is a picture of our puppy Louie and his brother Arlo, who fortunately just happens to live down the street:
June 20th, 2013
Let’s Move the HIV Testing Algorithm Into the 21st Century
As I’ve written before, the most widely used testing algorithm for HIV — enzyme immunoassay followed, if positive, by Western blot confirmation — is long overdue for an update.
A brief review why this is the case, and also why sticking with it is so problematic:
- Immunoassays have become progressively more sensitive, especially when paired with p24 antigen testing in “4th generation” tests.
- In recently acquired infection, the screening test turns positive way before the Western blot — it can be a difference of several weeks (figure from Branson J Acquir Immune Defic Syndr 2010;55:S102–S105):
- Clinicians are not familiar with this problem, so they might conclude that a reactive screening test followed by a negative Western blot means that the person doesn’t have HIV — it’s a “confirmatory test”, after all, so you can understand their confusion.
- Patients during this phase of early/acute HIV infection are at their most contagious, hence most likely to spread the virus to others — especially if given the wrong information about their HIV status.
- Patients may seek testing soon after high-risk exposures — they’re motivated! — and hence are potentially in this window before the Western blot turns positive.
The frustrating thing about this state of affairs is that we have had the tools to correct this problem for some time. Laboratory guidelines for HIV testing were updated in 2011, recommending the following algorithm for HIV diagnosis:
Now, thanks to CDC, we have some concrete data about how useful this new testing strategy can be — in particular for those with recently acquired HIV. A screening program in an Arizona emergency department identified 37 individuals with undiagnosed with HIV, and twelve of them — nearly a third — had acute HIV that otherwise would have been missed by the Western blot.
A second validation study looked at over 37,000 samples drawn from high-risk patients in sites from New York City, North Carolina, and San Francisco; there were 99 cases where the screening immunoassay was positive and the second antibody test negative. In this group, 55 had acute HIV infection (diagnosed by HIV RNA), many of whom had negative Western blots.
According to Bernie Branson — HIV testing guru from CDC — the FDA approval of the differentiation assay (step 2 in the algorithm) has led many labs to adopt the new strategy:
The number of labs doing this has picked up considerably since Multispot received its new indication … nearly half of public health labs (e.g., FL, MA, IL, IA, NY) have adopted it, as have Stroger/Cook County in Chicago, Howard University Hospital in DC, and LSU hospital system (to name a few). California has proposed emergency regulations (expected to be effective July 2) that will permit all labs in the state to perform the new algorithm, which their current regulation precludes, and New York State has issued 2 public health advisories encouraging its use.
It’s time for the rest of us to do the same.
And if you’re feeling bad for the Western blot, it still has a (rare) indication — as a confirmation of HIV infection in “elite controllers”, those with HIV antibodies but no detectable HIV RNA.
June 19th, 2013
FDA, IND, FMT: Nine Letters, Some Common Sense, and a Real Video Link
Good news here — the FDA has reconsidered their requirement for an IND for fecal microbiota transplantation (FMT) for C diff:
Some health care providers have stated that applying IND requirements will make FMT unavailable and have suggested that an alternative regulatory approach is needed to ensure the widespread availability of FMT for individuals with C. difficile infection unresponsive to standard therapies. The agency acknowledges these concerns and intends to exercise enforcement discretion regarding the IND requirements for the use of FMT to treat C. difficile infection not responding to standard therapies provided the treating physician obtains adequate informed consent from the patient.
This approach certainly makes sense.
Still, on reading the statement, one might wonder about the phrase “exercise enforcement discretion”. What precisely does this mean?
If I had to guess, they will choose to go after the clinicians who are using FMT for indications where the evidence for benefit is much weaker (thus far) than for C diff — e$pecially tho$e who $eem to be offering FMT for the wrong rea$on$.
And FYI, there are LOTS of those (still unproven) indications out there, as any brief internet search will reveal — as one site notes, they include “Ulcerative Colitis, Crohns, IBS, Constipation, Autoimmune disorders, Obesity, Parkinsons, Multiple Sclerosis, Anxiety and Depression.”
Will FMT work for some of these? As the cliche (and grant proposals) note, “more research is needed…”
Meanwhile, some were disappointed that the video I linked last time this topic was reviewed was a fake — you wanted the real thing.
Ask and you shall receive.
June 17th, 2013
Gallant is Answering Your HIV Questions and Zuger Writes About the Tough Practice of “Doing Nothing”
Two highly recommended products from a couple of my friends in the HIV/ID world:
First, the inimitable Joel Gallant — long time of Johns Hopkins, soon to be of Santa Fe — has resuscitated his terrific Patient Q & A Forum here. He used to answer patients’ questions regularly on www.hopkins-aids.edu, but that whole site appears to be gone — either truly gone, or Harvard Medical School controls our web searches, nixing anything having to do with a top rival.
(Nope — truly gone. Here’s a little archived material.)
The questions on the new forum are far-ranging in topic — though risk of transmission seems to be a recurring theme — and, not surprisingly with Joel’s writing the answers, the responses are always authoritative, and often very funny.
Fortunately, he’s populated his site with some of his favorites from the Hopkins days:
Is the actual risk of female-to-male transmission greater than the .0001 per contact that I am always hearing? If this is actually the case, it would seem that a policy of promiscuity would actually reduce risk, at least from a male perspective.
I’ve read your question several times now, and each time I read it my jaw drops lower. First, numbers like these are fairly meaningless because they don’t take into account the woman’s viral load, the nature of the sexual contact, the presence or absence of blood or genital ulcers, etc.
But unless I missed something in high school math, any number greater than zero means promiscuity is a bad idea. Engaging more frequently in an activity that has an identifiable risk, however low, cannot reduce the risk of infection. Granted, I took my last math class decades ago. Maybe there have been new developments in the field that I’m not aware of. If you are using an alternative form of mathematics that makes promiscuity not only safe but advisable, please enlighten us! I’m sure there would be great interest!
This one pretty much crystalizes what’s great about his Forum (and, come to think about it, Joel in general) — he can be academic and racy at the same time!
Meanwhile, over at the New York Times, there’s a superb piece by ID/HIV Specialist, Times staff writer, and Journal Watch editor Abbie Zuger.
It’s about how challenging it can be in clinical medicine sometimes to … do … nothing. Citing the example of one of her patents who has persistent and multiple complaints over a decade of care despite innumerable blood tests, scans, treatments, and referrals to specialists, Abbie realizes that what’s best for her is sometimes taking this passive but difficult approach:
That meant not treating her terrible sinus attacks, not investigating her continuing abdominal pain, not medicating her headaches and her crampy hands, not addressing her depression, her itch, her nausea … To really do nothing, all shamanic trappings must be abandoned: stethoscope, prescription pad, weighty pronouncements, the works. And yet — and this is key — doing nothing is also quite different from saying, “There’s nothing I can do for you; goodbye.” Most doctors are masters of this final nothing. But keeping a therapeutic relationship afloat without the usual tools, tricks or enticements — that is a rare achievement, and surely harder than the hardest microsurgery.
I kept nodding my head in recognition during the article; perhaps this is the best line of all: “In fact, one might hazard that doing nothing is the most subversive activity in all of modern medicine, undermining as it does the agendas of all doctors, all patients and all interested corporate parties.”
Maybe it’s no surprise that the reader comments on her piece drew wildly divergent opinions — some wondered how Abbie could bill for her services if she’s “doing nothing”; some accused her of saying that her patient was faking the symptoms (she never said that at all).
Fortunately a significant proportion of commenters realized just how accurate — and important — this practice for “doing nothing” sometimes is in modern medicine. Certainly it’s a whole lot safer than prescribing unnecessary medications or ordering low-yield, expensive, and potentially harmful tests.
Jerry Seinfeld would be proud.
June 13th, 2013
PrEP Works in Injection Drug Users, CDC Offers “Guidance”
From The Lancet comes this important study of tenofovir pre-exposure prophylaxis for injection drug users (IDUs):
In this randomised, double-blind, placebo-controlled trial, we enrolled volunteers from 17 drug-treatment
clinics in Bangkok, Thailand … We randomly assigned [2413] participants to either tenofovir or placebo … 50 became infected during follow-up: 17 in the tenofovir group and 33 in the placebo group, indicating a 48·9% reduction in HIV incidence (95% CI 9·6–72·2; p=0·01).
As with other PrEP studies, better adherence = more protection. There was more nausea and vomiting in the tenofovir treatment group, but no significant differences in serious adverse events. No one who acquired HIV in the TDF arm developed HIV resistance.
So now what? In parallel with publication of the study — which was done in part by CDC investigators — CDC has issued an update on their “Interim Guidance” on PrEP, now focusing on IDUs. Key aspects of the recommendation:
- Consider it only in those at “very high risk” for HIV via IDU, meaning: sharing of injection equipment, injecting at least daily, and use of cocaine or methamphetamine.
- Critical to exclude HIV infection before starting PrEP, monitor regularly for incident HIV, side effects, pregnancy, etc.
- Use tenofovir/emtricitabine (TDF/FTC), even though the Thai study used tenofovir.
The rationale behind this last recommendation, even though the cost of TDF/FTC is higher?
TDF/FTC contains the same dose of TDF (300 mg) proven effective for IDUs, 2) TDF/FTC showed no additional toxicities compared with TDF alone in PrEP trials that have provided both regimens, 3) IDUs also are at risk for sexual HIV acquisition for which TDF/FTC is indicated, and 4) TDF/FTC has an approved label indication for PrEP to prevent sexual HIV acquisition in the United States.
Makes sense to me.
(What also makes sense is that they’re abbreviating it “TDF/FTC”, rather than “FTC-TDF”, as in iPrEx — that was driving me crazy.)
Both the study and the Guidance are welcome additions to the HIV prevention effort. Still, I suspect PrEP in this population will prove particularly difficult to implement, as adherence to medical interventions — for example, HIV treatment — is notoriously challenging among those with active injection drug use.
June 11th, 2013
Both Simeprevir and Sofosbuvir Likely Approved by 2014 — Clinical/Ethical/Pharmacoeconomic Dilemmas Loom
As expected, simeprevir, and now also sofosbuvir, are being given “priority review” by the FDA.
With the 6-month rule under the Prescription Drug User Fee Act — usually just said as “pah-DOOF-ah” — that means there’s a good chance we’ll have both of these anti-HCV drugs some time in late 2013.
Which also means HCV treaters will soon face a major dilemma regarding management of HCV genotype 1.
For those not following this field closely, here’s the deal:
- If approved, both simeprevir and sofosbuvir will be indicated for treatment of HCV genotype 1, but only in combination with pegylated interferon/ribavirin. (Sofosbuvir approval is also expected for genotype 2/3, just with ribavirin.)
- Both will be one pill once daily. Simple!
- Both will cost a lot. Reminder, a course of telaprevir is $50,000, and these two new drugs are better.
- The interim results of the COSMOS study, presented at CROI this year, showed a >90% cure rate in 80 prior null responders (no cirrhosis) who received simeprevir and sofosbuvir together for 12 or 24 weeks, with and without ribavirin. There was no interferon in this study. (The full slide set of the presentation is on NATAP.)
So if these two drugs are both approved as expected, one could easily make the case that the best treatment for HCV genotype 1 — in terms of efficacy, safety, tolerability, pretty much everything except drug-drug interactions and cost — will be the COSMOS regimen of simeprevir and sofosbuvir, with or without ribavirin. And emphatically without interferon.
And that, my dear friends, is off-label use.
So let’s get inside the head of the various players in this potential drama to imagine what they’ll be thinking.
It’s January, 2014, and a patient previously treated with interferon/ribavirin for 48 weeks who relapsed is coming in to review his new treatment options. Here are some potential thought balloons:
Patient: I just want what works best. Sure would be nice to avoid all those nasty interferon side effects I had the last time I was treated.
Provider: I’d like to prescribe simeprevir plus sofosbuvir to avoid all those nasty interferon side effects the last time he was treated. I have some uncertainty about whether to include ribavirin, and whether to treat for 12 or 24 weeks.
Provider’s RN/PA/NP/PharmD who manages all HCV treatment: Sure will be nice to avoid all those nasty interferon side effects that happened the last time he was treated.
Patient’s insurance company: Both simeprevir and sofosbuvir? Two DAAs? You gotta be kidding me — we’re not paying since the regimen is not FDA-approved. Here’s a toll-free number for you to call and argue the case, but the estimated hold time is longer (by a factor of 10) than trying to call an airline to get a flight changed during a blizzard.
Phamaceutical company: We invested a gazillion dollars to bring these drugs to market. Plus, if you consider the net societal savings by curing HCV and avoiding cirrhosis, liver failure, hepatocellular carcinoma, liver transplants, secondary transmission etc, the price is justified.
Activists: The best treatment should be available for all!
Academic MD expert who has been asked to comment, but isn’t actually seeing this patient (or any patient) today because he/she is writing grants and papers, or traveling: The sample size of the COSMOS study is too small to influence clinical practice.
Of course, this will all settle out once there are multiple non-interferon HCV treatment options out there.
I’m an optimist.
June 6th, 2013
ID Learning Unit — Aminoglycosides
You young whippersnappers out there may not believe it, but we once used aminoglycosides all the time — literally every day on inpatient medical and surgical services, especially in the ICUs.
They were an inevitable part of “triples” (e.g., amp/gent/clinda), a broad-spectrum combination given to almost every critically ill patient way back when — think right around the time Pac-Man was state-of-the-art and George Bush Senior was President, saying he didn’t like broccoli.
(It’s just an association with the 1980s/early 1990s I’m after. How’d I do?)
Over the years, aminoglycoside prescribing has rapidly and progressively declined — there are other less toxic antibiotics that do the same thing — so these drugs are unfamiliar to many clinicians today.
But they still have their place, so here is brief refresher unit.
Let’s start with a table comparing the four agents in most common use, and finish with some factoids that could be clinically relevant — or at the very least quite helpful when trying to impress your friends. First, the table:
| Drug | Principal Indication | Distinguishing Characteristic Compared with Others |
| Gentamicin | Used in combination with ampicillin or penicillin or vancomycin for treatment of serious infections due to enterococcal (and some streptococcal) infections. | Least expensive. |
| Tobramycin | Used as inhalational therapy in patients with cystic fibrosis, bronchiectasis, and other conditions associated with recurrent bacterial respiratory tract infections. | Most active in vitro versus Pseudomonas aeruginosa. |
| Amikacin | Used as part of empiric broad therapy in patients with known highly resistant GNR infections, or in urinary tract infections with no oral alternatives. | Broadest antibacterial spectrum. |
| Streptomycin | Used as part of second-line combination therapy for tuberculosis and other mycobacterial infections. | Vestibular toxicity a particular problem. |
Now for the factoids:
- These are relatively toxic antibiotics, and patients receiving them should always be monitored closely. Renal, cochlear (hearing), and vestibular (balance) toxicity are the main concerns, and the big problem is that the side effects may be irreversible if the drugs are not stopped promptly.
- The risk factors for these toxicities are exactly what you’d predict. Older age. Impaired renal function. Other nephrotoxic drugs. Critical illness. Higher doses. Higher levels (especially trough concentrations). Longer duration of therapy. Genetic predisposition. You get the idea — can you say “multifactorial”? There, now you can charge for the renal consult you just did on that 87-year-old woman with diabetes and hypertension, taking NSAIDs, who received a course of gentamicin and now has a creatinine increase.
- Monitoring drug levels is essential. The problem is that even when they are “perfect,” end-organ toxicity still occurs. Oh well, it’s at least less likely to happen when toxic drug levels are averted.
- Extended-interval dosing is probably more effective than multiple-day dosing. It might be less toxic, too. (Data are mixed.) The killing of bacteria with aminoglycosides is concentration-dependent, and there’s also a nice post-antibiotic effect even after the drugs are cleared. As a result, we preferentially employ extended-interval dosing when treating serious GNR infections, under the careful guidance of our hospital pharmacy which uses the Hartford nomogram method. Note it’s not appropriate for several patient groups, including those with changing renal function, CF with pseudomonas (see below for clarification), or for endocarditis. [Edit: Extended interval dosing IS used for CF, but the doses are way higher, and the nomogram does not apply.]
- When aminoglycosides are used for endocarditis, use low-dose “synergy” dosing. In enterococcal and certain streptococcal endocarditis cases, you just need low levels of gentamicin — just enough to be detectable on trough measurements. You know, the vermouth in the very dry martini.
- With Staph aureus infections, resist the urge to “just add gent.” Every ID doctor has been there — consulted on a case of Staph aureus bacteremia that won’t go away, despite what should be appropriate therapy. In vitro, Staph aureus is killed faster by combining a beta-lactam with gentamicin than with the beta-lactam alone, so adding gentamicin sounds like a good idea. The problem is that people are vastly more complex than these lab experiments — for example, humans have kidneys and ears — and there has never been a clinical study showing a net clinical benefit from this practice to “just add gent.” With MRSA, we even have the opposite — that adding gentamicin to vancomycin worsens outcomes. So don’t do it. (Possible exception: Staph aureus prosthetic valve endocarditis. Maybe. But call the surgeons anyway.)
- Some gentamicin-resistant enterococci are still sensitive to streptomycin. But faced with using streptomycin for this indication over the past few years, I’ve gone with the ampicillin/ceftriaxone alternative combination instead of amp/streptomycin because: 1) Data are accumulating that this combination actually works; 2) Monitoring streptomycin levels in real-time is all but impossible in most hospitals today.
- Neuromuscular blockade is another complication of this drug class. It’s rare, but it happens — particularly a concern for patients with Parkinson’s or myasthenia gravis, or who received certain paralyzing anesthesia agents. Think of this when, in the ICU, a previously critically ill patient who was paralyzed for intubation is slow to regain muscle strength after receiving an aminoglycoside.
- The only indication for systemic aminoglycoside monotherapy is treatment of urinary tract infections resistant to other antibiotics. This has become a relatively common indication for these drugs, in particular amikacin, due to rising rates of quinolone resistance in GNR. But these are infamously poor drugs for treatment of pneumonia and abscesses, as low pH environments reduce aminoglycoside activity; in addition, single-drug therapy with aminoglycosides in fever and neutropenia was suboptimal. You wouldn’t do these things anyway.
- A trivia question: What rare infections still list aminoglycosides among preferred first-line treatments? Answer: tularemia, brucellosis, plague. Now you’re prepared!
Last, an observation with no apparent explanation: Back when we used quite a bit of gentamicin at our hospital, the doctors all abbreviated it by saying “gent” (one syllable), while most of the nurses said “genta” (two syllables).
Figure that one out.
May 31st, 2013
Fecal Microbiota Transplantation — Try This At Home?
As noted before, the FDA says that an investigational new drug (IND) application is required for therapeutic use of fecal microbiota transplantation.
The practical effect of this decision, at least at our institution, is to stop providing this service — it’s on hold pending those “internal discussions” planned by the FDA on the regulatory issues surrounding the procedure.
Which is why reading this anecdote from Mike Edmond, an ID doctor in Virginia, came as no surprise:
I was scheduled to perform a fecal transplant on a patient this morning, but notified her a few weeks ago that we could not proceed because of the new ruling. She presented to clinic this morning and informed me that she had performed the transplant at home a few days ago. And she was happy to report that she was feeling much better! As it turns out, I have at least 3 more patients in the process of preparing for self-administered fecal transplant at home.
He goes on to say that instructions for doing it home “are readily available on the internet,” which I’m sure is true but am too squeamish right now to check.
(OK, I did it — here is a comprehensive and detailed guide.)
(Fooled you.)
So here’s the irony: FDA’s decision to require an IND will undoubtedly drive quite a bit of FMT into peoples’ homes — where it is completely unregulated. Sigh, unintended consequences are so annoying …
Note that some clinical sites have in fact an IND from the FDA to continue FMT, so it’s worth checking around your local hospitals.
And for those of you who didn’t click the above link, here it is:
May 29th, 2013
The New SARS-Like Coronavirus (MERS-CoV), and What To Do When You Don’t Know Anything About The Latest Outbreak
From one of my close friends — a non-MD — comes this alarming video (sorry, can’t remove the preceding ad).
Concerned? Terrified? I bet your department is buzzing about this.
Um, not quite — especially since, among the 49 cases in the world (apparently there are 5 more than the WHO reported), exactly zero have occurred thus far in the United States. As of May 29, 2013, it hasn’t even cracked the front page of the CDC site.
Is MERS-CoV potentially of great concern? Of course. The WHO response seems right, especially with the parallels to SARS.
But do we garden-variety ID specialists know how serious it will be on a global basis? Of course not. As with the first SARS cases, the first anthrax cases, the first West Nile cases, the first hantavirus cases, even the first AIDS cases — we really don’t have enough points on the graph yet to make any sort of confident predictions.
And from a practical perspective, the clinical unfamiliarity doesn’t help. If someone walked into our emergency room tomorrow with fever, cough, and respiratory symptoms, would we know how to distinguish MERS-CoV from the hundreds (OK, thousands) of other causes of similar illnesses?
Initially, not a chance. The denominator of people with these complaints is just too gargantuan. It will probably take someone with a particularly severe respiratory illness, along with the appropriate exposure (“He just returned from a 10-day business trip to Riyadh”) for an astute clinician to make the connection.
So how should we ID doctors, who are supposed to know everything, respond to these emails in the interim? Stay informed efficiently by consulting these sites:
- ProMed-mail (outbreak updates from your ID colleagues/friends around the world).
- The always-fascinating CDC Outbreaks page, plus it’s coronavirus-specific info.
- Some non-MD news source — I like Google News.
And in response to queries from friends, family, and media, break out those three magic words doctors are often so reluctant to say — “I don’t know” or, if you want company, “We don’t know.”
Because it’s the truth.
(Also posted on WBUR’s CommonHealth site.)
May 21st, 2013
ID Learning Unit — “Isolator” Blood Cultures
Here’s a little secret about those brilliant ID consults we do on patients with mysterious fevers:
Sometimes we don’t know what’s going on either.
I know, I know — shocking.
But now that the secret is out, I can tell you something we do know, and that’s how to recommend lots of tests — the more obscure, the better. Including a particular favorite, isolator blood cultures. If you do inpatient medicine, chances are you’ve had an ID consultant recommend these and may even have ordered them without knowing precisely what they are, or more importantly, or how they differ from the regular blood cultures.
So here’s the story on isolator blood cultures — “isolators” for short — almost in plain English:
- Blood is collected in a sterile fashion.
- Instead of going into regular blood culture bottles, the blood is put into special tubes containing a chemical that lyses (explodes) both red and white blood cells, “releasing” intracellular organisms.
- In the micro lab, the tubes are centrifuged to concentrate any bugs that might be present.
- The sediment is aspirated and placed on appropriate culture media — e.g., fungal media for “fungal isolators” and mycobacterial media for “mycobacterial isolators.”
- Wait. Potentially for a very long time (weeks).
These cultures are also known as “lysis-centrifugation” cultures, which is more descriptive than “isolators” but harder to say.
So when should you order them? There is a literature about the superiority of isolators over standard blood cultures, but these comparisons are mostly outdated — for example, with advances in blood culture technology (see video below), candida grows just fine in regular blood cultures today.
Furthermore, even though isolators may be superior to standard blood cultures for certain rare infections (e.g., histoplasmosis, bartonella, blastomycosis), in most (all?) of these conditions, use of antigen, serology, or PCR testing has supplanted culture methods entirely.
So that leaves one proven and one possible remaining indication for isolator blood cultures:
- Proven: Diagnosis of disseminated mycobacterial infection (in particular, M. avium complex) in a patient with advanced AIDS or other severe immunodeficiency. Regular blood cultures are pretty much useless here.
- Possible: Diagnosis of some bizarre, fastidious pathogen (e.g., Malassezia furfur) in a patient with culture-negative endocarditis or a vascular line-related infection.
Which means that most of the time, when your ID consultants recommend isolator blood cultures, you can ignore them.
And show them this video by a Dr. Kimmitt, who certainly knows her stuff but clearly is in no joking mood:
https://youtu.be/ZZoIZkna4vo
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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