30 Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket


Sachin has to be the greatest Cricketer ever to step into the field and every Indian would swear by that fact. It has been almost two years since he retired and the world still misses him and how! As the God of Cricket turns 42, take a look at these 30 things other International Cricketers and commentators had to say about the legend. Whether or not you’re a Sachin fan, this will fill your heart with pride to have been born in the time when Sachin played!

Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Greatest Quotes About Sachin Tendulkar That Prove He Really Was The God Of Cricket

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Why so few people are snorting white powder for fun


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 “COCAINE”, said Robin Williams, a comedian who was rueful about addiction, “is God’s way of saying that you’re making too much money.” No longer. The total amount of pure cocaine consumed by Americans fell by half between 2006 and 2010, and there is nothing to suggest the trend has changed since. The Drug Enforcement Administration (DEA) says the supply of coke is stable. Cocaine-related deaths fell by 34% between 2006 and 2013.Credit for this decline must go to policing and changing fashion. In the 1970s and early 1980s, cocaine users were either well-off or had disposable income to waste. By the mid-1980s most cocaine was being smoked as crack by poorer Americans. Sentencing laws changed and incarceration rates, especially for young black men, began to soar. One 1986 study showed that in Manhattan 78% of those who agreed to be tested after an arrest for a serious crime tested positive for cocaine. In 1985 there were nearly 6m cocaine-users, according to the University of Michigan’s national household survey on drug use.

Beau Kilmer, who has pondered the “cocaine nosedive” for RAND, a think-tank, thinks some of the decline is due to supply-side changes. Cocaine’s slump began shortly after thousands of acres of coca were eradicated in Colombia. Large quantities of cocaine were seized there and in the rest of Central America from 2006 onwards. Around the same time, local criminal organisations became interested in illegal gold mining and were weakened, both by internal fighting and by government crackdowns. Mr Kilmer adds that increased demand outside the United States may also have played a role. Cocaine costs more in Europe than in America.

Yet part of the explanation lies in changing fashion. The University of Michigan’s survey reports that young people are less inclined to try cocaine than was once the case. Cigarette companies used to observe that nobody liked to smoke the same brand as their parents. The same may be true of drugs. Would-be cocaine-users have turned to other substances. Methamphetamine is one, but a striking variety of synthetic drugs are now available. “I went to see a dealer the other day in Manhattan and the guy had an astounding array of things,” says Ric Curtis, an anthropologist at John Jay College of Criminal Justice. Although cocaine is still very much on the DEA’s radar, says Russel Baer of the agency, it is not the threat it once was. Heroin, methamphetamine, opioid and synthetic consumption, meanwhile, are all going up.

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WE’LL NEVER UNDERSTAND PRINCE, AND THAT’S WHY WE LOVE HIM


The most enthralling—and often most frustrating—aspect of being a fan of Prince was this: No matter what, you were never going to figure him out. You’d never be able to fully decode all of his intricate, ornate, mischievous lyrics. You’d never quite understand the reasoning for some of his sideways-twisting business and personal-life decisions. You’d barely even be able to keep up with his musical output, a gargantuan-sized, decades-spanning collection of music that ranged from popping synth-funk numbers to scorching guitar anthems to delicate, lights-dimming R&B ballads (and those are just the songs we heard; who knows how many hours of unheard material still sit in his infamous Paisley Park vaults). Prince, who died today at the age of 57, was never going to let anyone fully into his world. At best, we got small glimpses from time to time. The rest was left to our imaginations.

But the parts of that world we did get to see were like nothing else. In his earliest years, as he workshopped and woodshedded within the R&B and funk scenes of his native Minneapolis, he was one-part funk disciple, one-part ’70s guitar-god; his first truly great album, 1979’s Prince, was pure alchemy, a record that brought together dancefloor come-ons like “I Wanna Be Your Lover” and heavenly axe-shredders like “Bambi” so smoothly, it was as if those two sounds had always existed in the same space. But those early efforts were also, by Prince standards, relatively tame—like so many first-timers, he seemed nervous, almost endearingly so.

And so, we followed him, no matter what: We were his dearly beloved, he was our revolutionary leader, and even if we couldn’t fully understand where he was going, it was always going to be someplace new.

Then came Dirty Mind, an exquisitely sexed-up punk-funk masterpiece that solidified Prince’s reputation as a malleable, constantly-in-motion force that would be forever impossible to predict. Listen to the spare, aching bass of “When You Were Mine”; the whirling, kaleidoscopic keyboards of “Uptown”; or the touchingly horny lyrics of the title track: “I just want to lay ya down/In my daddy’s car/It’s you I really want to drive/but you never go too far.” This was a more forthright, dance-up-in-your-face Prince than just the year before, and he’d emerge again with 1982’s aptly titled Controversy; whether Prince had been holding himself back before, or whether he was simply growing up in front of the audience, was impossible to know. Really, who was this guy?

Amazingly, even as Prince (and his sound) got bigger—as he moved R&B and funk past the nearly all-white boundaries of rock radio—that question was never answered. He was always full of contradictions: A guy who sang about sex with alarming, turn-the-dial-before-mom-hears frankness, yet who somehow never seemed crass nor déclassé. An image-aware provocateur who dressed like this, yet retained an aura of shyness and vulnerability. A rock god who worshiped Joni Mitchell.

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By the mid-’80s, Prince aspired to (and achieved) the kind of Top 40 infamy that very few of his contemporaries could manage. At the same time, he seemed to detest so much of the machinations of fame—particularly interviews, which he either dodged, canceled, or conducted with maddening vagueness. This became especially true when he’d reached the upper-stratosphere heights of pop stardom that came with 1982’s 1999 and 1984’s Purple Rain—two records that incited (and downright encouraged!) countless make-out sessions and slow-dances and shotgun-seat air-guitar riffs. (Quick sidebar: Perhaps because he was such a compelling frontman, it sometimes gets lost that Prince was one of the most remarkable guitar players ever, especially live; watching him burn through the opening the maelstrom of “When Doves Cry” was like seeing … I don’t know. I don’t know how to describe it. But if Prince were here, he’d be able to do so with a cozy, succinct one-liner that would put the rest of the room to shame.)

And so, we followed him, no matter what: We were his dearly beloved, he was our revolutionary leader, and even if we couldn’t fully understand where he was going, it was always going to be someplace new. In 1987, he released Sign o’ the Times, a record that would be his most personal and political album—and, among diehards, forever rank as his best, a two-disc extravaganza that found him addressing everything from social blight (the title track) to gender roles (“If I Was Your Girlfriend”) to religious epiphany (“The Cross”). On Sign, he was telling us more about himself than ever before, but he was also copping to confusion—about God, about sex, about who he was. Even Prince didn’t fully know Prince.

Even Prince didn’t fully know Prince.

By then, Prince had also become as much of a social icon as he had a musical one, albeit quietly. Who knows how many lonely teenagers, regardless of sex or race or gender, took inspiration from this soft-spoken, Midwestern boy who wore and sang whatever he wanted, who mixed with genres that had normally been kept in separate silos, and apologized for none of it? Prince, much like David Bowie or Madonna, bestowed upon his fans a giant permission slip, one that allowed them to be as strange or outrageous as they wanted to be. With Prince, experimentation was never taboo; it was simply a sign o’ the times.

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Which is why, as the ’80s ended and Prince’s off-stage adventures became just as intriguing as his on-the-record work, he remained as vital as ever. There’s plenty to be said about his ’90s albums, some of which were phenomenal—especially 1991’s Diamonds and Pearlsand 1992’s Symbol (or whatever we’re calling it these days)—and some of which found him either struggling to keep pace with hip-hop or letting his passion for prolificness get the best of him. But even then, he was a pop-culture progressive: Embracing the web at time when most other artists thought it was a scam or a fad (though, being Prince, he’d reverse his opinion on this many times); taking on the record industry and demanding his rights as an artist, even though the big labels were still superpowers; and adopting a D.I.Y. attitude, both in his dealings and his music, that most big-name contemporaries wouldn’t have dared.

Did he always make it easy to love him? No. Did we ever stop? Of course not. In recent years, his concerts—full of medleys and solos and just general good times—were glorious to behold: Here was Prince, within our sights and our grasps, playing as though he were 30 years younger, still this beautiful and thoroughly unknowable force. You could pick any face out in the crowd, and ask what Prince they loved. For some, it was the sly funkster. For others, it was the stadium-commanding rocker or the spiritual inquisitor. We all dug our own picture of Prince; he could be whoever we wanted him to be, because of who he was—a smirking mystery open to interpretation, and a perpetual tease whose flirtations weren’t always consummated. Now that he’s gone, I’m guessing there’s nothing that would delight him more than knowing we’ll be spending the rest of our lives trying to figure him out—analyzing every song, testing every theory, and still talking about … Prince. That’s what he’d want. So let’s go crazy.

 

RIP PRINCE.

Interventional technologists have higher cancer risk


Radiologic technologists who perform fluoroscopically guided interventional procedures appear to be at increased risk for a variety of cancers — specifically, more than twofold for brain cancer — according to a new study published online in the American Journal of Roentgenology.

The findings suggest that there’s work to be done to better protect technologists, researchers from the U.S. National Cancer Institute wrote.

“Because the brain is unprotected by thyroid shields, lead goggles, or lead aprons, doses to the head are likely to be higher than those to other anatomic sites on radiologic technologists,” lead author Dr. Preetha Rajaraman and colleagues noted (AJR, March 21, 2016).

Long-term tracking

Fluoroscopically guided interventional procedures offer patients advances in medical treatment of common diseases, such as cardiovascular conditions, and over the past two decades the use of fluoroscopy intervention has grown, according to Rajaraman’s team. Interventional radiology procedures increased by more than 10% per year on average between 1992 and 2001; in 2006, 17 million fluoroscopically guided interventional exams were performed in the U.S., and more than a fourth were for cardiac applications.

But the negative effect of radiation doses that such interventional procedures confer on the staff who perform them has not yet been thoroughly studied.

“Our specific objective was to examine whether cancer incidence and mortality of selected cancers are elevated among radiologic technologists who perform or assist with fluoroscopically guided interventional procedures in comparison with other radiologic technologists,” the study authors wrote.

Rajaraman’s group used data from the U.S. Radiologic Technologists Study, a collaboration between the National Cancer Institute, the University of Minnesota, and the American Registry of Radiologic Technologists (ARRT). The study includes a nationwide cohort of more than 146,000 radiologic technologists certified after 1981; the cohort is followed through yearly ARRT recertification records. The records of those who have died are linked with the National Death Index.

Two questionnaires administered between two periods, 1983 to 1989 and 1994 to 1998, collected information about technologists’ employment, disease risk factors, history of personal diagnostic or therapeutic imaging procedures, and diagnoses of specific types of cancer.

Between 1994 and 1998, 72% of living technologists completed the survey, which included information on whether they performed fluoroscopically guided interventional procedures. This data was used for Rajaraman’s study, as well as follow-up survey data from 2003 and 2005 to track cancer incidence and follow-up survey data from 2008 to track cancer mortality (causes of death were taken from the National Death Index). Unfortunately, the survey data did not include detailed information on radiation doses associated with performing these procedures, Rajaraman’s group said.

The researchers’ data analysis found a twofold increased risk of brain cancer mortality, as well as a modest increased incidence of melanoma and breast cancer — but not mortality — among technologists who performed fluoroscopically guided interventional procedures compared with those who did not. There was no elevated risk of cancers of the thyroid, skin other than melanoma, prostate, lung, colon, or rectum.

Hazard ratios for cancer incidence and mortality in radiologic technologists who performed fluoroscopically guided interventional procedures compared with those who did not are as follows, with a figure above 1.0 indicating elevated risk:

Cancer risk among RTs performing interventional fluoroscopy
Type of cancer Incidence hazard ratio Mortality hazard ratio
All cancers (except nonmelanoma skin cancer) 1.07 1.03
Brain cancer 2.16
Female breast cancer 1.18 1.10
Melanoma 1.32 0.66

Because the data used in the study did not include specific radiation exposure measures, more research must be done to confirm the findings, since other factors besides radiation could contribute to increased cancer risk among technologists, according to the study authors.

“Our findings must be confirmed in future epidemiologic studies of technologists and physicians performing fluoroscopically guided interventional procedures, ideally incorporating detailed individual radiation dose to clarify the risks of a broad range of cancers,” the team wrote.

In any case, can the patient benefit from fluoroscopically guided interventional procedures be balanced against technologists’ increased cancer risk? Yes, according to Rajaraman and colleagues.

“The immense patient benefit provided by [these procedures] is indisputable, and the risks that we observed for brain cancer, breast cancer, and melanoma among technologists who reported working with these procedures should be interpreted in that context,” the researchers concluded. “Patients should continue to undergo medically necessary imaging examinations, but healthcare providers should keep radiation exposure as low as reasonably achievable without compromising essential diagnostic information.”

CT has replaced radiography for abdominal imaging


Over the past 20 years, the use of abdominal imaging among Medicare beneficiaries has changed significantly, with dramatic increases in CT and MR and dramatic decreases in gastrointestinal (GI) fluoroscopic and urologic radiographic imaging, according to research presented at the American Roentgen Ray Society (ARRS) meeting.

The good news is that radiologists remain the dominant providers of abdominal imaging, said presenter Dr. Courtney Moreno of Emory University in Atlanta. However, the decrease in GI and urologic exams may bode ill for resident training, Moreno and colleagues wrote in a paper on the research published simultaneously in the Journal of the American College of Radiology (April 12, 2016).

“The declining numbers of barium studies could have negative implications for resident and fellow training, as well as for maintenance of expertise of practicing radiologists,” they wrote.

Who’s doing what?

Moreno and colleagues evaluated the use of abdominal imaging in the Medicare population between 1994 and 2012, parsing the data by modality, billing provider, and site of service. The data included claims from more than 39 million Medicare fee-for-service beneficiaries. Moreno’s group first identified exam volumes for MR, CT, ultrasound, x-ray, and fluoroscopic examinations of the abdomen using current procedural terminology (CPT) codes. Next, they determined the type of provider and site of service (emergency department, inpatient, or outpatient) by using self-reported claims-based codes.

The researchers found striking changes over the decades. For example, in 1994, x-ray was the most frequently used abdominal imaging modality (207 exams per 1,000 beneficiaries), followed by ultrasound and CT.

But by 2012, CT was the most frequently performed modality (169 exams per 1,000 beneficiaries), followed by ultrasound and radiography. Claims for abdominal MR increased by 1,226% during the study time frame, while abdominal CT claims increased by 207% and ultrasound claims increased by 41%.

The group found significant declines in utilization of some tests as well:

  • Abdominal radiography: -41%
  • Barium enema: -93%
  • Upper GI studies: -81%
  • Small bowel follow-through exams: -49%
  • Kidney-ureter-bladder (KUB) tomography and IV pyelography: -96%

“Services that were common previously [GI fluoroscopy, genitourinary radiography] have fallen into disuse as CT, MR, and ultrasound have all grown in popularity,” Moreno and colleagues wrote in their JACR article.

Despite these changes, radiologists have remained the dominant providers of abdominal imaging across most modalities, Moreno told session attendees at ARRS 2016.

No. of abdominal imaging procedures provided by radiologists, 1994-2012
1994 2012
Abdominal radiographs 90% 87%
CT 95% 93%
MR 92% 93%
Ultrasound 78% 77%

As for site of service, in 2012, most abdominal MR and CT exams were conducted in the outpatient hospital setting; meanwhile, physicians’ offices were the most common site for ultrasound and the hospital inpatient setting was the most common site for abdominal x-ray, the group found.

Training challenges

What do these results suggest for clinical practice? The decline in fluoroscopic studies presents a challenge for resident training, according to Moreno.

“When residents go out into practice, they will be expected to do these gastrointestinal fluoroscopic procedures, and they need to learn how to perform the different types of studies,” she said. “Since these procedures have declined, we’re going to need to get creative in how we train our residents.”

Lou Gehrig and motor neurone disease (MND)


Lou Gehrig was an American who played 17 seasons in major league baseball for the New York Yankees from 1923 to 1939. Gehrig was renowned for his prowess as a hitter and for his stamina – traits that earned him his nickname, “The Iron Horse”. He set several major league records during his career, including the most career grand slams (23) and most consecutive games played (2,130), a record that stood for 56 years and had been considered unbreakable.

When the Yankees began their 1939 training it was clear that Gehrig no longer possessed his once-formidable power. His running between bases was affected, and at one point he collapsed at the Yankees’ spring training park. By the end of spring training, he had not hit a home run. Throughout his career, Gehrig was considered an excellent baserunner, but as the 1939 season got underway, his co-ordination and speed had deteriorated significantly.

By the end of April, his statistics were the worst of his career. One journalist who often wrote about him said: “I think there is something wrong with him. Physically wrong, I mean. I don’t know what it is, but I am satisfied that it goes far beyond his ball-playing. I have seen ballplayers ‘go’ overnight, as Gehrig seems to have done. But they were simply washed up as ballplayers. It’s something deeper than that in this case, though. I have watched him very closely and this is what I have seen: I have seen him time a ball perfectly, swing on it as hard as he can, meet it squarely – and drive a soft, looping fly over the infield. In other words, for some reason that I do not know, his old power isn’t there… He is meeting the ball, time after time, and it isn’t going anywhere.”

In 1939 he was diagnosed with motor neurone disease (MND) – most commonly, amyotrophic lateral sclerosis (AML) – usually referred to as ‘Lou Gehrig’s disease’ in North America. This forced him to retire at age 36 and was the cause of his death two years later.

MND is a rare but devastating illness which leads to progressive paralysis and eventual death. Although rare, many patients are both aware and fearful of it, as there have been several high-profile media campaigns concerning it recently, and one Oscar-winning film.NICE released new guidelines for its recognition and management in February 2016 and a few of the new points relevant to primary care that have been included this year, are covered below.

MND is mostly a sporadic disease of middle and elderly life with patients usually presenting in their sixties and seventies. However, it can present in younger patients, usually in familial types. The classic form of the disease is ALS which tends to be focal in onset, with a particular group of muscles affected first. This occurs in three patterns; limb onset (most common), bulbar (20%) and respiratory onset.

Although the least common presentation, the wary clinician should be mindful that the effects of reduced respiratory function, such as excessive daytime sleepiness, fatigue, early morning headache or shortness of breath when lying down, may indicate the diagnosis. Another atypical presentation is altered cognitive functioning, including fronto-temporal dementia. If you suspect MND, you are recommended to refer immediately and specify the possible diagnosis in the referral letter. Contact the consultant neurologist directly if you think the person needs to be seen urgently.

The guidelines recommend you consider advance care planning and offer the person with MND the opportunity to discuss their preferences and concerns about end of life care at trigger points such as: at diagnosis, if there is a significant change in respiratory function, or if interventions such as gastrostomy or non‑invasive ventilation are needed. These are often very difficult conversations to have and you are reminded to be sensitive about the timing of discussions and take into account the person’s current communication ability, cognitive status and mental capacity. When planning care take into account the following prognostic factors, which are associated with shorter survival if they are present at diagnosis, such as speech and swallowing problems (bulbar presentation), weight loss, poor respiratory function, older age and shorter time from first developing symptoms to time of diagnosis.

For symptom control, discuss the available treatment options for muscle problems and take into account the person’s needs and preferences, and whether they have any difficulties taking medicine (for example, if they have problems swallowing). Specific medicines are recommended within the guidance but if these treatments are not effective, not tolerated or are contra-indicated, consider referral to a specialist service for the treatment of severe spasticity.

 

Synonyms: amyotrophic lateral sclerosis (ALS), Lou Gehrig’s disease (USA form – named for a famous baseball player who succumbed to the disease), Charcot’s disease, Charcot’s syndrome, Charcot’s sclerosis

Motor neurone disease (MND) is a rare but devastating illness which leads to progressive paralysis and eventual death. Although rare, many patients are both aware and fearful of it.[1] It is therefore important in primary care to understand the presentation and to be able confidently to reassure worried patients who are unlikely to have a diagnosis of MND. A review of life-prolonging interventions, symptom-control and disease mechanisms is appropriate for non-specialists and outlined in this article.

Most cases of MND are due to ALS. However, other forms occasionally occur. These include:

  • Progressive bulbar palsy – about 2 in 10 people with MND have this type. The muscles first affected are those used for talking, chewing and swallowing. See separate article Bulbar and Pseudobulbar Palsy for more details.
  • Progressive muscular atrophy – this is an uncommon form of MND. The small muscles of the hands and feet are usually first affected, but muscle spasticity is absent.
  • Primary lateral sclerosis – this is another rare type of MND. It mainly causes weakness in the leg muscles. Some patients with this type may also develop clumsiness in the hands or develop speech problems.

This is a degenerative condition that affects motor neurons, namely the anterior horn cells of the spinal cord and the motor cranial nuclei. It causes lower motor neurone (LMN) and upper motor neurone (UMN) dysfunction, leading to a mixed UMN/LMN picture of muscular paralysis, usually with LMN signs predominating. The cause of the disease is unknown, although 5% of those affected have a familial form of the disease due to a mutation in the superoxide dismutase-1 gene.[2][3]

Current aetiological hypotheses focus on an abnormality of mitochondrial function causing oxidative stress in motor neurons. There may be several causes for such oxidative damage to motor neurons and the disease may just represent an end-stage phenotypic expression of these abnormalities.[4]

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  • MND is relatively uncommon with an annual incidence of about 2 cases per 100,000 population. Prevalence is about 5-7 per 100,000.[1] General practitioners can expect to see one or two cases in their career.[1]
  • It can occur at any age but is more common in people aged over 50. The male to female ratio is 2:1.[3]
  • About 5-10% of cases are inherited.[5]
  • The mean age of onset is 43-52 years in familial and 58-63 years in sporadic cases of ALS.[6]
  • Male sex, increasing age and hereditary disposition are the main risk factors.[6]

MND is mostly a sporadic disease of middle and elderly life presenting in the sixth and seventh decades. However, it can present in younger patients, usually with familial MND.

  • The classic form of the disease is also called amyotrophic lateral sclerosis (ALS). It tends to be focal in onset, with a particular group of muscles affected first. This presents In three recognised patterns:
    • Limb onset – by far the most common.
    • Bulbar onset – 20% of cases.
    • Respiratory onset – the least common.
  • ALS:[6]
    • Presents with symptoms and signs of degeneration of the upper and lower motor neurons, leading to progressive weakness of the bulbar, limb, thoracic and abdominal muscles.
    • Other brain functions, including oculomotor and sphincter function, are relatively spared, but may be involved in some patients.
    • Cognitive dysfunction may occur and 5-15% of patients develop dementia, usually of frontotemporal type.
  • The rarer variants of the disease can present in two ways:
    • With pure UMN features (primary lateral sclerosis).
    • With pure LMN features (progressive muscular atrophy).

Symptoms

Patients or their families often notice problems occurring in one or more of the patterns below:

  • Limb weakness – usually affects the upper limbs:
    • Causes patients to drop objects or have difficulty manipulating objects with one hand (turning keys, writing and opening bottles).
    • Wrist drop, stiffness, weakness or cramping of the hands may also occur.
    • Patients may also notice a change in the appearance of their hands (due to wasting of the intrinsic muscles).
    • Fasciculations of the muscles of the limbs may be noticed prior to weakness developing.

    However, occasionally problems in the leg or legs may occur:

    • Foot drop (early).
    • Gait disorder.
    • A sensation of heaviness of one or both legs.
    • A tendency to trip.
    • Difficulty in rising from low chairs and climbing stairs.
    • Excessive fatigue when walking.
  • Bulbar onset:
    • The first sign is usually slurring of the speech (impaired tongue movement).
    • Wasting and fasciculation of the tongue.
    • Dysphagia (usually a late feature with significant speech difficulties).
    • Accompanying emotional lability (inappropriate laughing or crying) – as with pseudobulbar palsies.
    • Other symptoms are difficulty eating, drooling, dysarthria, dysphonia, choking events with meals, nasal regurgitation of fluids or pulmonary aspiration.
  • Respiratory onset can present with:
    • Dyspnoea and orthopnoea.
    • Clinical features resulting from hypoventilation overnight (for example, waking, unrefreshing sleep, hypersomnolence and early morning headaches).[1]
  • Rarer features:
    • Pain or sensory disturbance is not unknown but is not a common feature of the disease; it is usually the absence of pain or sensory disturbance that helps to distinguish MND from radiculopathies (nerve root pathology) that can cause a similar presentation in peripheral limbs.
    • Symptoms due to impaired respiratory muscle function usually occur late in the disease but can occasionally be a presenting feature, causing ‘air hunger’. Acute respiratory failure has been reported.[7]
    • Some patients with pseudobulbar palsy may have ’emotional incontinence’, an over-reaction to sad or funny events that they are aware of as being abnormal.
    • Cognitive impairment is not a normal feature but can affect some patients with bulbar palsy.

Signs

  • LMD dysfunction in the limbs manifests as weakness, atrophy, fasciculations and hyporeflexia. The thighs are often a site of marked fasciculation. Fasciculation can be difficult to distinguish from arterial pulsation, so consider if there is an underlying arterial course before defining twitching movements as fasciculation.
  • UMN dysfunction manifests as weakness predominating in the arm extensors and leg flexors with evidence of hypertonia, hyper-reflexia and upgoing plantar responses; the bulbar muscles may also show spasticity with an exaggerated jaw jerk.
  • Ocular, sensory or autonomic dysregulation signs are usually late features of the disease.
Diagnostic pointers in limb-onset MND[1]

  • Asymmetrical distal weakness frequently occurs.
  • Brisk reflexes will occur in a wasted limb.
  • There is an absence of major sensory symptoms and pain.
  • There is a relentless progression of symptoms and signs.

Diagnostic criteria

This is of course a diagnosis which needs a great deal of careful consideration given the poor prognosis. Nevertheless, it is equally important to ensure that the diagnosis is not unduly delayed. One study found that the average time from suspected diagnosis to confirmation was one year. The authors called for greater educational input in primary and secondary care and a fast-track referral service.[8]

Diagnosis should be made after consideration of the clinical signs and symptoms together with investigations to exclude other causes. Important diagnoses which may cause confusion are listed in the box under ‘Differential diagnosis’, below.

Because of the very variable clinical presentation, the diagnostic criteria below have been devised, taking into account investigations to confirm the diagnosis and refute other possible causes (revised El Escorial Criteria):

  • Presence of:
    • Evidence of LMN degeneration by clinical, electrophysiological or neuropathological examination.
    • Evidence of UMN degeneration by clinical examination.
    • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination.
  • Together with the absence of:
    • Electrophysiological and pathological evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration.
    • Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs.

The World Federation of Neurology (WFN) has proposed further revision in the light of advances in neurophysiological techniques which can accurately detect degenerative neurological changes. They recommend upgrading the neurophysiological findings and making them as significant as the clinical findings in the diagnosis of ALS.

The differential diagnosis is vast, dependent on the mode of presentation, clinical findings and comorbidities. Diagnoses of particular importance have been singled out in the box below with features which distinguish them from MND.

Important diseases that can mimic MND[1]

  • Benign cramp fasciculation syndrome:
    • Fasciculation or cramps usually affecting large muscles (for example, calves).
    • The fasciculation is more common after exercise or with lack of sleep.
    • There is no wasting or weakness on examination.
    • There is no progression over time.
  • Cervical radiculomyelopathy (multilevel degenerative disease of the cervical spine):
    • This can present with a mixture of LMN wasting and weakness and UMN brisk reflexes and spasticity signs.
    • There is pain (localised to the neck or radicular) and sensory disturbance.
    • There are no bulbar symptoms and signs.
    • The absence of UMN signs above the LMN signs increases the possibility of this diagnosis.
    • MRI scan of the cervical spine can confirm the diagnosis.
  • Dual pathologies:
    • A cervical myelopathy and a co-existent peripheral neuropathy can present as a mixed upper-lower motor neurone picture.
    • Sensory signs and symptoms and absence of bulbar symptoms help to diagnose this.
    • Neurophysiological assessment and imaging will confirm the diagnosis.
  • Multifocal motor neuropathy with conduction block:
    • Often presents in young or middle-aged men as unilateral distal upper limb weakness with little evidence of wasting initially.
    • This is an important rare diagnosis to consider in differential diagnosis of MND.
    • In the correct clinical context, it can be diagnosed or excluded only by careful neurophysiological evaluation looking for conduction block.
    • It is treatable and has a markedly different prognosis than that for MND.
  • Inclusion body myositis:
    • An inflammatory myopathy which presents with distal weakness without sensory symptoms.
    • Clinically long finger flexors are affected preferentially (unusual in MND).
    • Electromyography (EMG) and occasionally muscle biopsy are needed to confirm the diagnosis.
    • Inclusion body myositis has a more benign prognosis than MND.

The list below shows further conditions that may have similar clinical features:

There are no specific investigations that will confirm a diagnosis of MND. A range of investigations is carried out to confirm consistent features and exclude other possible pathologies, usually under the direction of a neurologist. It may take several months to decide that the clinical presentation, progression and investigation findings are consistent with the diagnosis. This cautious approach is understandable, given the prognosis of the illness and the devastation that being given the diagnosis may cause to a person’s life. The investigations below may be conducted during the course of making the diagnosis:

  • Electrophysiological studies such as EMG and nerve-conduction studies (NCS) will show a characteristic pattern but require careful interpretation, along with a consideration of the clinical features. In MND, EMG shows fibrillation and fasciculations. The motor units are polyphasic and have high amplitude and long duration. NCS should show normal motor and sensory conduction in MND. More sophisticated techniques have prompted recommendations (Awaji-shima consensus recommendations for the application of electrophysiological tests, as applied to the revised El Escorial Criteria) that the electrophysiological findings should be given equal weight to the clinical findings in the diagnosis of the condition.[10]
  • CT and/or MRI scanning of the brain and spinal cord are useful in excluding other pathologies with similar presentations. Neuro-imaging is not yet considered to be sufficiently sensitive to assess responses to treatment but the European Federation of Neurological Societies recommends that it should be incorporated into the evaluation of research trials.[11]
  • Blood tests to exclude other conditions, such as vitamin B12 and folate levels, HIV serology, Lyme disease serology, creatine kinase assay, serum protein electrophoresis, anti-GM1 antibodies (multifocal motor neuropathy with conduction block), urinary hexosaminidase-A assay (Tay-Sachs) and a host of other more specialised tests for rare conditions.
  • Muscle biopsy may be considered to exclude or to diagnose myopathic conditions.

Giving the diagnosis

Part of the management of MND is giving the diagnosis and explaining the condition in an appropriately sensitive and informative way. The following points have been made:[1]

  • This is a difficult task and time; experience and expertise are needed.
  • Follow the well-established good practice principles of breaking bad news.
  • Impart information honestly but without destroying hope.
  • Maintain a positive emphasis on what can be done to help.

Although specialists lead the diagnostic and monitoring process, GPs have a large part to play in the day-to-day management of the symptoms arising from the condition and the side-effects of medication.[13]

Non-drug

MND is an incurable condition that usually, although not always, leads to death within a few years, with a period of distressing disability preceding it. Thus, the mainstay of management is in supporting the patient, their family and carers through this process and in delivering palliative care at the appropriate juncture. The following measures are helpful in prolonging the survival of those with MND and in helping them to maintain a sense of health, well-being and control over their lives:

  • A multidisciplinary approach involving GPs, primary care nurses, occupational therapists, physiotherapists, speech therapists, dieticians, respite care providers, home care workers, hospital physicians and neurologists, along with many others, is likely to best serve the patient, and effective communication between all the interested parties is essential.
  • GPs are particularly well placed in ensuring that patients and their carers know where to get information about any social or financial support that may be required.[14]
  • Regular physical, occupational and speech therapy to maintain strength and utility of the affected motor functions and allow use of aids designed to overcome specific disability problems.
  • Dietetic support to allow adequate hydration and nutrition whilst the patient is able to feed independently, or with the aid of carers.
  • Insertion of a gastrostomy tube should be considered when the patient is no longer able to feed by mouth. Current practice is to offer the option of enteral feeding to patients, either through percutaneous endoscopic gastrostomy (PEG), percutaneous radiological insertion of gastrostomy, or nasogastric tube (with 10% weight lost or a body mass index below 18.5).[1]
  • Communication can be greatly enhanced by the use of picture-boards or more advanced IT-based solutions tailored to the individual patient’s needs and disabilities.
  • When respiratory function is impaired, physiotherapy helps to clear pulmonary secretions and maintain respiratory health.
  • Positive pressure ventilation may be used in patients who are no longer able to maintain adequate ventilation. This has been shown to improve quality of life and survival greatly.[1] The machines are small and portable and various face masks are available . Patients quickly get used to wearing the masks overnight. In later stages some patients may use non-invasive ventilation (NIV) during the day, using a small nasal mask.
Non-invasive ventilation
The greatest advance in treating MND has been the discovery of the beneficial effects of NIV, in which the patient uses a mask ventilator system (usually bilateral positive airway pressure) overnight during sleep.[1]National Institute for Health and Care Excellence (NICE) guidelines recommend:[15]

  • Discussion about NIV at the time of diagnosis and at appropriate opportunities thereafter.
  • The patient should be assessed for the symptoms and signs of respiratory impairment at three-monthly intervals.
  • Patients who meet the NICE criteria for treatment of their respiratory impairment should be offered NIV. However, if the patient suffers from severe bulbar impairment or severe cognitive problems related to their respiratory impairment, NIV should only be offered if the patient has sleep-related symptoms or hypoventilation.
  • If commenced, acclimatisation should occur during the day.
  • Regular treatment should be given at night, before and during sleep.
  • Hours of use should be built up as necessary.
  • In patients with cognitive impairment, issues of capacity and consent may need to be considered.

Drug treatments

  • Riluzole (a neuroprotective glutamate-release inhibitor) is the only drug of proven disease-modifying efficacy.[16]
    • Its effects are modest, probably only prolonging lifespan by between two and four months.
    • It may have a more significant effect on prolonging tracheostomy-free survival.[17]
    • It appears to be well tolerated and of greater benefit the earlier it is started in the course of the disease.[18]
    • It has been shown to act by blocking muscle acetylcholine receptors.[19]
  • It was hoped that antioxidants might prove beneficial. However, a recent Cochrane review concluded that the use of antioxidants was not supported by currently available clinical trial data.[20]
  • Other medications may be used to treat symptoms of the disease; for example:
    • Drooling may be reduced by the use of anticholinergics such as hyoscine.[21]
    • Muscle cramps and spasticity can be treated with agents such as diazepam, baclofen, tizanidine, phenytoin and quinine.
    • Respiratory distress and the sensation of choking may respond to opioid medications but this must be balanced against their tendency to cause respiratory suppression; they are very useful to treat this symptom in the palliative phase.
    • Depression associated with MND may respond to the use of antidepressant medications.
    • Pain often goes under-recognised and undertreated. It is thought to be due to spasticity but other mechanisms may be operant. The antispasmodic agents listed above are usually helpful but non-steroidal anti-inflammatory drugs and opioids, such as oral morphine, subcutaneous diamorphine and fentanyl patches, are also utilised, particularly in the palliative phase.[22]

End of life care

Inevitably, the disease will progress and both patients and carers may wish to discuss the terminal phase of the illness. Careful discussion about this at a pace determined by the patient, family and carers helps to shape what form care will take. Issues which frequently come up include:

  • Hospice care – this may be useful in the later stages of the disease for respite.
  • Advance directives – information on these can be given and this can help implementation of patients’ wishes.
  • Management of symptoms – for example:
    • Respiratory distress – this can be treated with opiates.
    • Choking – lorazepam sublingually can quickly relieve choking episodes.
    • Dyspnoea – if severe and prolonged, is an indication for subcutaneous morphine.
  • Respiratory failure and death.
  • Pneumonia due to infection or aspiration.
  • Urinary tract infections.
  • Constipation.
  • Spasticity and cramping of muscles.
  • Depression
  • Loss of speech as a means of communication.
  • Immobility and attendant disability.
  • Complications of immobility such as skin infections/bedsores and ulcers.
  • Cognitive deterioration is rare but is seen occasionally.
  • MND is usually a rapidly progressive and fatal disease but the rate of progression is variable.[23]
  • Median survival is two to four years.[24]
  • End of life care with all that this implies needs a co-ordinated sensitive approach. More than 90% of patients die in their sleep, as a result of increasing hypercapnia (respiratory failure with or without pneumonia) and choking to death is not seen in clinical practice.[1]
  • There appears to be a small subgroup of patients (5-10%) surviving for a decade or more.[6]

CDC Reveals Leading Causes Of Death In The U.S.; Heart Disease, Cancer Lead The Pack


Americans may be enjoying the highest life expectancy the country has ever seen, but certain diseases are still taking far too many lives. The Centers for Disease Control and Preventionhas released its listing of the top causes of death in the United States for 2013, the most recent year for which data was available. As a whole, the list includes some very familiar, very formidable conditions, but many of them are at least somewhat preventable. Take a look at the slideshow for the top ten things that kill Americans.

Watch the slideshow. URL: http://www.medicaldaily.com/leading-causes-death-cdc-number-one-382974

From Their Tongues To Chubby Cheeks, How Babies’ Mouths Are Designed To Be Breastfed


While breastfeeding rates dipped in the 20th century due to the advent of baby formula, in recent years they’ve begun to increase again — to the benefit of both infants and mothers. Babies are physically designed to be breastfed, so it only makes sense that they are.

baby breastfeeding

Babies’ mouths and airways are equipped to enhance breastfeeding.

In a video shared on Facebook by Amytime – The Healthy Breastfeeder, we can see how that’s the case. First, an infant’s tongue is large compared to the rest of the mouth, which increases contact with breast milk — the child’s ultimate goal. A baby’s tongue is cushioned on either side by fat reserves in the cheeks, what’s commonly referred to as “baby fat” or “chubby cheeks.” Fat pads in the cheeks allow the baby’s tongue to remain in place while sucking, and prevent the cheeks from sinking in.

In addition to the physicality of the mouth, babies’ upper airways are equipped to enhance breastfeeding. The epiglottis is a small flap of cartilage that covers the baby’s windpipe and prevents milk from going into the airway; instead, the milk is directed to the esophagus.

Breastfeeding rates are likely increasing due to the myriad of evidence that has proven it’s healthy and strengthening for both baby and mother. For example, research has shown that breastfeeding an infant for over six months is linked to a lower chance of childhood leukemia, as well as an improved immune system and gut microbiome. One 2015 study even found that babies who had been breastfed for over 12 months had higher IQ scores and made more money by the time they were 30, hinting that breast milk can enhance a baby’s brainpower. For mothers who breastfeed, they experience health benefits too: including lower depression risk, as well as a reduced risk of some cancers.

“[B]abies who are breastfed have lower risks of ear and gastrointestinal infections, diabetes and obesity, and mothers who breastfeed have lower risks of breast and ovarian cancers,” CDC Director Dr. Tom Frieden said in a press release. “Also, breastfeeding lowers healthcare costs.”

Preexposure Prophylaxis for HIV: Where Are We Now and How Did We Get Here?


In July 2012, the US Food and Drug Administration (FDA) approved a once-daily, fixed-dose combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) for preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection. FTC/TDF, initially approved in 2004 to treat HIV in combination with other antiretroviral agents, became the first drug to be approved to prevent HIV infection in people who are at high risk for infection.1 In May 2014, the US Public Health Service (USPHS) released a set of clinical practice guidelines for PrEP. 2

Take Note

  • PrEP is one of several prevention options for sexually active adults who are at high risk for HIV infection based on their sexual practices.
  • PrEP may be indicated for gay and bisexual men, heterosexual men and women, and partners in serodiscordant relationships, among others.
  • PrEP should be provided in the context of access to appropriate risk-reduction services

The FDA approved FTC/TDF for PrEP on the basis of 2 large, randomized, double-blind, placebo-controlled trials.1,3,4

One, the iPrEX (Preexposure prophylaxis initiative) study, was conducted among 2499 HIV-negative men and transgender women who have sex with men. Participants received FTC/TDF or placebo once daily along with HIV testing, risk-reduction counseling, condoms, and treatment for sexually transmitted infections (STIs). After a median 1.2 years of follow-up, 100 participants were found to have acquired HIV infection: 36 in the active prophylaxis group and 64 in the placebo group. This result amounted to a significant 44% reduction in the incidence of new HIV infections among the participants receiving PrEP.3 While demonstrating the efficacy of PrEP, the study also showed the importance of adherence to the regimen. That is, study participants in the active arm who became infected were found to have low levels of FTC/DTF in their blood.3

The other study, called Partners PrEP, was conducted among 4758 serodiscordant heterosexual couples (couples in which 1 partner was HIV-positive and the other was HIV-negative) in Kenya and Uganda. The HIV-negative partners in this study received FTC/TDF, TDF alone, or placebo. A total of 82 of the HIV-negative partners became infected with HIV during the study. Compared with placebo, there was a 67% reduction in the incidence of infection among participants who received TDF alone, and a 75% reduction with FTC/TDF. Both of these results were statistically significant.4

The 2014 USPHS guidelines are based on these studies plus a number of others. Among the most important were the TDF2 Study and the Bangkok Tenofovir Study.5

The TDF2 Study evaluated PrEP in heterosexual men and women in Botswana. The 1219 participants (48% women, 52% men) were randomly assigned to FTC/TDF or placebo with monthly follow-up and prevention services including HIV testing, risk-reduction and adherence counseling, and management of STIs, as well as monitoring for potential drug side effects. Compared with placebo, PrEP reduced the risk of HIV infection by 62%. Again, efficacy correlated strongly with adherence as measured by drug levels.6

The Bangkok Tenofovir Study evaluated PrEP among a group of injection drug users (IDUs) in Thailand, a population that had not previously been studied as candidates for PrEP. The 2413 participants were assigned to receive either TDF or placebo along with monthly HIV testing, risk-reduction and adherence counseling, and safety assessments, and were offered condoms and methadone treatment. Compared with placebo, TDF reduced the risk of HIV infection by 49%. Once again, efficacy was correlated with adherence: among patients with detectable TDF in their blood, the reduction in risk of HIV infection was 74%.7

The USPHS guidelines are based on the premise that daily oral PrEP with FTC/TDF has been proven safe and effective at reducing the risk of becoming infected with HIV through sex with an infected partner. The guidelines recommend PrEP as 1 prevention option for sexually active adults who are at high risk for HIV infection based on their sexual practices. This includes gay and bisexual men, heterosexual men and women, and members of serodiscordant couples. The guidelines note that the safety and efficacy of PrEP for adolescents has not been fully characterized, so clinicians should weigh the risks and benefits of PrEP in counseling adolescent patients.2

Before prescribing PrEP to an eligible patient, clinicians must rule out current HIV infection. PrEP should be prescribed for daily use; the USPHS does not recommend PrEP for so-called coitally-timed or other noncontinuous use. Once a patient has initiated PrEP, the prescribing physician should test for HIV infection at least every 3 months. It is important for patients who acquire HIV infection while on PrEP to discontinue the medication, as the 2-drug FTC/TDF regimen is not sufficient treatment for HIV infection and its continued use may lead to viral resistance to 1 or both drugs.2

Before patients initiate PrEP, clinicians should assess renal function and test for hepatitis B virus (HBV) infection. Impaired renal function and loss of bone mineral density are potential safety concerns with the use of FTC/TDF. It is also important for clinicians to know if a patient is co-infected with HBV as FTC/TDF can be used to combat HBV, and discontinuation of HBV therapy may not be advisable. Clinicians should not prescribe FTC/TDF to any person with an estimated creatinine clearance rate (CrCL) of < 60 mL/min. In patients on PrEP, clinicians should assess renal function at least every 6 months so that patients who develop renal failure do not continue to take PrEP.2

As reflected in the clinical trial data, a high level of adherence is important for the success of PrEP but was not always achieved by participants in trials. Consequently, patients on PrEP should be encouraged to use PrEP in combination with other effective prevention methods (including condoms) and should be provided with access to such methods (directly by the prescribing clinician or via referral to appropriate risk-reduction services).2

Finally, a French study termed Ipergay has shown the success of an approach termed “PrEP on demand,” in which individuals at risk for acquisition of HIV were prescribed FTC/TDF only on the day of anticipated sexual relations and for 2 days thereafter instead of every day. The advantage of the latter approach is that it may lower the side effects associated with FTC/TDF since some patients would be taking fewer pills that once daily. This would also help reduce costs.8 As previously mentioned, however, the USPHS does not sanction this approach.

The complete USPHS Clinical Practice Guidelines for PrEP and A Clinical Provider’s Supplement are available online.The supplement includes a patient checklist to help maximize the benefit of PrEP and informational patient handouts. It also includes a risk measurement tool for MSM, allowing physicians to identify those patients at highest risk for HIV infection for whom PrEP may be indicated. Information about adherence and risk-reduction counseling is also provided, as well as information on administrative and billing codes for PrEP-related services.

Managing Patients with HIV Virologic Failure: Key US Guideline Updates


The US Department of Health and Human Services has revised its guidelines on the management of virologic failure, and a summary of key updates is provided here. The guidelines now include treatment recommendations for (1) virologic failure in various clinical scenarios involving first-line and second-line antiretroviral regimens and (2) isolated central nervous system (CNS) virologic failure with the onset of new neurologic symptoms.1 The complete guidelines are available on the AIDSinfo website at http://www.aidsinfo.nih.gov.

Take Note

  • The US Department of Health and Human Services guidelines now include recommendations for managing virologic failure in several clinical scenarios regarding first-line and second-line antiretroviral regimens, as well as isolated central nervous system virologic failure with new onset neurologic symptoms.
  • Treatment modification after careful analysis of the potential underlying causes of virologic failure is a complex undertaking. Expert consultation is crucial.

Virologic failure after first-line antiretroviral therapy

Failure of NNRTI plus NRTI modality: Viral resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) component of a regimen, with or without resistance to the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine and emtricitabine, is common in patients whose NNRTI-based regimen fails. Recent studies suggest that patients in these cases often may be treated with a pharmacokinetically boosted protease inhibitor (PI), such as lopinavir/ritonavir or darunavir/ritonavir, in combination with NRTIs or the integrase strand transfer inhibitor (INSTI) raltegravir. Other possible choices in this setting include the second-generation NNRTI etravirine or other INSTIs (ie, elvitegravir or dolutegravir) in conjunction with a pharmacokinetically boosted PI, although data on clinical effectiveness are limited.1

Failure of a pharmacokinetically boosted PI plus NRTI modality: Most patients who fail a regimen consisting of a pharmacokinetically boosted PI plus NRTIs will not have resistance mutations for the PI and resistance is likely to be limited to lamivudine and emtricitabine. Virologic failure is usually related to poor adherence or drug-drug or drug-food interactions. If the regimen is well tolerated and no drug-drug or drug-food interaction concerns are apparent, this modality can be continued with compliance support and viral load monitoring. If drug intolerance or adverse interactions may possibly be contributing to virologic failure, the modality may be modified such that a new regimen includes two fully active NRTIs without a PI or a different pharmacokinetically boosted PI plus NRTIs, even if not all of the NRTIs are fully active.1

Failure of an INSTI plus NRTI modality: A combination of raltegravir plus two NRTIs or the four-drug combination of elvitegravir, cobicistat (a cytochrome P450 enzyme inhibitor), emtricitabine, and tenofovir disoproxil fumarate (a NRTI) may lead to virologic failure due to resistance to the NRTI (ie, lamivudine or emtricitabine) and possibly to the INSTI. Based on data extrapolation regarding NNRTI failures, a pharmacokinetically boosted PI plus NRTIs may yield responses in patients with first-line INSTI failures. For those with no INSTI resistance, a pharmacokinetically boosted PI plus an INSTI may be a feasible alternative. When raltegravir and elvitegravir resistance, but not dolutegravir resistance, is observed, dolutegravir may be combined with a pharmacokinetically boosted PI in a subsequent regimen. Patients in whom no resistance is identified should be managed according to previously existing US guidelines for patients experiencing virologic failure with no resistance.1

Virologic failure after second-line antiretroviral therapy

Agents to be used in subsequent regimens should be selected according to predictors of complete virologic suppression, including the patient’s treatment history, results of previous and present drug-resistance testing, as well as tropism testing when a CCR5 antagonist is being considered as a treatment option.1

No consensus recommendations are available for optimal treatment strategies in patients unable to achieve complete virologic suppression due to multidrug resistance. In this clinical setting, antivirals are utilized to maintain immunologic function, impede disease progression, and minimize an increase in resistance to the same or other drug classes, so that as many antiretroviral agents as possible, including possibly some still in development, will be active and useful in future regimens. NNRTIs, as well as enfuvirtide (a fusion inhibitor), elvitegravir, and raltegravir should usually be discontinued if resistance to these antivirals becomes apparent, since most evidence shows they will no longer be able to hinder disease progression. In fact, continuing these agents may lead to selection of additional mutations, leading to higher-level resistance and within-class cross-resistance, thus limiting future treatment alternatives.1

“The stakes are high,” notes Christine Durand, MD, Assistant Professor in the Departments of Medicine and Oncology at the Johns Hopkins University School of Medicine, Baltimore, MD. “With repeated treatment failure, HIV can become resistant to multiple classes of antiretroviral drugs….This could lead to disease progression and death in the individual patient and, if this ‘superbug’ is transmitted to others, then it can become a public health problem, as well.”

Isolated CNS virologic failure

In rare instances, patients experience new onset neurologic symptoms with HIV infection breakthrough in the CNS, despite suppressed viral load.1 Although this condition, referred to as neurosymptomatic cerebrospinal fluid (CSF) escape, is uncommon, it is essential to identify it clinically so that its management and the implications therof can be addressed.2 MRI brain imaging is needed to document encephalitis and to reveal other abnormalities, including variable lesions typically presenting in the white matter.2 In addition, CSF analysis is also critical to detect and evaluate various CSF abnormalities, such as the characteristic lymphocytic pleocytosis. The differential diagnosis of isolated CNS virologic failure should include other CNS infections that may temporarily increase CSF HIV RNA levels, such as herpes zoster, chronic neurocognitive disorders without CNS HIV breakthrough commonly reported in HIV-infected patients, and mild, incidental increases in CSF HIV RNA levels in the absence of neurologic symptoms. Modification in antiretroviral therapy is not currently recommended for these other conditions.1

Experts recommend CSF HIV drug-resistance testing to guide treatment alternatives, considering CNS pharmacokinetics and principles recommended for plasma HIV RNA resistance. If such testing is unavailable, clinicians should modify the regimen based on the patient’s treatment history and predicted drug CNS penetration.1

“The most important goal is to suppress HIV systemically,” Dr. Durand comments. “If there are persistent neurocognitive deficits, referral to a neurologist with HIV expertise would be important. She adds, “Adjunctive neurological and psychiatric medications may provide benefit.”

A complex undertaking

As US guidelines continue to emphasize, an understanding of the underlying cause of virologic failure and determining the best course of action when modifying antiretroviral regimens often necessitate consultation with specialists.1 Optimal management of treatment-experienced patients requires, first and foremost, a thorough analysis of the possible contributing factors to failed antiretroviral therapy, including suboptimal adherence, adverse effects, drug intolerance, comorbidities, drug-drug and drug-food interactions, absorption issues, and psychosocial factors. Also essential are assessments of treatment history, viral load and CD4 count trends, as well as previous and current drug-resistance test results.1“Evaluating the potential reasons for failure and making a plan to address them,” explains Dr. Durand, “require expert knowledge in antiretroviral side effects, pharmacokinetics, and antiretroviral drug resistance, as well as a good understanding of the stigma and psychosocial issues faced by this patient population.”