Nov 3, 2017

Find and replace

The story

With Game of Thrones long over and Westworld yet to begin, maybe it's time to seek escapism in your day job. New advances in gene therapy look a lot like science fiction.

The background

Like your sleep cycle in the ICU, spinal muscular atrophy (SMA) varies widely but is always bad. The disease, among the most common inherited neuromuscular disorders, stems from a defect in the gene SMN1 that impairs the production of SMN, a protein essential for motor neuron survival. Patients experience muscle atrophy and respiratory failure beginning in early childhood. Severe cases can be fatal within two years.

New genes

One way of fixing a defunct gene is to replace it. And while gene therapy is inevitably more complicated, that's the basic idea behind infusion of a non-replicating virus designed to genetically code for the missing SMN protein. A phase 1 dose escalation study found that a one-time infusion of an SMN-coding viral vector met safety endpoints and demonstrated promising efficacy. Two of the patients in the highest dose group were able to walk, a milestone previously unachievable for patients with severe disease.

Old proteins, new tricks

Remember DNA→RNA→protein? Choose your target. In another approach, researchers used antisense RNA to modify a closely-related protein to act like SMN. The antisense compound nusinersin, when injected regularly into the central nervous system, improved motor milestone development and the likelihood of overall survival compared to sham procedure in an 80-patient phase 3 trial that was stopped early due to efficacy.

The takeaway

On a scale of 1 to Gattaca, we're still at the very beginning. But these are milestone treatments for SMA patients and for the field of gene therapy.

Say it on rounds

When you think you learned something in noon conference, but you were actually just asleep

Some placebo effects are more comforting than others. The most common use for percutaneous coronary intervention (PCI) is to relieve angina in patients with stable coronary artery disease (CAD). The double-blinded ORBITA trial compared PCI to sham procedure in 200 patients with stable single-vessel CAD on optimal medical therapy. In results that have stunned the cardiology community, the sham and stent groups both reported substantial relief of anginal symptoms at 6-week follow-up. Even though PCI markedly improved coronary flow, the similar benefits between groups point to a procedure-related placebo effect.

When you compare your residency salary with friends in other fields

Money can't buy happiness, but what about loyalty? A study of Medicare providers in Washington DC found that docs given gifts like cash and meals wrote 2.3x more prescriptions per patient than non-gift recipients. They also prescribed more branded medications. Larger gifts (> $500) had a greater effect on prescribing patterns, but even small gifts were associated with increased prescription activity.
PLoS One

When your patient looks good but the labs scream sepsis

Think about early escalation. The CALM trial looked at the early use of biologic therapy in 200 patients with moderate to severe Crohn's disease. Patients in a tight control group were given therapy based on a rise in inflammatory biomarkers, while a loose control group was escalated to biologics based on traditional clinical symptoms. The biomarker-guided group was 50% more likely to achieve mucosal healing than the symptom-guided group at 48 weeks, suggesting a clear benefit for early action.

Brush up

Adrenal insufficiency

The prevalence of primary adrenal insufficiency (AI) is on the rise. In developed countries, 80 - 90% of cases are due to autoimmune adrenalitis. Look for unexplained hypoglycemia, and remember that hyperpigmentation occurs in chronic but not acute disease. Hormone replacement and patient education are pillars of treatment. Patients must know how to self-inject emergency hydrocortisone and how to titrate steroid doses when they become sick at home.

What's the evidence

For adrenal crisis in patients with chronic adrenal insufficiency? A 2010 postal survey of 850 patients with chronic AI on treatment found an estimated annual hospitalization rate for adrenal crisis of roughly 8%. Concomitant diabetes and asthma placed patients at higher risk. Since crisis is life-threatening, keep a high index of suspicion and treat promptly with steroid infusion and fluids. 

What your fine dining friends are talking about

“Who else can take raw ingredients that are seemingly unassociated and make them into delicious food and do it under extreme pressure?” Take a look at how José Andrés used skills unique to chefs to serve millions of meals in Puerto Rico after Hurricane Maria.

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