An opinionated take on NEJM highlights for July 2020

Stunting and the microbiome

Stunting (low growth for age) affects > 20% of children across the globe and has major impact on the brain, on health, and on opportunities for success in life. The precise mechanism of stunting has remained elusive. Sanitation and diet diversity play a role but targeted interventions in these areas have had less impact than hoped for. Jeff Gordon from WashU has spent the last decade exploring the relationship between stunting and the microbiome, and now his group reports on a study that shows a clear correlation between certain microbe populations in the gut and stunting in children from Bangladesh. In addition, when the microbiome from stunted children is transferred into young mice, they themselves develop gut dysfunction.  The findings suggest new targets for intervention, biomarkers to predict and monitor stunting, and new ways to quickly screen approaches without having to wait to see effect on the growth curve.  Duodenal Microbiota in Stunted Undernourished Children with Enteropathy; Growth and the Microbiome — Integrating Global Health with Basic Science (free access)


Understanding and predicting autoimmune flares

Many autoimmune diseases are characterized by quiescent periods punctuated by unpredictable exacerbations (flares). In a longitudinal study lasting several years, a Rockefeller group followed 4 patients with rheumatoid arthritis (RA) tracking their symptoms while at the same time collecting weekly data on the state of circulating immune cells via RNA-seq. What they found was a consistent change in transcriptional profile 1-2 weeks before a symptomatic flare of the disease. While small, this study could have a large impact on the way we approach autoimmune diseases: first, by elucidating the cascade of events that lead to a flare and potentially identifying new therapeutic targets; second, by potentially enabling intermittent preventative treatment (rather than continuously or post-facto with drugs that have considerable side-effects); and finally, although RA is bad, it’s not the worse autoimmune condition: this opens the door to similar work on profoundly debilitating diseases such as MS and lupus.   RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares; PRIME Time in Rheumatoid Arthritis (subscriber access)


New approaches to ALS

Although only a few % of patients with ALS have a SOD1 mutation, this was the first gene discovered to be associated with ALS, and led to the creation of animal models of ALS. These models have shown that SOD1 mutation(s) can lead to toxic gain of function of SOD1 and that suppressing expression can be beneficial. Two small studies, one from Biogen/Ionis using anti-sense RNA (ASO), the other from U Mass using AAV delivered encoded RNAi have tested this approach in ALS patients with a SOD1 mutation and report results with evidence of target engagement with decreased SOD1. And while it’s too early for evidence of clinical effect, those reports bring much needed positive news to a disease that really needs it.  Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS; SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS; The Beginning of Genomic Therapies for ALS (subscriber access)


Hard falls

For many older adults, the triggering events to end-of-life or end-of-life at home is a fall, and as a result there has been a focus over the last decade on devising interventions to reduce serious falls. A recent PCORI-funded pragmatic trial tested such an intervention including fall risk assessment, care plan, and follow-up vs. usual care in a cohort of several thousands of community-dwelling patients > 70 with risk factors. For the primary end-point of serious falls, it made no difference. As for many other “care-management” like interventions that try to mitigate poor outcomes that have multifactorial health, psychosocial, and other contextual drivers, this shows how difficult it is to figure out what will make a difference.  In the case, it appears that like for thermodynamics, the 2nd law of the House of God is particularly hard to circumvent.  A Randomized Trial of a Multifactorial Strategy to Prevent Serious Fall Injuries (subscriber access)


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.

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