BACKGROUNDSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODSWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTSIn the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONSAmong infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074.)

The world's population living on low-lying deltas is increasingly vulnerable to flooding, whether from intense rainfall, rivers or from hurricane-induced storm surges. High-resolution SRTM and MODIS satellite data along with geo-referenced historical map analysis allows quantification of the extent of low-lying delta areas and the role of humans in contributing to their vulnerability. Thirty-three major deltas collectively include ~26,000 km 2 of area below local mean sea level and ~96,000 km 2 of vulnerable area below 2 m a.s.l. The vulnerable areas may increase by 50% under projected 21st Century eustatic sea level rise, a conservative estimate given the current trends in the reduction in sedimentary deposits forming on the surface of these deltas. Analysis of river sediment load and delta topographical data show that these densely populated, intensively farmed landforms, that often host key economic structures, have been destabilized by human-induced accelerated sediment compaction from water, oil and gas mining, by reduction of incoming sediment from upstream dams and reservoirs, and from floodplain engineering. IntroductionClose to 0.5 billion people live on, or near, world deltas, inclusively in many mega-cities (1, 2). Ten countries (China, India, Bangladesh, Vietnam, Indonesia, Japan, Egypt, USA, Thailand, and the Philippines) account for 73% of the people that live in the world's coastal zone, defined as within 10 m a.s.l. (3). 20 th -century catchment developments and population and economic growth within subsiding deltas have placed these environments and their populations under a growing risk of coastal flooding, wetland loss, shoreline retreat, and loss of infrastructure (4, 5). It is estimated that more than 10 million people per year experience flooding due to storm surges, and most of these people are living on Asian deltas (6). Using new, globally-consistent and highresolution topographic data, three hypotheses are tested: 1) deltas are rapidly sinking, often to below local sea level, 2) the lack of sediment getting to delta floodplains is the main reason so many deltas are sinking, and 3) human activities are largely responsible for the present vulnerability of deltas. For a representative suite of deltas, Shuttle Radar Topography Mission (SRTM) data are applied to evaluate delta topography, in relation to mean sea level. Historical maps are geo-referenced against detailed topographic data to map morphodynamic patterns and quantify how rivers once flowed through deltas. Visible and near-infrared Moderate Resolution Imaging Spectroradiometer (MODIS) satellite images are used to assess flooding in modern deltas and investigate whether such flooding is mainly from river runoff or instead from coastal storm surges, and whether present river suspended load is sufficient to maintain delta plain aggradation and stability.

Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537 .).

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.

Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.