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.)

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Introduction:The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutation-positive non–small-cell lung cancer (NSCLC) patients necessitates accurate, timely testing. Although EGFR mutation testing has been adopted by many laboratories in Asia, data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods.Methods:A retrospective survey of records from NSCLC patients tested for EGFR mutations during 2011 was conducted in 11 Asian Pacific countries at 40 sites that routinely performed EGFR mutation testing during that period. Patient records were used to complete an online questionnaire at each site.Results:Of the 22,193 NSCLC patient records surveyed, 31.8% (95% confidence interval: 31.2%–32.5%) were tested for EGFR mutations. The rate of EGFR mutation positivity was 39.6% among the 10,687 cases tested. The majority of samples were biopsy and/or cytology samples (71.4%). DNA sequencing was the most commonly used testing method accounting for 40% and 32.5% of tissue and cytology samples, respectively. A pathology report was available only to 60.0% of the sites, and 47.5% were not members of a Quality Assurance Scheme.Conclusions:In 2011, EGFR mutation testing practices varied widely across Asia. These data provide a reference platform from which to improve the molecular diagnosis of NSCLC, and EGFR mutation testing in particular, in Asia.

Objectives: Clinicians often base the implementation of therapies on the presence of postural instability in subjects with Parkinson's disease (PD). These decisions are frequently based on the pull test from the Unified Parkinson's Disease Rating Scale (UPDRS). We sought to determine whether combining the pull test, the one-leg stance test, the functional reach test, and UPDRS items 27-29 (arise from chair, posture, and gait) predicts balance confidence and falling better than any test alone. Methods: The study included 67 subjects with PD. Subjects performed the one-leg stance test, the functional reach test, and the UPDRS motor exam. Subjects also responded to the Activities-specific Balance Confidence (ABC) scale and reported how many times they fell during the previous year. Regression models determined the combination of tests that optimally predicted mean ABC scores or categorised fall frequency. Results: When all tests were included in a stepwise linear regression, only gait (UPDRS item 29), the pull test (UPDRS item 30), and the one-leg stance test, in combination, represented significant predictor variables for mean ABC scores (r 2 = 0.51). A multinomial logistic regression model including the one-leg stance test and gait represented the model with the fewest significant predictor variables that correctly identified the most subjects as fallers or non-fallers (85% of subjects were correctly identified). Conclusions: Multiple balance tests (including the one-leg stance test, and the gait and pull test items of the UPDRS) that assess different types of postural stress provide an optimal assessment of postural stability in subjects with PD.

OmpR and PhoB are response regulators that contain an N-terminal phosphorylation domain and a C-terminal DNA binding effector domain connected by a flexible interdomain linker. Phosphorylation of the N terminus results in an increase in affinity for specific DNA and the subsequent regulation of gene expression. Despite their sequence and structural similarity, OmpR and PhoB employ different mechanisms to regulate their effector domains. Phosphorylation of OmpR in the N terminus stimulates the DNA binding affinity of the C terminus, whereas phosphorylation of the PhoB N terminus relieves inhibition of the C terminus, enabling it to bind to DNA. Chimeras between OmpR and PhoB containing either interdomain linker were constructed to explore the basis of the differences in their activation mechanisms. Our results indicate that effector domain regulation by either N terminus requires its cognate interdomain linker. In addition, our findings suggest that the isolated C terminus of OmpR is not sufficient for a productive interaction with RNA polymerase.Escherichia coli contains 28 histidine kinases and 32 response regulators (43) that couple changes in the environment to changes in gene expression or protein function (for a review, see reference 56). In their simplest form, two-component systems are comprised of a sensor kinase and a response regulator. The sensor kinase, typically a membrane-bound protein, responds to specific environmental signals by modulating its ability to phosphorylate (and in some cases dephosphorylate) its cognate response regulator. Response regulators are usually DNA binding proteins containing two domains separated by a flexible linker. The N-terminal receiver domain modulates the activity of the C-terminal effector domain. Most often, phosphorylation of the N terminus enhances the affinity of its C terminus for specific DNA, resulting in a subsequent change in gene expression.In E. coli and related enteric bacteria, EnvZ is a membranebound histidine kinase (12) that undergoes autophosphorylation by intracellular ATP (EnvZ-P) (1,13,20). EnvZ-P transfers the phosphate to its cognate response regulator, OmpR (1,2,13,21,22). OmpR reciprocally regulates transcription of the outer membrane porin genes ompF and ompC in response to changes in medium osmolarity (14,18,32,47,53,54). OmpF is the predominant porin at low osmolarity, whereas OmpC predominates at high osmolarity (4). PhoB is a response regulator in the same subfamily and is highly homologous to OmpR. Under conditions of limiting inorganic phosphate, PhoB activates the transcription of a regulon involved in the metabolism and uptake of phosphorus-containing compounds (33, 51, 63, 64; for a review, see reference 65). Phosphorylation by the inner-membrane-bound histidine kinase PhoR controls the levels of phosphorylated PhoB in response to extracellular inorganic phosphate levels (34, 37, 66).Response regulators share a conserved, doubly wound ␣/␤ fold and phosphorylation site geometry in their N terminus but are grouped into subfamilies ba...