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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Numerous studies indicate that child maltreatment increases the risk for the development of internalizing and externalizing behavior problems. Great variations in outcome, however, have been noted among victims of maltreatment. From an ecological perspective, this review examines how the effects of maltreatment may be influenced by the contexts in which children develop, including their families, peer groups, schools, and communities. The literature reviewed suggests that contextual factors not only influence the incidence of maltreatment but also may moderate its developmental effects, thereby accounting for some of the heterogeneity in the outcomes associated with abuse and neglect. Closer examination of the influence contextual factors exert on the psychosocial sequelae of maltreatment will better inform the interventions, treatments, and public policies directed toward the maltreated population. Methodological considerations for conducting research in this area are also discussed.

Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).

This study examined the effects of the Nurse Family Partnership (NFP), a program of prenatal and infancy home visiting by nurses, on the timing of verified reports of child maltreatment. A sample of predominantly unmarried, low-income mothers and their first-born children were randomly assigned to receive either home visitation services by nurses beginning in pregnancy and lasting until the child was age 2, or comparison services. Previous studies have found that this program was effective in reducing the overall number of substantiated Child Protective Service reports by age 15. In the current study, survival analyses were used to assess temporal differences between nurse visited (n = 93) and comparison (n = 144) children's onset rates for maltreatment. The two groups' survival functions remained nearly identical until age 4, at which point the nurse-visited group's risk for onset began to significantly diminish. These results were more pronounced among the highest risk subgroup and among victims of neglect. The findings provide evidence that the NFP's success in reducing the number of maltreatment reports resulted in part from in its impact on the timing of the maltreatment process.

Previously, flow cytometric determination of peroxidase activity, cell size, and reactivity to lymphocyte antibodies were used to produce bone marrow differentials in untreated rats. In the present study, abnormal hematologic profiles were induced with erythropoietin (EPO), recombinant murine stem cell factor (rm‐SCF), granulocyte–macrophage stimulating factor (GM‐CSF), and cyclophosphamide (CP). Manual and flow cytometric data showed comparable levels of erythroid and myeloid hyperplasia in EPO‐ and rm‐SCF/GM‐CSF‐treated animals, respectively. In CP‐treated animals, flow cytometric data revealed significant decreases in cellularity at concentrations of CP ≥ 5 mg/kg. In contrast, 20 mg/kg CP were necessary to induce microscopically apparent hypoplasia in histologic bone sections, showing that the automated methodology was a more sensitive indicator of bone marrow hypocellularity than was the more conventional manual method. Megakaryocyte counts were consistently higher by flow cytometer than by manual counts performed on cytocentrifuge preparations made from the same cell suspensions but were similar to megakaryocyte counts performed on histologic sections of femur, indicating that the automated methodology produced a more accurate reflection of true megakaryocyte numbers. Induction of hematologic abnormalities in the present study showed that manual bone marrow differentials can be replaced with the more efficient and reliable flow cytometric method in most preclinical toxicology studies. Cytometry 32:18–27, 1998. © 1998 Wiley‐Liss, Inc.

This study investigated the relationship between child maltreatment and the early onset of problem behaviors in the Elmira Nurse Home Visitation Program. Participants were predominantly low-income and unmarried mothers and their first-born children who were randomized either to receive over 2 years of home-visitation services by nurses or to be placed in a comparison group. Data were drawn from a follow-up study that took place when the children were 15 years of age. Results demonstrated that, in the comparison group, child maltreatment was associated with significant increases in the number of early onset problem behaviors reported by the youth. For the youth in the nurse-visited group there was no relationship between maltreatment and early onset problem behaviors. We suggest that this finding was due to the effects of the intervention in reducing the number as well as the developmental timing of the maltreatment incidents. Results suggest that prenatal and infancy home visiting by nurses can moderate the risk of child maltreatment as a predictor of conduct problems and antisocial behavior among children and youth born into at-risk families.