Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease.

BACKGROUND: Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. BCL11A is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF. METHODS: We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment. RESULTS: As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period. CONCLUSIONS: This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).

A Parenting and Life Skills Intervention for Teen Mothers: A Randomized Controlled Trial.

: media-1vid110.1542/5985300176001PEDS-VA_2018-2303Video Abstract BACKGROUND: Teen mothers often present with depression, social complexity, and inadequate parenting skills. Many have rapid repeat pregnancy, which increases risk for poor outcomes. We conducted a randomized controlled trial of a parenting and life skills intervention for teen mothers aimed at impacting parenting and reproductive outcomes. METHODS: Teen mothers were recruited from a teen-tot clinic with integrated medical care and social services. Participants were randomly assigned 1:1 to receive (1) teen-tot services plus 5 interactive parenting and life skills modules adapted from the Nurturing and Ansell-Casey Life Skills curricula, delivered by a nurse and social worker over the infant's first 15 months or (2) teen-tot services alone. A computerized questionnaire was self-administered at intake, 12, 24, and 36 months. Outcomes included maternal self-esteem, parenting attitudes associated with child maltreatment risk, maternal depression, life skills, and repeat pregnancy over a 36-month follow-up. We used generalized linear mixed modeling and logistic regression to examine intervention effects. RESULTS: Of 152 invited, 140 (92%) participated (intervention = 72; control = 68). At 36 months, maternal self-esteem was higher in the intervention group compared with controls (P = .011), with higher scores on preparedness for mothering role (P = .011), acceptance of infant (P = .008), and expected relationship with infant (P = .029). Repeat pregnancy by 36 months was significantly lower for intervention versus control participants. CONCLUSIONS: A brief parenting and/or life skills intervention paired with medical care for teens and their children has positive effects on maternal self-esteem and repeat pregnancy over 36 months.

Predictors of soft-tissue complications and deep infection in allograft reconstruction of the proximal tibia.

BACKGROUND AND OBJECTIVES: Reconstruction of the proximal tibia after wide resection of malignant tumors in the pediatric population is very challenging. Advocates of allograft reconstruction argue as advantages bone preservation, biological reconstruction that facilitates reattachment of the extensor mechanism and other soft-tissue structures, delay of metallic prosthesis use and preservation of the distal femoral growth plate. However, complications are significant, infection being very common. METHODS: Under IRB-approved protocol, 32 patients (17 males, 15 females), 13 years old in average (2-20), who underwent 33 allograft reconstructions of the proximal tibia, were evaluated for the occurrence of soft-tissue complications and/or deep infection (infection affecting the allograft). Potential predictors of soft-tissue complications and deep infection, categorized as pre- and perioperative variables, were analyzed in relation to the risk for developing a soft-tissue complication or a deep infection. RESULTS: The prevalence of soft-tissue complications was 48% (16/33). However, we were not able to identify any significant predictors. The prevalence of deep (allograft) infection was 15% (5/33). Multivariate logistic regression determined higher BMI at the index surgical procedure and lower pre-operative WBC to be independent predictors of deep infection. For each unit of increase in BMI, the odds of deep infection increased by 40% (OR = 1.40; CI = 1.07-3.06; P < 0.05). For each one unit (1,000) of increase in the pre-operative white cell-count, the odds of deep infection decreased by 70% (OR = 0.30; 95%CI = 0.01-0.89; P < 0.05). Four of the five deep infections were in patients with soft-tissue complications, mainly wound dehiscence. However, wound dehiscence or soft-tissue complications were not predictive of deep infection. CONCLUSION: Soft-tissue complications are prevalent in allograft reconstruction of the proximal tibia. Prevention is important as these may progress to deep infection. Careful attention to nutritional (BMI) and immunological status may help in patient selection for allograft reconstruction. If allograft reconstruction is opted for, efforts should focus on optimization of these factors as they proved to be independent predictors of subsequent deep infection. J. Surg. Oncol. 2016;113:811-817. © 2016 Wiley Periodicals, Inc.