A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: The ACT cluster-randomised trial

Background Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries. Methods In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096. Findings The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47 394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50 743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0·0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0·96, 95% CI 0·87-1·06, p=0·65) and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1·67, 1·33-2·09, p<0·0001). Among the whole population, 28-day neonatal mortality was 27·4 per 1000 livebirths for the intervention group and 23·9 per 1000 livebirths for the control group (RR 1·12, 1·02-1·22, p=0·0127) and suspected maternal infection was reported in 1207 (3%) of 48 219 women in the intervention group and 867 (2%) of 51 523 in the control group (OR 1·45, 1·33-1·58, p<0·0001). Interpretation Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development.Fil: Althabe, Fernando. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Belizan, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: McClure, Elizabeth M.. Rti International;Fil: Hemingway Foday, Jennifer. Rti International;Fil: Berrueta, Amanda Mabel. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Mazzoni, Agustina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Ciganda, Alvaro. Unicem; Uruguay. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Goudar, Shivaprasad S.. Jawaharlal Nehru Medical College Belgaum; IndiaFil: Kodkany, Bhalachandra S.. Jawaharlal Nehru Medical College Belgaum; IndiaFil: Mahantshetti, Niranjana S.. Jawaharlal Nehru Medical College Belgaum; IndiaFil: Dhaded, Sangappa M.. Jawaharlal Nehru Medical College Belgaum; IndiaFil: Katageri, Geetanjali M.. S. Nijalingappa Medical College; IndiaFil: Metgud, Mrityunjay C.. Jawaharlal Nehru Medical College Belgaum; IndiaFil: Joshi, Anjali M.. Jawaharlal Nehru Medical College Belgaum; IndiaFil: Bellad, Mrutyunjaya B.. Jawaharlal Nehru Medical College Belgaum; IndiaFil: Honnungar, Narayan V.. Jawaharlal Nehru Medical College Belgaum; IndiaFil: Derman, Richard J.. Christiana Health Care Services; Estados UnidosFil: Saleem, Sarah. The Aga Khan University; PakistánFil: Pasha, Omrana. The Aga Khan University; PakistánFil: Ali, Sumera. The Aga Khan University; PakistánFil: Hasnain, Farid. The Aga Khan University; PakistánFil: Goldenberg, Robert L. Columbia University; Estados UnidosFil: Esamai, Fabian. Moi University; KeniaFil: Nyongesa, Paul. Moi University; KeniaFil: Ayunga, Silas. University of Alabama at Birmingahm; Estados UnidosFil: Liechty, Edward A. Indiana University; Estados UnidosFil: Garces, Ana L. Francisco Marroquin University; Guatemala. Fundacion Para la Alimentacion y Nutricion de Centro America y Panama; GuatemalaFil: Figueroa, Lester. Fundacion Para la Alimentacion y Nutricion de Centro America y Panama; GuatemalaFil: Hambidge, K Michael. State University of Colorado - Fort Collins; Estados UnidosFil: Krebs, Nancy F. State University of Colorado - Fort Collins; Estados UnidosFil: Patel, Archana. Government Medical College Nagpur; India. Lata Medical Research Foundation; IndiaFil: Bhandarkar, Anjali. Lata Medical Research Foundation; IndiaFil: Waikar, Manjushri. Lata Medical Research Foundation; IndiaFil: Hibberd, Patricia L. Massachusetts General Hospital; Estados UnidosFil: Chomba, Elwyn. University Teaching Hospital Lusaka; ZambiaFil: Carlo, Waldemar A. University of Alabama at Birmingahm; Estados UnidosFil: Mwiche, Angel. University Teaching Hospital Lusaka; ZambiaFil: Chiwila, Melody. Centre For Infectious Disease Research; ZambiaFil: Manasyan, Albert. University of Alabama at Birmingahm; Estados UnidosFil: Pineda, Sayury. Fundacion Para la Alimentacion y Nutricion de Centro America y Panama; GuatemalaFil: Meleth, Sreelatha. Rti International; Estados UnidosFil: Thorsten, Vanessa. Rti International; Estados UnidosFil: Stolka, Kristen. Rti International; Estados UnidosFil: Wallace, Dennis D. Rti International; Estados UnidosFil: Koso-Thomas, Marion. National Instituto Of Child Health & Human Developm.; Estados UnidosFil: Jobe, Alan H. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Buekens, Pierre M. Tulane University School Of Public Health And Tropical Medicine; Estados Unido

A noncoding antisense RNA in tie-1 locus regulates tie-1 function in vivo

Recently, messenger RNAs in eukaryotes have shown to associate with antisense (AS) transcript partners that are often referred to as long noncoding RNAs (lncRNAs) whose function is largely unknown. Here, we have identified a natural AS transcript for tyrosine kinase containing immunoglobulin and epidermal growth factor homology domain-1 (tie-1), tie-1AS lncRNA in zebrafish, mouse, and humans. In embryonic zebrafish, tie-1AS lncRNA transcript is expressed temporally and spatially in vivo with its native target, the tie-1 coding transcript and in additional locations (ear and brain). The tie-1AS lncRNA selectively binds tie-1 mRNA in vivo and regulates tie-1 transcript levels, resulting in specific defects in endothelial cell contact junctions in vivo and in vitro. The ratio of tie-1 versus tie-1AS lncRNA is altered in human vascular anomaly samples. These results directly implicate noncoding RNA-mediated transcriptional regulation of gene expression as a fundamental control mechanism for physiologic processes, such as vascular development