Abstract: BACKGROUND: As the number of deaths among children younger than 5 years of age continues to decline globally through programs to address the health of older infants, neonatal mortality is becoming an increasingly large proportion of under-5 deaths. Lack of access to safe delivery care, emergency obstetric care and postnatal care continue to be challenges for reducing neonatal mortality. This article reviews the available evidence regarding the effectiveness of community-based primary health care (CBPHC) and common components of programs aiming to improve health during the first 28 days of life. METHODS: A database comprising evidence of the effectiveness of projects, programs and field research studies (referred to collectively as projects) in improving maternal, neonatal and child health through CBPHC has been assembled and described elsewhere in this series. From this larger database (N = 548), a subset was created from assessments specifically relating to newborn health (N = 93). Assessments were excluded if the primary project beneficiaries were more than 28 days of age, or if the assessment did not identify one of the following outcomes related to neonatal health: changes in knowledge about newborn illness, care seeking for newborn illness, utilization of postnatal care, nutritional status of neonates, neonatal morbidity, or neonatal mortality. Descriptive analyses were conducted based on study type and outcome variables. An equity assessment was also conducted on the articles included in the neonatal subset. RESULTS: There is strong evidence that CBPHC can be effective in improving neonatal health, and we present information about the common characteristics shared by effective programs. For projects that reported on health outcomes, twice as many reported an improvement in neonatal health as did those that reported no effect; only one study demonstrated a negative effect. Of those with the strongest experimental study design, almost three-quarters reported beneficial neonatal health outcomes. Many of the neonatal projects assessed in our database utilized community health workers (CHWs), home visits, and participatory women's groups. Several of the interventions used in these projects focused on health education (recognition of danger signs), and promotion of and support for exclusive breastfeeding (sometimes, but not always, including early breastfeeding). Almost all of the assessments that included a measurable equity component showed that CBPHC produced neonatal health benefits that favored the poorest segment of the project population. However, the studies were quite biased in geographic scope, with more than half conducted in South Asia, and many were pilot studies, rather than projects at scale. CONCLUSIONS: CBPHC can be effectively employed to improve neonatal health in high-mortality, resource-constrained settings. CBPHC is especially important for education and support for pregnant and postpartum mothers and for establishing community-facility linkages to facilitate referrals for obstetrical emergencies; however, the latter will only produce better health outcomes if facilities offer timely, high-quality care. Further research on this topic is needed in Africa and Latin America, as well as in urban and peri-urban areas. Additionally, more assessments are needed of integrated packages of neonatal interventions and of programs at scale.

Abstract: BACKGROUND: As the number of deaths among children younger than 5 years of age continues to decline globally through programs to address the health of older infants, neonatal mortality is becoming an increasingly large proportion of under-5 deaths. Lack of access to safe delivery care, emergency obstetric care and postnatal care continue to be challenges for reducing neonatal mortality. This article reviews the available evidence regarding the effectiveness of community-based primary health care (CBPHC) and common components of programs aiming to improve health during the first 28 days of life. METHODS: A database comprising evidence of the effectiveness of projects, programs and field research studies (referred to collectively as projects) in improving maternal, neonatal and child health through CBPHC has been assembled and described elsewhere in this series. From this larger database (N = 548), a subset was created from assessments specifically relating to newborn health (N = 93). Assessments were excluded if the primary project beneficiaries were more than 28 days of age, or if the assessment did not identify one of the following outcomes related to neonatal health: changes in knowledge about newborn illness, care seeking for newborn illness, utilization of postnatal care, nutritional status of neonates, neonatal morbidity, or neonatal mortality. Descriptive analyses were conducted based on study type and outcome variables. An equity assessment was also conducted on the articles included in the neonatal subset. RESULTS: There is strong evidence that CBPHC can be effective in improving neonatal health, and we present information about the common characteristics shared by effective programs. For projects that reported on health outcomes, twice as many reported an improvement in neonatal health as did those that reported no effect; only one study demonstrated a negative effect. Of those with the strongest experimental study design, almost three-quarters reported beneficial neonatal health outcomes. Many of the neonatal projects assessed in our database utilized community health workers (CHWs), home visits, and participatory women's groups. Several of the interventions used in these projects focused on health education (recognition of danger signs), and promotion of and support for exclusive breastfeeding (sometimes, but not always, including early breastfeeding). Almost all of the assessments that included a measurable equity component showed that CBPHC produced neonatal health benefits that favored the poorest segment of the project population. However, the studies were quite biased in geographic scope, with more than half conducted in South Asia, and many were pilot studies, rather than projects at scale. CONCLUSIONS: CBPHC can be effectively employed to improve neonatal health in high-mortality, resource-constrained settings. CBPHC is especially important for education and support for pregnant and postpartum mothers and for establishing community-facility linkages to facilitate referrals for obstetrical emergencies; however, the latter will only produce better health outcomes if facilities offer timely, high-quality care. Further research on this topic is needed in Africa and Latin America, as well as in urban and peri-urban areas. Additionally, more assessments are needed of integrated packages of neonatal interventions and of programs at scale.

Abstract: Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17 92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM. Consistently, CDK4/6 inhibition with palbociclib preferentially inhibited cell proliferation in vitro in a majority of proneural GSCs versus those of other subtypes. Palbociclib treatment significantly prolonged survival of mice with established intracranial xenografts of a proneural GSC line. We show that most of these sensitive PN GSCs expressed higher levels of CDK6 and had intact Rb1, while two GSC lines with CDK4 overexpression and null Rb1 were highly resistant to palbociclib. Importantly, palbociclib treatment of proneural GSCs upregulated mesenchymal-associated markers and downregulated proneural-associated markers, suggesting that CDK4/6 inhibition induced proneural-mesenchymal transition and underscoring the enhanced role of the E2F cell cycle pathway in the proneural subtype. Lastly, the combination of palbociclib and N,N-diethylaminobenzaldehyde, an inhibitor of the mesenchymal driver ALDH1A3, showed strong synergistic inhibitory effects against proneural GSC proliferation. Taken together, our results reveal that proneural GBM has increased vulnerability to CDK4/6 inhibition, and the proneural subtype undergoes dynamic reprogramming upon palbociclib treatment-suggesting the need for a combination therapeutic strategy.