Stanford Maternal and Child Health Research Institute

CONTEXT: Current evidence that breastfeeding is beneficial for infant and child health is based exclusively on observational studies. Potential sources of bias in such studies have led to doubts about the magnitude of these health benefits in industrialized countries. OBJECTIVE: To assess the effects of breastfeeding promotion on breastfeeding duration and exclusivity and gastrointestinal and respiratory infection and atopic eczema among infants. DESIGN: The Promotion of Breastfeeding Intervention Trial (PROBIT), a cluster-randomized trial conducted June 1996-December 1997 with a 1-year follow-up. SETTING: Thirty-one maternity hospitals and polyclinics in the Republic of Belarus. PARTICIPANTS: A total of 17 046 mother-infant pairs consisting of full-term singleton infants weighing at least 2500 g and their healthy mothers who intended to breastfeed, 16491 (96.7%) of which completed the entire 12 months of follow-up. INTERVENTIONS: Sites were randomly assigned to receive an experimental intervention (n = 16) modeled on the Baby-Friendly Hospital Initiative of the World Health Organization and United Nations Children's Fund, which emphasizes health care worker assistance with initiating and maintaining breastfeeding and lactation and postnatal breastfeeding support, or a control intervention (n = 15) of continuing usual infant feeding practices and policies. MAIN OUTCOME MEASURES: Duration of any breastfeeding, prevalence of predominant and exclusive breastfeeding at 3 and 6 months of life and occurrence of 1 or more episodes of gastrointestinal tract infection, 2 or more episodes of respiratory tract infection, and atopic eczema during the first 12 months of life, compared between the intervention and control groups. RESULTS: Infants from the intervention sites were significantly more likely than control infants to be breastfed to any degree at 12 months (19.7% vs 11.4%; adjusted odds ratio [OR], 0.47; 95% confidence interval [CI], 0.32-0.69), were more likely to be exclusively breastfed at 3 months (43.3% vs 6.4%; P<.001) and at 6 months (7.9% vs 0.6%; P =.01), and had a significant reduction in the risk of 1 or more gastrointestinal tract infections (9.1% vs 13.2%; adjusted OR, 0.60; 95% CI, 0.40-0.91) and of atopic eczema (3.3% vs 6.3%; adjusted OR, 0.54; 95% CI, 0.31-0.95), but no significant reduction in respiratory tract infection (intervention group, 39.2%; control group, 39.4%; adjusted OR, 0.87; 95% CI, 0.59-1.28). CONCLUSIONS: Our experimental intervention increased the duration and degree (exclusivity) of breastfeeding and decreased the risk of gastrointestinal tract infection and atopic eczema in the first year of life. These results provide a solid scientific underpinning for future interventions to promote breastfeeding.

OBJECTIVE: To assess whether exclusive and prolonged breast feeding reduces the risk of childhood asthma and allergy by age 6.5 years. DESIGN: Cluster randomised trial. SETTING: 31 Belarussian maternity hospitals and their affiliated polyclinics. PARTICIPANTS: A total of 17,046 mother-infant pairs were enrolled, of whom 13,889 (81.5%) were followed up at age 6.5 years. INTERVENTION: Breastfeeding promotion intervention modelled on the WHO/UNICEF baby friendly hospital initiative. MAIN OUTCOME MEASURES: International study of asthma and allergies in childhood (ISAAC) questionnaire and skin prick tests of five inhalant antigens. RESULTS: The experimental intervention led to a large increase in exclusive breast feeding at 3 months (44.3% v 6.4%; P<0.001) and a significantly higher prevalence of any breast feeding at all ages up to and including 12 months. The experimental group had no reduction in risks of allergic symptoms and diagnoses or positive skin prick tests. In fact, after exclusion of six sites (three experimental and three control) with suspiciously high rates of positive skin prick tests, risks were significantly increased in the experimental group for four of the five antigens. CONCLUSIONS: These results do not support a protective effect of prolonged and exclusive breast feeding on asthma or allergy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37687716 [controlled-trials.com].

Adverse pregnancy outcomes occur frequently in women with sickle cell disease (SCD) across the globe. In the United States, Black women experience disproportionately worse maternal health outcomes than all other racial groups. To better understand how social determinants of health impact SCD maternal morbidity, we used California's Department of Health Care Access and Information data (1991-2019) to estimate the cumulative incidence of pregnancy outcomes in Black women with and without SCD-adjusted for age, insurance status, and Distressed Community Index (DCI) scores. Black pregnant women with SCD were more likely to deliver at a younger age, use government insurance, and live in at-risk or distressed neighborhoods, compared to those without SCD. They also experienced higher stillbirths (26.8, 95% confidence interval [CI]: 17.5-36.1 vs. 12.4 [CI: 12.1-12.7], per 1000 births) and inpatient maternal mortality (344.5 [CI: 337.6-682.2] vs. 6.1 [CI: 2.3-8.4], per 100 000 live births). Multivariate logistic regression models showed Black pregnant women with SCD had significantly higher odds ratios (OR) for sepsis (OR 14.89, CI: 10.81, 20.52), venous thromboembolism (OR 13.60, CI: 9.16, 20.20), and postpartum hemorrhage (OR 2.25, CI 1.79-2.82), with peak onset in the second trimester, third trimester, and six weeks postpartum, respectively. Despite adjusting for sociodemographic factors, Black women with SCD still experienced significantly worse pregnancy outcomes than those without SCD. We need additional studies to determine if early introduction to reproductive health education, continuation of SCD-modifying therapies during pregnancy, and increasing access to multidisciplinary perinatal care can reduce morbidity in pregnant women with SCD.

Gene therapy is a flourishing field with the potential to revolutionize the treatment of genetic diseases. The emergence of CRISPR-Cas9 has significantly advanced targeted and efficient genome editing. Although CRISPR-Cas9 has demonstrated promising potential applications in various genetic disorders, it faces limitations in simultaneously targeting multiple genes. Novel CRISPR systems, such as Cas12 and Cas13, have been developed to overcome these challenges, enabling multiplexing and providing unique advantages. Cas13, in particular, targets mRNA instead of genomic DNA, permitting precise gene expression control and mitigating off-target effects. This review investigates the potential of Cas12 and Cas13 in ocular gene therapy applications, such as suppression of inflammation and cell death. In addition, the capabilities of Cas12 and Cas13 are explored in addressing potential targets related with disease mechanisms such as aberrant isoforms, mitochondrial genes, cis-regulatory sequences, modifier genes, and long non-coding RNAs. Anatomical accessibility and relative immune privilege of the eye provide an ideal organ system for evaluating these novel techniques' efficacy and safety. By targeting multiple genes concurrently, CRISPR-Cas12 and Cas13 systems hold promise for treating a range of ocular disorders, including glaucoma, retinal dystrophies, and age-related macular degeneration. Nonetheless, additional refinement is required to ascertain the safety and efficacy of these approaches in ocular disease treatments. Thus, the development of Cas12 and Cas13 systems marks a significant advancement in gene therapy, offering the potential to devise effective treatments for ocular disorders.

OBJECTIVES: Efforts to study potential overuse of NICU admissions and hospital variation in practice are often hindered by a lack of an appropriate data source. We examined the concordance of hospital-level NICU admission rates between birth certificate data and California Children’s Services (CCS) data to inform the utility of birth certificate data in studying hospital variation in NICU admissions. METHODS: We analyzed birth certificate data from California in 2012 and hospital-specific summary data from CCS regarding NICU admissions. NICU admission rates were calculated for both data sets while using CCS data as the gold standard. The difference between birth certificate–based and CCS-based NICU admission rates was assessed by using the Wilcoxon signed rank test, and concordance between the 2 rates was evaluated by using Lin’s concordance correlation coefficient and Kendall’s W concordance coefficient. RESULTS: Among a total of 103 hospitals that were linked between the 2 data sets, birth certificate data generally underreported NICU admission rates compared with CCS data (median = 7.72% vs 11.51%; P &amp;lt; .001). However, in a subset of 35 hospitals where the difference in NICU admission rates between the 2 data sets was small, the birth certificate–based NICU admission rate showed good concordance with the rate from CCS data (Lin’s concordance correlation coefficient = 0.91; 95% confidence interval: 0.84–0.95; Kendall’s W concordance coefficient = 0.99; P &amp;lt; .001). Hospitals with good-concordance data did not differ from other hospitals in the institutional characteristics assessed. CONCLUSIONS: For a selected subset of hospitals, birth certificate data may offer a reasonable means to investigate hospital variation in NICU admissions.

Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.

OBJECTIVE: Health care inequities are common among individuals who speak languages other than English (LOE). Within our PICU, LOE families prefer communication via in-person interpreters (IPI). Spanish-speaking patient families are our largest LOE population; therefore, we sought to increase Spanish IPI utilization for medical updates in the PICU. METHODS: A quality improvement initiative in a 36-bed PICU included: the addition of a dedicated weekday Spanish-speaking IPI, the creation of communication tools, staff education, optimized identification of LOE families, and development of a language dashboard across multiple Plan, Do, Study, Act cycles. The primary outcome was IPI utilization rates for daily medical updates. RESULTS: Spanish IPI utilization for daily weekday medical updates among 442 Spanish-speaking patient families increased from a median of 39.4% at baseline to a new centerline median of 51.9% during implementation, exhibiting 66.3% (465 of 701) utilization in the final 6 months of implementation. The greatest sustained increases in Spanish IPI utilization occurred after PICU-based IPI implementation, staff education, electronic health record optimization, and a split work week between 2 PICU-based IPIs. CONCLUSIONS: This quality improvement initiative increased Spanish IPI utilization for daily weekday medical updates in the PICU across multiple Plan, Do, Study, Act cycles. Future work will adapt these interventions to other languages and other hospital-based units.

Cancer Informatics for Cancer Centers (CI4CC) is a grassroots, nonprofit 501c3 organization intended to provide a focused national forum for engagement of senior cancer informatics leaders, primarily aimed at academic cancer centers anywhere in the world but with a special emphasis on the 70 National Cancer Institute-funded cancer centers. This consortium has regularly held topic-focused biannual face-to-face symposiums. These meetings are a place to review cancer informatics and data science priorities and initiatives, providing a forum for discussion of the strategic and pragmatic issues that we faced at our respective institutions and cancer centers. Here, we provide meeting highlights from the latest CI4CC Symposium, which was delayed from its original April 2020 schedule because of the COVID-19 pandemic and held virtually over three days (September 24, October 1, and October 8) in the fall of 2020. In addition to the content presented, we found that holding this event virtually once a week for 6 hours was a great way to keep the kind of deep engagement that a face-to-face meeting engenders. This is the second such publication of CI4CC Symposium highlights, the first covering the meeting that took place in Napa, California, from October 14-16, 2019. We conclude with some thoughts about using data science to learn from every child with cancer, focusing on emerging activities of the National Cancer Institute's Childhood Cancer Data Initiative.

CASE: Julia is a 13-year-old White adolescent girl who was referred for psychological counseling given concerns related to mood, nonadherence, and adjustment secondary to her new diagnosis of type 1 diabetes. The family lives in a rural town located several hours from the academic medical center where she was diagnosed. After several months on a waitlist, the family was contacted to schedule a telehealth appointment with a predoctoral psychology trainee. When the scheduler informed the mother that her daughter would be scheduled with Ms. Huang, the mother abruptly stopped the conversation stating, "I do not want to waste everyone's time" and initially declined the appointment offered. When the scheduler asked about her hesitance, the mother disclosed previous interactions with doctors at the hospital who were "not born in the United States" that she felt were "textbook" (e.g., smiling even when discussing a new chronic medical condition) and "hard to understand" (i.e., because of different dialect/accent). The mother shared that she found these experiences to be stressful and felt the interactions had negatively affected Julia's care. When informed about the length of the waitlist for another clinician, the mother agreed to initiate services with the trainee.The supervising psychologist shared the mother's concerns and comments with Ms. Huang. After discussion, Ms. Huang agreed to provide intervention services, "as long as the family was willing." During the initial telehealth sessions, Ms. Huang primarily focused on building rapport and strengthening the therapeutic alliance with the family. During this time, Julia's mother was reluctant to incorporate suggested parent management strategies at home. Julia also made minimal improvement in her medical management (i.e., A1c levels remained high), had difficulty using behavioral coping strategies, and experienced ongoing mood symptoms (i.e., significant irritability, sleep difficulties, and depressive symptoms). Ms. Huang began to wonder whether the family's resistance and inability to implement recommendations were in some part because of the family's initial concerns and reluctance to engage in therapy with her as a clinician.Should Ms. Huang address the previously identified concerns with the patient and her family? What should be considered when determining how to approach this situation to ensure provision of both the best care for this patient and support for this trainee?

Abstract Background: Neonatal sepsis (NS), a life-threatening condition, is characterized by organ dysfunction and is the most common cause of neonatal death. However, the pathogenesis of NS is unclear and the clinical inflammatory markers currently used are not ideal for diagnosis of NS. Thus, exploring the link between immune responses in NS pathogenesis, elucidating the molecular mechanisms involved, and identifying potential therapeutic targets is of great significance in clinical practice. Herein, we study aimed to explore immune-related genes in NS and identify potential diagnostic biomarkers. Datasets for patients with NS and healthy controls were downloaded from the GEO database; GSE69686 and GSE25504 were used as the analysis and validation datasets, respectively. Differentially expressed genes (DEGs) were identified and Gene set enrichment analysis (GSEA) was performed to determine their biological functions. Composition of immune cells was determined and immune-related genes (IRGs) between the two clusters were identified and their metabolic pathways were determined. Key genes with correlation coefficient &gt; 0.5 and p &lt; 0.05 were selected as screening biomarkers. Logistic regression models were constructed based on the selected biomarkers, and the diagnostic models were validated. Results: Fifty-two DEGs were identified, and GSEA indicated involvement in acute inflammatory response, bacterial detection, and regulation of macrophage activation. Most infiltrating immune cells, including activated CD8+ T cells, were significantly different in patients with NS compared to the healthy controls. Fifty-four IRGs were identified, and GSEA indicated involvement in immune response and macrophage activation and regulation of T cell activation. Diagnostic models of DEGs containing five genes ( PROS1, TDRD9, RETN, LOC728401, and METTL7B ) and IRG with one gene ( NSUN7 ) constructed using LASSO algorithm were validated using the GPL6947 and GPL13667 subset datasets, respectively. The IRG model outperformed the DEG model. Additionally, statistical analysis suggested that risk scores may be related to gestational age and birth weight, regardless of sex. Conclusions: We identified six IRGs as potential diagnostic biomarkers for NS and developed diagnostic models for NS. Our findings provide a new perspective for future research on NS pathogenesis.

Abstract Context Despite high mortality rates from both communicable and non-communicable diseases, bereavement studies are under-researched in African countries. The 9-cell bereavement tool was designed to assist individuals to reflect on their feelings in bereavement, and identify resources in families and communities to manage bereavement. This study aimed to determine the feasibility of implementing the 9-cell bereavement tool and recruitment to experimental evaluation. Methods: A feasibility cluster randomized trial with embedded qualitative interviews was conducted in two comparable neighborhoods in Chitungwiza, Zimbabwe. Community leaders identified potential community lay bereavement supporters (interventionists). Each recruited 2-3 recently bereaved community members (trial participants). Following baseline data collection, the communities were randomly allocated to intervention or wait-list control. Self-administered questionnaires were completed at T0 (month 0), T1(3 months) and T2 (6 months). Grief, mental health and social support were assessed. Focus group discussions with selected interventionists described training impact and intervention processes. Quantitative and qualitative analysis were performed. Results Objectives were achieved as follows(i) feasibility of recruitment and retention (ii) feasibility of implementing the intervention (iii) determining contamination(iv) completeness of data(v) participants’ views on intervention and mechanisms(vi) estimating potential effect size (vii) determining whether full trial warranted. In line with the aim of the study, the processes of the randomized cluster trial were possible. We successfully conducted the randomized control trial of the 9-cell bereavement tool and successfully recruited study participants. In addition, the 9-cell intervention allowed interventionists to share and learn from their grieving process. All of the above was conducted within the intended timeframe of 3 weeks, with an over recruitment of 112% of interventionists and 43% more trial participants. This means we were able to recruit at least 75% of the suggested sample size; and to retain at least 75% of the trial participants for the total duration of the study. Conclusion The processes of the randomized controlled trial were possible. The 9-cell bereavement intervention was delivered and process data assessed. The study was funded through the BuildCARE fund from the Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation Protocol Registration: http://www.isrctn.com/ISRCTN16484746.Protocol Publication: https://pilotfeasibilitystudies.biomedcentral.com/articles/10.1186/s40814-019-0450-5