Building strong health and career trajectories through translational research.

Translational research (TR) is the movement of fundamental scientific discoveries into healthcare settings and population health policy, and parallels the goals of DOHaD research. Unfortunately, there is little guidance on how to become a translational researcher. To understand the opinions of DOHaD trainees towards TR, we conducted a workshop at the DOHaD World Congress 2022. We found that trainees were enthusiastic for their work to have translational impact, and that they feel that holistic, multidisciplinary solutions may lead to more generalisable research. However, there lacks support for TR career pathways, which may stall the execution of the long-term vision of the DOHaD agenda. We put forward recommendations for trainees to clarify their purpose in pursuing TR and for seeking relevant people and patronages to support their training paths. For mentors, training institutions, and scientific societies, we recommend developing TR-specific programmes, and implementing training opportunities, networking events, and funding to support these endeavours.

Maternal Underweight and Obesity Are Associated with Placental Pathologies in Human Pregnancy.

Maternal underweight and obesity are prevalent conditions, associated with chronic, low-grade inflammation, poor fetal development, and long-term adverse outcomes for the child. The placenta senses and adapts to the pregnancy environment in an effort to support optimal fetal development. However, the mechanisms driving these adaptations, and the resulting placental phenotypes, are poorly understood. We hypothesised that maternal underweight and obesity would be associated with increased prevalence of placental pathologies in term and preterm pregnancies. Data from 12,154 pregnancies were obtained from the Collaborative Perinatal Project, a prospective cohort study conducted from 1959 to 1974. Macro- and microscopic placental pathologies were analysed across maternal prepregnancy body mass index (BMI) to assess differences in the presence of pathologies among underweight, overweight, and obese BMI groups compared to normal weight reference BMI at term and preterm. Placental pathologies were also assessed across fetal sex. Pregnancies complicated by maternal obesity had placentae with increased fetal inflammation at preterm, and increased inflammation of maternal gestational tissues at term. In term pregnancies, increasing maternal BMI associated with increased maternal vascular malperfusion (MVM), odds of an appropriately mature placenta for gestational age, and placental weight, and decreased placental efficiency. Male placentae, independent of maternal BMI, had increased inflammation, MVM, and placental efficiency than female placentae, particularly at term. Maternal underweight and obesity are not inert conditions for the placenta, and the histomorphological changes driven by suboptimal maternal BMI may serve as indicators of adversities experienced in utero and potential predictors of future health trajectories.

A Quality Improvement Project on Pain Management at a Tertiary Pediatric Hospital.

To assess and improve pain management practices for hospitalized children in an urban tertiary pediatric teaching hospital. METHODS: Health Quality Ontario Quality Improvement (QI) framework informed this study. A pre (T1) - post (T2) intervention assessment included chart reviews and children/caregiver surveys to ascertain pain management practices. Information on self-reported pain intensity, painful procedures, pain treatment and satisfaction were obtained from children/caregivers. Documented pain assessment, pain scores, and pharmacological/non-pharmacological pain treatments were collected by chart review. T1 data was fed back to pediatric units to inform their decisions and pain management targets. RESULTS: At T1, 51 (58% of eligible participants) children/caregivers participated. At T2, 86 (97%) chart reviews and 51 (54%) children/caregivers surveys were completed. Most children/caregivers at T1 (78%) and T2 (80%) reported moderate to severe pain during their hospitalization. A mean of 2.6 painful procedures were documented in the previous 24 h, with the most common being needle-related procedures at both T1 and T2. Pain management strategies were infrequently used during needle-related procedures at both time points. CONCLUSION: No improvements in pain management as measured by the T1 and T2 data occurred. Findings informed further pain management initiatives in the participating hospital.

Preterm Birth Associates With Increased Placental Expression of MDR Transporters Irrespective of Prepregnancy BMI.

CONTEXT: Preterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition; however, few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected proinflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype. OBJECTIVE: To determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and proinflammatory cytokine levels are altered by PTB and maternal BMI. METHODS: A cross-sectional study was conducted to assess the effect of PTB (with/without chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin (IL)-6 and -8 expression in 60 preterm and 36 term pregnancies. RESULTS: ABCB1 expression was increased in preterm compared to term placentae (P = .04). P-gp (P = .008) and BCRP (P = .01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, P = .007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (P = .0005) and PTC associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes. CONCLUSION: PTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6. This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.

Human small intestinal organotypic culture model for drug permeation, inflammation, and toxicity assays.

The gastrointestinal tract (GIT), in particular, the small intestine, plays a significant role in food digestion, fluid and electrolyte transport, drug absorption and metabolism, and nutrient uptake. As the longest portion of the GIT, the small intestine also plays a vital role in protecting the host against pathogenic or opportunistic microbial invasion. However, establishing polarized intestinal tissue models in vitro that reflect the architecture and physiology of the gut has been a challenge for decades and the lack of translational models that predict human responses has impeded research in the drug absorption, metabolism, and drug-induced gastrointestinal toxicity space. Often, animals fail to recapitulate human physiology and do not predict human outcomes. Also, certain human pathogens are species specific and do not infect other hosts. Concerns such as variability of results, a low throughput format, and ethical considerations further complicate the use of animals for predicting the safety and efficacy xenobiotics in humans. These limitations necessitate the development of in vitro 3D human intestinal tissue models that recapitulate in vivo-like microenvironment and provide more physiologically relevant cellular responses so that they can better predict the safety and efficacy of pharmaceuticals and toxicants. Over the past decade, much progress has been made in the development of in vitro intestinal models (organoids and 3D-organotypic tissues) using either inducible pluripotent or adult stem cells. Among the models, the MatTek's intestinal tissue model (EpiIntestinal™ Ashland, MA) has been used extensively by the pharmaceutical industry to study drug permeation, metabolism, drug-induced GI toxicity, pathogen infections, inflammation, wound healing, and as a predictive model for a clinical adverse outcome (diarrhea) to pharmaceutical drugs. In this paper, our review will focus on the potential of in vitro small intestinal tissues as preclinical research tool and as alternative to the use of animals.