Association of Prenatal Exposure to Maternal Drinking and Smoking With the Risk of Stillbirth.

Importance: Prenatal smoking is a known modifiable risk factor for stillbirth; however, the contribution of prenatal drinking or the combination of smoking and drinking is uncertain. Objective: To examine whether prenatal exposure to alcohol and tobacco cigarettes is associated with the risk of stillbirth. Design, Setting, and Participants: The Safe Passage Study was a longitudinal, prospective cohort study with data collection conducted between August 1, 2007, and January 31, 2015. Pregnant women from Cape Town, South Africa, and the Northern Plains region of the US were recruited and followed up throughout pregnancy. Data analysis was performed from November 1, 2018, to November 20, 2020. Exposure: Maternal consumption of alcohol and tobacco cigarettes in the prenatal period. Main Outcomes and Measures: The main outcomes were stillbirth, defined as fetal death at 20 or more weeks' gestation, and late stillbirth, defined as fetal death at 28 or more weeks' gestation. Self-reported alcohol and tobacco cigarette consumption was captured at the recruitment interview and up to 3 scheduled visits during pregnancy. Participants were followed up during pregnancy to obtain delivery outcome. Results: Of 11663 pregnancies (mean [SD] gestational age at enrollment, 18.6 [6.6] weeks) in 8506 women for whom the pregnancy outcome was known by 20 weeks' gestation or later and who did not terminate their pregnancies, there were 145 stillbirths (12.4 per 1000 pregnancies) and 82 late stillbirths (7.1 per 1000 pregnancies). A total of 59% of pregnancies were in women from South Africa, 59% were in multiracial women, 23% were in White women, 17% were in American Indian women, and 0.9% were in women of other races. A total of 8% were older than 35 years. In 51% of pregnancies, women reported no alcohol or tobacco cigarette exposure (risk of stillbirth, 4 per 1000 pregnancies). After the first trimester, 18% drank and smoked (risk of stillbirth, 15 per 1000 births), 9% drank only (risk of stillbirth, 10 per 1000 pregnancies), and 22% smoked only (risk of stillbirth, 8 per 1000 pregnancies). Compared with the reference group (pregnancies not prenatally exposed or without any exposure after the first trimester), the adjusted relative risk of late stillbirth was 2.78 (98.3% CI, 1.12-6.67) for pregnancies prenatally exposed to drinking and smoking, 2.22 (98.3% CI, 0.78-6.18) for pregnancies prenatally exposed to drinking only after the first trimester, and 1.60 (98.3% CI, 0.64-3.98) for pregnancies prenatally exposed to smoking only after the first trimester. The adjusted relative risk for all stillbirths was 1.75 (98.3% CI, 0.96-3.18) for dual exposure, 1.26 (98.3% CI, 0.58-2.74) for drinking only, and 1.27 (98.3% CI, 0.69-2.35) for smoking only compared with the reference group. Conclusions and Relevance: These results suggest that combined drinking and smoking after the first trimester of pregnancy, compared with no exposure or quitting before the end of the first trimester, may be associated with a significantly increased risk of late stillbirth.

Postbaccalaureate terminal degree and career choices of students who performed undergraduate research.

This study analyzed terminal degree and career choices of students who performed undergraduate research. In one analysis, the study compared terminal degree and career choices between a course-based undergraduate research experience (CURE) and traditional non-course-based undergraduate research experiences at one primarily undergraduate institution (PUI). Students who pursued postbaccalaureate programs chose terminal degrees at levels exceeding 75%, with no significant difference between a CURE experience and a traditional research experience. Analysis of terminal degree and career choices at four PUIs providing traditional research experiences showed a marked difference in the number of students pursuing terminal degrees. Two PUIs showed rates > 75%, whereas students at the other two PUIs pursued terminal degrees <50% of the time. The majority of students not pursuing terminal degrees chose M.S. degrees in education and healthcare. An analysis was also performed among students participating in traditional summer undergraduate research on a research-intensive university (RIU) campus with a medical school. Students were accepted from two programs, an NIH IDeA Network of Biomedical Research Excellence (INBRE) program recruiting students from the RIU and an NSF Research Experiences for Undergraduates (REU) program recruiting undergraduates from rural PUIs and minority-serving institutions, particularly tribal colleges. Analysis showed that >70% of the students who pursued postbaccalaureate programs chose terminal degrees. INBRE undergraduates displayed a marked preference for the M.D. degree (73.9% vs. 17.4%), whereas the REU students chose the Ph.D. degree (75.0% vs. 22.9%). American Indian students were also analyzed separately for career choice and showed an equal preference for the M.D. and Ph.D. degrees when pursuing postbaccalaureate education. Overall, the results provide evidence that undergraduate student research stimulates student careers in areas needed by the nation's citizen stakeholders.

Amyloid precursor protein modulates macrophage phenotype and diet-dependent weight gain.

It is well known that mutations in the gene coding for amyloid precursor protein are responsible for autosomal dominant forms of Alzheimer's disease. Proteolytic processing of the protein leads to a number of metabolites including the amyloid beta peptide. Although brain amyloid precursor protein expression and amyloid beta production are associated with the pathophysiology of Alzheimer's disease, it is clear that amyloid precursor protein is expressed in numerous cell types and tissues. Here we demonstrate that amyloid precursor protein is involved in regulating the phenotype of both adipocytes and peripheral macrophages and is required for high fat diet-dependent weight gain in mice. These data suggest that functions of this protein include modulation of the peripheral immune system and lipid metabolism. This biology may have relevance not only to the pathophysiology of Alzheimer's disease but also diet-associated obesity.

Amyloid precursor protein mediates a tyrosine kinase-dependent activation response in endothelial cells.

Amyloid precursor protein (APP) is a ubiquitously expressed type 1 integral membrane protein. It has the ability to bind numerous extracellular matrix components and propagate signaling responses via its cytoplasmic phospho-tyrosine, (682)YENPTY(687), binding motif. We recently demonstrated increased protein levels of APP, phosphorylated APP (Tyr682), and beta-amyloid (Abeta) in brain vasculature of atherosclerotic and Alzheimer's disease (AD) tissue colocalizing primarily within the endothelial layer. This study demonstrates similar APP changes in peripheral vasculature from human and mouse apoE(-/-) aorta, suggesting that APP-related changes are not restricted to brain vasculature. Therefore, primary mouse aortic endothelial cells and human umbilical vein endothelial cells were used as a model system to examine the function of APP in endothelial cells. APP multimerization with an anti-N-terminal APP antibody, 22C11, to simulate ligand binding stimulated an Src kinase family-dependent increase in protein phospho-tyrosine levels, APP phosphorylation, and Abeta secretion. Furthermore, APP multimerization stimulated increased protein levels of the proinflammatory proteins, cyclooxygenase-2 and vascular cell adhesion molecule-1 also in an Src kinase family-dependent manner. Endothelial APP was also involved in mediating monocytic cell adhesion. Collectively, these data demonstrate that endothelial APP regulates immune cell adhesion and stimulates a tyrosine kinase-dependent response driving acquisition of a reactive endothelial phenotype. These APP-mediated events may serve as therapeutic targets for intervention in progressive vascular changes common to cerebrovascular disease and AD.