Grandmaternal pre-pregnancy body mass index and infant birthweight: a mediation analysis of maternal pre-pregnancy body mass index.

The objectives of this study were to examine the total effect of grandmaternal [G0] pre-pregnancy body mass index (BMI) on infant [G2] birthweight z-score and to quantify the mediation role of maternal [G1] pre-pregnancy BMI. Data were extracted from the Nova Scotia 3G Multigenerational Cohort. The association between G0 pre-pregnancy BMI and G2 birthweight z-score and the mediated effect by G1 pre-pregnancy BMI were estimated using g-computation with adjustment for confounders identified using a directed acyclic graph and accounting for intermediate confounding. 20822 G1-G2 dyads from 18450 G0 were included. Relative to G0 normal weight, G0 underweight decreased mean G2 birthweight z-score (-0.11, 95% confidence interval (CI) -0.20, -0.030), while G0 overweight and obesity increased mean G2 birthweight z-score (0.091 [95% CI 0.034, 0.15] and 0.22 [95% CI 0.11, 0.33]). G1 pre-pregnancy BMI partly mediated the association, with the largest effect size observed for G0 obesity (0.11, 95% CI 0.080, 0.14). Estimates of the direct effect were close to the null. In conclusion, grandmaternal pre-pregnancy BMI was associated with infant birthweight z-score. Maternal pre-pregnancy BMI partly mediated the association, suggesting that factors related to BMI may play an important role in the transmission of weight across the maternal line.

Birth by Caesarean section and otitis media in childhood: a retrospective cohort study.

The objective of the present study was to examine the association between birth by Caesarean section (CS) and otitis media (OM) in childhood. We assembled a retrospective cohort of children born between 2003 and 2007 in Nova Scotia and followed them through to 2014. The cohort was derived through a linkage of the Nova Scotia Atlee Perinatal Database with provincial administrative health data. Cox proportional hazards, negative binomial regression and logistic regression were used to examine the association between CS and OM. Among the 36,318 children, 27% were born by CS, and 78% had at least one OM episode (median 2 episodes). Children born by CS were at a slightly higher risk of OM (hazard ratio 1.06, 95% confidence interval (CI) 1.03, 1.09), had more OM episodes in the first 7 years of life (incidence rate ratio 1.04, 95% CI 1.01, 1.07), and were more likely to be above the 95th percentile for OM episodes than children born vaginally (odds ratio 1.10, 95% CI 0.99, 1.23). Our study shows that birth by CS is weakly associated with OM in childhood, but the clinical and public health impact of these findings is small.

The 3G Multigenerational Cohort of Nova Scotian women and their mothers and offspring.

BACKGROUND: The negative impact of exposures such as maternal obesity, excessive gestational weight gain, and hypertension in pregnancy on the health of the next generation has been well studied. Evidence from animal studies suggests that the effects of in utero exposures may persist into the second generation, but the epidemiological literature on the influence of pregnancy-related exposures across three generations in humans is sparse. OBJECTIVES: This cohort was established to investigate associations between antenatal and perinatal exposures and health outcomes in women and their offspring. POPULATION: The cohort includes women who were born and subsequently had their own pregnancies in the Canadian province of Nova Scotia from 1980 onward. DESIGN: Intergenerational linkage of data in the Nova Scotia Atlee Perinatal Database was used to establish a population-based dynamic retrospective cohort. METHODS: The cohort has prospectively collected information on sociodemographics, maternal health and health behaviours, pregnancy health and complications, and obstetrical and neonatal outcomes for two generations of women and their offspring. PRELIMINARY RESULTS: As of October 2018, the 3G cohort included 14 978 grandmothers (born 1939-1986), 16 766 mothers or cohort women (born 1981-2003), and 28 638 children (born 1996-2018). The cohort women were generally younger than Nova Scotian women born after 1980, and as a result, characteristics associated with pregnancy at a younger age were more frequently seen in the cohort women; sampling weights will be created to account for this design effect. The cohort will be updated annually to capture future deliveries to women who are already in the cohort and women who become eligible for inclusion when they deliver their first child. CONCLUSIONS: The 3G Multigenerational Cohort is a population-based cohort of women and their mothers and offspring, spanning a time period of 38 years, and provides the opportunity to study inter- and transgenerational associations across the maternal line.

Electronic cigarette liquid exposure induces flavor-dependent osteotoxicity and increases expression of a key bone marker, collagen type I.

Electronic cigarettes (e-cigarettes) are nicotine delivery devices advertised as a healthier alternative to conventional tobacco products, but their rapid rise in popularity outpaces research on potential health consequences. As conventional tobacco use is a risk factor for osteoporosis, this study examines whether exposure to electronic liquid (e-liquid) used in e-cigarettes affects bone-forming osteoblasts. Human MG-63 and Saos-2 osteoblast-like cells were treated for 48 hours with 0.004%-4.0% dilutions of commercially available e-liquids of various flavors with or without nicotine. Changes in cell viability and key osteoblast markers, runt-related transcription factor 2 and Col1a1, were assessed. With all e-liquids tested, cell viability decreased in a dose-dependent manner, which was least pronounced in flavorless e-liquids, most pronounced in cinnamon-flavored e-liquids and occurred independently of nicotine. Col1a1, but not runt-related transcription factor 2, mRNA expression was upregulated in response to coffee-flavored and fruit-flavored e-liquids. Cells treated with a non-cytotoxic concentration of fruit-flavored Mango Blast e-liquid with or without nicotine showed significantly increased collagen type I protein expression compared to culture medium only. We conclude that the degree of osteotoxicity is flavor-dependent and occurs independently of nicotine and that flavored e-liquids reveal collagen type I as a potential target in osteoblasts. This study elucidates potential consequences of e-cigarette use in bone.

Maternal pre-pregnancy obesity and health care utilization and costs in the offspring.

BACKGROUND/OBJECTIVE: The association between maternal pre-pregnancy obesity and adverse child health outcomes is well described, but there are few data on the relationship with offspring health service use. We examined the influence of maternal pre-pregnancy obesity on offspring health care utilization and costs over the first 18 years of life. METHODS: This was a population-based retrospective cohort study of children (n = 35,090) born between 1989 and 1993 and their mothers, who were identified using the Nova Scotia Atlee Perinatal Database and linked to provincial administrative health data from birth through 2014. The primary outcome was health care utilization as determined by the number and cost of physician visits, hospital admissions and days, and high utilizer status (>95th percentile of physician visits). The secondary outcome was health care utilization by ICD chapter. Maternal pre-pregnancy weight was categorized as normal weight, overweight, or obese. Multivariable-adjusted regression models were used to examine the association between maternal weight status and offspring health care use. RESULTS: Children of mothers with pre-pregnancy obesity had more physician visits (10%), hospital admissions (16%), and hospital days (10%) than children from mothers of normal weight over the first 18 years of life. Offspring of mothers with obesity had C$356 higher physician costs and C$1415 hospital costs over 18 years than offspring of normal weight mothers. Children of mothers with obesity were 1.74 times more likely to be a high utilizer of health care and had higher rates of physician visits and hospital stays for nervous system and sense organ disorders, respiratory disorders, and gastrointestinal disorders compared to children of normal weight mothers. CONCLUSION: Our findings suggest that maternal pre-pregnancy overweight and obesity are associated with slightly higher offspring health care utilization and costs in the first 18 years of life.

Etiology and functional validation of gastrointestinal motility dysfunction in a zebrafish model of CHARGE syndrome.

CHARGE syndrome is linked to autosomal-dominant mutations in the CHD7 gene and results in a number of physiological and structural abnormalities, including heart defects, hearing and vision loss, and gastrointestinal (GI) problems. Of these challenges, GI problems have a profound impact throughout an individual's life, resulting in increased morbidity and mortality. A homolog of CHD7 has been identified in the zebrafish, the loss of which recapitulates many of the features of the human disease. Using a morpholino chd7 knockdown model complemented by a chd7 null mutant zebrafish line, we examined GI structure, innervation, and motility in larval zebrafish. Loss of chd7 resulted in physically smaller GI tracts with normal epithelial and muscular histology, but decreased and disorganized vagal projections, particularly in the foregut. chd7 morphant larvae had significantly less ability to empty their GI tract of gavaged fluorescent beads, and this condition was only minimally improved by the prokinetic agents, domperidone and erythromycin, in keeping with mixed responses to these agents in patients with CHARGE syndrome. The conserved genetics and transparency of the zebrafish have provided new insights into the consequences of chd7 gene dysfunction on the GI system and cranial nerve patterning. These findings highlight the opportunity of the zebrafish to serve as a preclinical model for studying compounds that may improve GI motility in individuals with CHARGE syndrome.

The Contribution of the International Pain Policy Fellowship in Improving Opioid Availability in Georgia.

In the Republic of Georgia, the incidence and prevalence of cancer are increasing, signifying a growing need for palliative care and pain relief, including with controlled opioid medicines. As a signatory to the Single Convention, the Georgian government has a responsibility to ensure the adequate availability of controlled medicines for medical purposes; however, the consumption of morphine is very low, suggesting a high occurrence of unrelieved pain. In Georgia, palliative care development began in the 2000s including the adoption of a policy document in 2005, the creation of the National Palliative Care Coordinator in 2006, and important changes in Georgian legislation in 2007 and 2008, which served to lay a foundation for improving opioid availability. In 2008, a neurologist from the Sarajishvili Institute of Neurology and Neurosurgery in Tbilisi, and member of the Georgia National Association for Palliative Care, was selected to be an International Pain Policy Fellow to focus on improving opioid availability. Working with colleagues, government officials, and international experts, the Fellow contributed to several improvements to opioid availability, such as 1) positive changes to opioid prescribing legislation, 2) clarification of legislative terminology regarding dependence syndrome, 3) initiating the importation of both sustained-release and immediate-release oral morphine, and 4) improvements in the availability of sustained-release morphine. Despite these varied achievements, morphine consumption remains low in Georgia relative to the estimated amounts needed. The Fellow is continuing to study and understand the barriers that are impeding physician's prescription of opioids and patient's acceptance of them.

An alteration of the gut-liver axis drives pulmonary inflammation after intoxication and burn injury in mice.

Approximately half of all adult burn patients are intoxicated at the time of their injury and have worse clinical outcomes than those without prior alcohol exposure. This study tested the hypothesis that intoxication alters the gut-liver axis, leading to increased pulmonary inflammation mediated by burn-induced IL-6 in the liver. C57BL/6 mice were given 1.2 g/kg ethanol 30 min prior to a 15% total body surface area burn. To restore gut barrier function, the specific myosin light chain kinase inhibitor membrane-permeant inhibitor of kinase (PIK), which we have demonstrated to reduce bacterial translocation from the gut, was administered 30 min after injury. Limiting bacterial translocation with PIK attenuated hepatic damage as measured by a 47% reduction in serum alanine aminotransferase (P < 0.05), as well as a 33% reduction in hepatic IL-6 mRNA expression (P < 0.05), compared with intoxicated and burn-injured mice without PIK. This mitigation of hepatic damage was associated with a 49% decline in pulmonary neutrophil infiltration (P < 0.05) and decreased alveolar wall thickening compared with matched controls. These results were reproduced by prophylactic reduction of the bacterial load in the intestines with oral antibiotics before intoxication and burn injury. Overall, these data suggest that the gut-liver axis is deranged when intoxication precedes burn injury and that limiting bacterial translocation in this setting attenuates hepatic damage and pulmonary inflammation.