Relative importance of metabolic syndrome components for developing gestational diabetes.

PURPOSE: To assess the independent and joint contribution of the individual components of metabolic syndrome, and known risk factors for gestational diabetes (GDM), on risk of GDM. METHODS: Two thousand nine hundred and fifteen women from Australia and New Zealand, who participated in The Screening for Pregnancy Endpoints Study (SCOPE), were included. Using the SCOPE clinical data set and biomarkers obtained at 14-16 weeks' gestation, a logistic regression model was fitted to the binary outcome GDM, with individual metabolic syndrome components (waist circumference, blood pressure, glucose, HDL-C, triglycerides), recruitment site, and other established factors associated with GDM. Hierarchical partitioning was used to assess the relative contribution of each variable. RESULTS: Of the 2915 women, 103 women (3.5%) developed GDM. The deviance explained by the logistic regression model containing all variables was 18.65% and the AUC was 0.809. Seventy percent of the independent effect was accounted for by metabolic syndrome components. The highest independent relative contribution to GDM was circulating triglycerides (17 ± 3%), followed by waist circumference (13 ± 3%). Glucose and maternal BMI contributed 12 ± 2% and 12 ± 3%, respectively. The remaining factors had an independent relative contribution of < 10%. CONCLUSION: Triglyceride concentrations had the highest independent relative importance for risk of GDM. Increased focus for lowering triglycerides as an important risk factor for GDM is warranted.

The BlastGen study: a randomized controlled trial of blastocyst media supplemented with granulocyte-macrophage colony-stimulating factor.

RESEARCH QUESTION: Does Embryogen®/BlastGen™ culture medium improve live birth rates compared with standard culture medium for women undergoing IVF and intracytoplasmic sperm injection (ICSI) with poor prognosis. DESIGN: Randomized clinical trial. A total of 100 couples undergoing IVF/ICSI were randomly allocated to having their inseminated oocytes incubated in either Embryogen®/BlastGen™ sequential culture media or standard Cleavage/Blastocyst sequential culture media for 5 days (ClinicalTrials.gov Identifier: NCT02305420). RESULTS: No statistically significant difference in live birth rate was found between the control group and the Embryogen®/BlastGen™ group (17 [34%] versus 11 [22%], respectively) (OR 0.55; 95% CI 0.22 to 1.32; P = 0.18). After adjustment for maternal age, body mass index and fertilization procedure, the blastulation rate reduced (40.6 ± 26.5 versus 24.6 ± 26.7; RR 0.70, CI 0.52 to 0.95; P < 0.05), and grade of the embryo transferred (OR 0.35, CI 0.16 to 0.77; P < 0.01) when Embryogen®/BlastGen™ medium was used. CONCLUSION: A significant reduction in day-5 embryo outcome parameters was found using Embryogen®/BlastGen™ compared with standard medium, and insufficient evidence of a difference in pregnancy outcomes. Taking into consideration the small samples size, study limitations and strict inclusion criteria of this single-centre study, further research is needed to determine the efficacy of Embryogen®/BlastGen™ medium in couples undergoing IVF/ICSI.

The deleterious effects of cannabis during pregnancy on neonatal outcomes.

OBJECTIVES: To evaluate whether cannabis use during pregnancy is associated with adverse neonatal outcomes that are independent of cigarette smoking. DESIGN: Prospective cohort study. SETTING: Adelaide (Australia), Auckland (New Zealand), Cork (Ireland), and Leeds, London and Manchester (United Kingdom). PARTICIPANTS: 5610 pregnant nulliparous women with low risk pregnancies recruited for the Screening for Pregnancy Endpoints (SCOPE) study, November 2004 - February 2011. At 14-16 weeks of pregnancy, women were grouped by self-reported cannabis use. MAIN OUTCOME MEASURES: Infant birthweight, head circumference, birth length, gestational age, and severe neonatal morbidity or mortality. RESULTS: 314 women (5.6%) reported using cannabis in the 3 months before or during their pregnancy; 97 (31%) stopped using it before and 157 (50%) during the first 15 weeks of pregnancy, while 60 (19%) were still using cannabis at 15 weeks. Compared with babies of mother who had never used cannabis, infants of those who still used it at 15 weeks had lower mean values for birthweight (adjusted mean difference [aMD], -127 g; 95% CI, -238 to -17 g), head circumference (aMD, -0.5 cm; 95% CI, -0.8 to -0.1 cm), birth length (aMD, -0.8 cm; 95% CI, -1.4 to -0.2 cm), and gestational age at birth (aMD, -8.1 days; 95% CI, -12.1 to -4.0 days). The differences for all outcomes except gestational age were greater for women who used cannabis more than once a week than for those who used it less frequently. CONCLUSIONS: Continuing to use cannabis during pregnancy is an independent risk factor for poorer neonatal outcomes.

Dairy-based preexercise meal does not affect gut comfort or time-trial performance in female cyclists.

Some athletes avoid dairy in the meal consumed before exercise due to fears about gastrointestinal discomfort. Regular exclusion of dairy foods may unnecessarily reduce intake of high quality proteins and calcium with possible implications for body composition and bone health. This study compared the effects of meals that included (Dairy) or excluded (Control) dairy foods on gastric comfort and subsequent cycling performance. Well-trained female cyclists (n = 32; mean ± SD; 24.3 ± 4.1 y; VO(2peak) 57.1 ± 4.9 ml/kg/min) completed two trials (randomized cross-over design) in which they consumed a meal (2 g/kg carbohydrate and 54 kJ/kg) 2 hr before a 90-min cycle session (80 min at 60% maximal aerobic power followed by a 10-min time trial; TT). The dairy meal contained 3 servings of dairy foods providing ~1350 mg calcium. Gut comfort and palatability were measured using questionnaires. Performance was measured as maximum mean power during the TT (MMP10(min)). There was no statistical or clinical evidence of an effect of meal type on MMP10(min) with a mean difference (Dairy - Control) of 4 W (95% CI [-2, 9]). There was no evidence of an association between pretrial gut comfort and meal type (p = .15) or between gut comfort delta scores and meal type postmeal (p = .31), preexercise (p = .17) or postexercise (p = .80). There was no statistical or clinical evidence of a difference in palatability between meal types. In summary, substantial amounts of dairy foods can be included in meals consumed before strenuous cycling without impairing either gut comfort or performance.

Protocol for a nested case-control study design for omics investigations in the Environmental Determinants of Islet Autoimmunity cohort.

Background: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D.Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case's onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood.Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation.KEY MESSAGESThe ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored.

The Australian Feeding Infants and Toddler Study (OzFITS 2021): Breastfeeding and Early Feeding Practices.

The Australian Feeding Infants and Toddler Study 2021 (OzFITS 2021) is a nationwide survey of Australian caregivers' infant and toddler feeding practices. Here, we describe breastfeeding rates and duration, use of breastmilk substitutes, and introduction of complementary (solid) foods, including common food allergens. Caregivers (n = 1140) were recruited by a digital marketing company and were interviewed using a structured telephone questionnaire to obtain information. Breastfeeding was initiated in 98% of infants, but the duration of exclusive breastfeeding to six months was less than 1%. Nearly 40% of children continued to receive breastmilk beyond one year, with 10% of toddlers receiving breastmilk at two years. One-quarter of infants were introduced to solid foods between 4 to 5 months, and nearly all infants had received solid foods by 7 months. New guidelines encourage the early introduction of potential food allergens to reduce the risk of allergy, and by 12 months, over 90% of children had been given eggs and peanuts. One-third of children received no breastmilk substitutes during their first year. One-third of infants first received breastmilk substitutes following birth and before discharge from the hospital. Of these infants, 30% ceased breastmilk substitute use after discharge. Our findings suggest a high rate of continued breastfeeding with 44% receiving breastmilk beyond 1 year. One approach to increase the duration of exclusive breastfeeding is to reduce breastmilk substitute use while in hospital.

Kin selection in den sharing develops under limited availability of tree hollows for a forest marsupial.

Animal social behaviour is not static with regard to environmental change. Flexibility in cooperative resource use may be an important response to resource decline, mediating the impacts of resource availability on fitness and demography. In forest ecosystems, hollow trees are key den resources for many species, but are declining worldwide owing to forestry. Altered patterns of den sharing may mediate the effects of the decline of this resource. We studied den-sharing interactions among hollow-dependent Australian mountain brushtail possums to investigate how spatial variation in hollow tree availability affects resource sharing and kin selection. Under reduced den availability, individuals used fewer dens and shared them less often. This suggests increased territoriality in the presence of resource competition. Further, there was a switch from kin avoidance to kin preference with decreasing hollow tree availability. This was driven primarily by a change in den sharing among siblings. The inclusive fitness benefits of den sharing with kin are likely to increase under resource-limiting conditions, but are potentially outweighed by the benefits of associating with non-relatives (avoidance of inbreeding or pathogen transmission) where dens are abundant. We discuss how predictions from social evolutionary theory can contribute to understanding animal responses to landscape change.

Systematic review of the use of "magnitude-based inference" in sports science and medicine.

Magnitude-based inference (MBI) is a controversial statistical method that has been used in hundreds of papers in sports science despite criticism from statisticians. To better understand how this method has been applied in practice, we systematically reviewed 232 papers that used MBI. We extracted data on study design, sample size, and choice of MBI settings and parameters. Median sample size was 10 per group (interquartile range, IQR: 8-15) for multi-group studies and 14 (IQR: 10-24) for single-group studies; few studies reported a priori sample size calculations (15%). Authors predominantly applied MBI's default settings and chose "mechanistic/non-clinical" rather than "clinical" MBI even when testing clinical interventions (only 16 studies out of 232 used clinical MBI). Using these data, we can estimate the Type I error rates for the typical MBI study. Authors frequently made dichotomous claims about effects based on the MBI criterion of a "likely" effect and sometimes based on the MBI criterion of a "possible" effect. When the sample size is n = 8 to 15 per group, these inferences have Type I error rates of 12%-22% and 22%-45%, respectively. High Type I error rates were compounded by multiple testing: Authors reported results from a median of 30 tests related to outcomes; and few studies specified a primary outcome (14%). We conclude that MBI has promoted small studies, promulgated a "black box" approach to statistics, and led to numerous papers where the conclusions are not supported by the data. Amidst debates over the role of p-values and significance testing in science, MBI also provides an important natural experiment: we find no evidence that moving researchers away from p-values or null hypothesis significance testing makes them less prone to dichotomization or over-interpretation of findings.

Microhabitat heterogeneity influences offspring sex allocation and spatial kin structure in possums.

1. Sex allocation theory predicts that where dispersal is sex biased, the fitness consequences of producing male or female offspring are mediated by resource availability and maternal competitive ability. Females in poorer condition are expected to favour dispersing offspring to minimize resource competition with kin. Environmental heterogeneity may drive spatial variation in sex allocation through resource competition-related benefits to females and territory quality benefits to dispersing or philopatric offspring. 2. Here, we demonstrate that microhabitat heterogeneity can drive extremely fine-scale spatial heterogeneity in offspring sex allocation. Female bobucks (Trichosurus cunninghami) in temperate rainforest were more likely to produce male offspring than those in surrounding Eucalyptus forest. 3. A maternal physiological effect was identified, in that females of lower body mass were more likely to produce male offspring. This finding is consistent with resource competition predictions, in that smaller females are expected to have poorer competitive ability. 4. Genetic spatial autocorrelation analysis identified males as the more dispersing sex. Furthermore, overproduction of males by mothers in the rainforest habitat was geographically concordant with reduced philopatry, as inferred from spatial genetic analysis. This provides empirical validation of dispersal-related explanations of offspring sex allocation: that production of offspring of the dispersing sex minimizes the potential for resource competition with kin. 5. Spatial variation in dispersal via sex allocation responses to environmental heterogeneity can potentially contribute to spatial patterns in population dynamics.

Inflammatory markers in human follicular fluid correlate with lipid levels and Body Mass Index.

The detrimental consequences of obesity on female fertility are well known, but the functional changes that occur in the ovary in response to elevated BMI are not clear. Obesity induces multiple components of a systemic inflammatory state that is a key pathway by which it initiates tissue dysfunction in adipose, liver and muscle; however whether obesity induces similar inflammatory changes in the ovary has not been fully investigated. This is important to understand because it is increasingly clear that obesity at conception impacts not only pregnancy rates but also influences pre-implantation embryo development. To further understand the characteristics of inflammation in the ovaries of obese women we analysed a panel of cytokines (IL6, IL10 and TNFα), adipokines (adiponectin, leptin and monocyte chemotactic factor 1 (MCP-1)) and acute phase proteins (C-Reactive Protein (CRP) and sICAM-1) in the ovarian follicular fluid obtained at oocyte aspiration from women (n = 48) who were lean, overweight or obese. We hypothesised that adipokines and pro-inflammatory cytokines would be correlated with and/or dysregulated by increasing Body Mass Index (BMI). Surprisingly however, the majority were not related to BMI but instead were positively correlated with lipid levels in follicular fluid, namely triglycerides and free fatty acids. Further, as is typical of metabolic inflammation, the inflammatory markers that were associated with intra-follicular lipids included both pro-inflammatory (CRP, IL6, TNFα) and anti-inflammatory (adiponectin, IL10) mediators. The direct consequences of an ovarian microenvironment containing high levels of lipids and inflammatory mediators are not known but could impact luteinisation, ovulation and/or oocyte developmental competence.

Within-subject haemoglobin variation in elite athletes: a longitudinal investigation of 13 887 haemoglobin concentration readings.

The Athlete Biological Passport (ABP) estimates individualized reference ranges for key blood markers, such as haemoglobin concentration ([Hb]), using predetermined population mean, between- and within-subject variances. Here, we aim to reassess previously published estimates for within-subject [Hb] variance and determine whether sex-, analyzer-, sport-, or season-specific values are required. Our reference population contains 7723 male (mean ± SD, 22.3 ± 4.6 years of age) and 6164 female (21.6 ± 4.3) athlete observations from 49 sports. [Hb] was calculated using one of three cytometers; Bayer-H3 (1997-1999, n = 4554), ADVIA-120 (1999-2010, n = 8636) and Sysmex XT-2000i (2010-2012, n = 697). The final model was a linear mixed model for [Hb] with analyzer (H3, ADVIA, Sysmex), sex (male, female), sport (power-endurance, endurance, skill, team, disabled and non-athletes), season (summer, winter), and the interaction between sex and sport as fixed effects and athlete as a random effect. The model included an exponential correlation structure to allow for within-subject autocorrelation, and allowed different within-subject variances for each sport. Within-subject [Hb] variance (g(2) /L(2) ) was significantly less for power endurance (35.09, 95% CI 33.50 to 36.76), disabled (25.82, 95% CI 21.71 to 35.28) and non-athletes (34.30, 95% CI 28.53 to 35.87) than for endurance (40.35, 95% CI 39.62 to 47.22) and team sports (38.70, 95% CI 37.68 to 39.76) athletes. No new evidence was found to justify adjusting the current within-subject [Hb] variance estimate.

Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation.

PURPOSE: The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen-deprived prostate cancer cells leads to formation of double-strand breaks (DSB). Here, we exploit this finding and investigate the extent and timing of androgen-induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR). EXPERIMENTAL DESIGN: Androgen-induced DNA damage was assessed by comet assays and γH2A.X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models. RESULTS: We document that androgen treatment of androgen-deprived prostate cancer cell lines resulted in a dose- and time-dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor and topoisomerase II beta but not on cell-cycle progression. In vitro models demonstrated a synergistic interaction between IR and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice. CONCLUSIONS: These results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy. Clin Cancer Res; 22(13); 3310-9. ©2016 AACRSee related commentary by Chua and Bristow, p. 3124.

"Magnitude-based inference": a statistical review.

PURPOSE: We consider "magnitude-based inference" and its interpretation by examining in detail its use in the problem of comparing two means. METHODS: We extract from the spreadsheets, which are provided to users of the analysis (http://www.sportsci.org/), a precise description of how "magnitude-based inference" is implemented. We compare the implemented version of the method with general descriptions of it and interpret the method in familiar statistical terms. RESULTS AND CONCLUSIONS: We show that "magnitude-based inference" is not a progressive improvement on modern statistics. The additional probabilities introduced are not directly related to the confidence interval but, rather, are interpretable either as P values for two different nonstandard tests (for different null hypotheses) or as approximate Bayesian calculations, which also lead to a type of test. We also discuss sample size calculations associated with "magnitude-based inference" and show that the substantial reduction in sample sizes claimed for the method (30% of the sample size obtained from standard frequentist calculations) is not justifiable so the sample size calculations should not be used. Rather than using "magnitude-based inference," a better solution is to be realistic about the limitations of the data and use either confidence intervals or a fully Bayesian analysis.

The effects of a calcium-rich pre-exercise meal on biomarkers of calcium homeostasis in competitive female cyclists: a randomised crossover trial.

Cycling is recognised as a sport in which there is a high incidence of poor bone health. Sweat calcium losses may contribute to this. PURPOSE: To examine whether a calcium-rich pre-exercise meal attenuates exercise-induced perturbations of bone calcium homeostasis caused by maintenance of sweat calcium losses. METHODS: Using a randomized, counterbalanced crossover design, 32 well-trained female cyclists completed two 90 min cycling trials separated by 1 day. Exercise trials were preceded 2 hours by either a calcium-rich (1352 ± 53 mg calcium) dairy based meal (CAL) or a control meal (CON; 46 ± 7 mg calcium). Blood was sampled pre-trial; pre-exercise; and immediately, 40 min, 100 min and 190 min post-exercise. Blood was analysed for ionized calcium and biomarkers of bone resorption (Cross Linked C-Telopeptide of Type I Collagen (CTX-I), Cross Linked C-Telopeptide of Type II Collagen (CTX-II), Parathyroid Hormone (PTH), and bone formation (Procollagen I N-Terminal Propeptide (PINP)) using the established enzyme-linked immunosorbent assay technique. RESULTS: PTH and CTX-I increased from pre-exercise to post-exercise in both conditions but was attenuated in CAL (p < 0.001). PTH was 1.55 [1.20, 2.01] times lower in CAL immediately post-exercise and 1.45 [1.12, 1.88] times lower at 40 min post-exercise. CTX-I was 1.40 [1.15, 1.70] times lower in CAL at immediately post-exercise, 1.30 [1.07, 1.57] times lower at 40 min post-exercise and 1.22 [1.00, 1.48] times lower at 190 min post-exercise (p < 0.05). There was no significant interaction between pre-exercise meal condition and time point for CTX-II (p = 0.732) or PINP (p = 0.819). CONCLUSION: This study showed that a calcium-rich pre-exercise breakfast meal containing ~1350 mg of calcium consumed ~90 min before a prolonged and high intensity bout of stationary cycling attenuates the exercise induced rise in markers of bone resorption--PTH and CTX-I. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614000675628.

The effects of wildfire on mortality and resources for an arboreal marsupial: resilience to fire events but susceptibility to fire regime change.

BACKGROUND: Big environmental disturbances have big ecological effects, yet these are not always what we might expect. Understanding the proximate effects of major disturbances, such as severe wildfires, on individuals, populations and habitats will be essential for understanding how predicted future increases in the frequency of such disturbances will affect ecosystems. However, researchers rarely have access to data from immediately before and after such events. Here we report on the effects of a severe and extensive forest wildfire on mortality, reproductive output and availability of key shelter resources for an arboreal marsupial. We also investigated the behavioural response of individuals to changed shelter resource availability in the post-fire environment. METHODOLOGY/PRINCIPAL FINDINGS: We fitted proximity-logging radiotransmitters to mountain brushtail possums (Trichosurus cunninghami) before, during and after the 2009 wildfires in Victoria, Australia. Surprisingly, we detected no mortality associated with the fire, and despite a significant post-fire decrease in the proportion of females carrying pouch young in the burnt area, there was no short-term post-fire population decline. The major consequence of this fire for mountain brushtail possums was the loss of over 80% of hollow-bearing trees. The types of trees preferred as shelter sites (highly decayed dead standing trees) were those most likely to collapse after fire. Individuals adapted to resource decline by being more flexible in resource selection after the fire, but not by increased resource sharing. CONCLUSIONS/SIGNIFICANCE: Despite short-term demographic resilience and behavioural adaptation following this fire, the major loss of decayed hollow trees suggests the increased frequency of stand-replacing wildfires predicted under climate change will pose major challenges for shelter resource availability for hollow-dependent fauna. Hollow-bearing trees are typically biological legacies of previous forest generations in post-fire regrowth forests but will cease to be recruited to future regrowth forests if the interval between severe fires becomes too rapid for hollow formation.