Offspring conceived through ART have normal thyroid function in adolescence and as young adults.

STUDY QUESTION: Are there differences in thyroid function between adolescents and young adults conceived with and without ART? SUMMARY ANSWER: This study demonstrated no evidence of clinically relevant differences in thyroid function between adolescents and young adults conceived with and without ART. WHAT IS KNOWN ALREADY: Studies to date have reported an increase in subclinical hypothyroidism in offspring conceived after ART. It has been suggested that the increase in maternal estrogen (E2) after fresh embryo transfers could affect thyroid function of the offspring. Suboptimal thyroid function at a young age can cause irreversible damage to the central nervous system, which makes early detection and correct treatment essential. STUDY DESIGN, SIZE, DURATION: The Growing Up Healthy Study (GUHS) is a prospective cohort study, which aimed to recruit all adolescents born after conception with ART between 1991 and 2001 in the study area. The included participants (n = 303, aged 13-20 years) completed various health assessments. Depending on the age at enrolment, participants completed thyroid assessments at the 14- or 20-year follow-up. The outcomes of these replicated thyroid assessments were compared to those of participants conceived without ART from the Raine Study Generation 2 (Gen2). The Gen2 participants (n = 2868) were born between 1989 and 1992 and have been recognized to be representative of the local population. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thyroid function assessments were compared between n = 134 GUHS and n = 1359 Gen2 adolescents at age 14 years and between n = 47 GUHS and n = 914 Gen2 young adults at age 20 years. The following mean thyroid hormone concentrations were compared between the cohorts: thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) and thyroid peroxidase antibodies (TPOAb). The prevalence of the following thyroid hormone profiles, based on individual thyroid hormone concentrations, was compared: euthyroidism, subclinical and overt hypo- and hyperthyroidism and thyroid autoimmunity. Outcomes were compared between the cohorts, and univariately between fresh embryo transfers (ET) and frozen ET (FET) within the GUHS. The correlation between maternal peak E2 concentrations (pE2) and fT4 was assessed within the GUHS. MAIN RESULTS AND THE ROLE OF CHANCE: All mean thyroid function outcomes fell within the normal range. At both ages, we report no differences in TSH concentrations. At age 14 years, lower fT3 concentrations (4.80 versus 5.35 pmol/L, P < 0.001) and higher fT4 concentrations (12.76 versus 12.19 pmol/L, P < 0.001) were detected in the GUHS adolescents compared to Gen2 adolescents. At age 20 years, higher fT3 and fT4 concentrations were reported in GUHS adolescents (4.91 versus 4.63 pmol/L, P = 0.012; 13.43 versus 12.45 pmol/L, P < 0.001, respectively) compared to Gen2 participants. No differences in the prevalence of subclinical and overt hypo- and hyperthyroidism or thyroid autoimmunity were demonstrated between the cohorts at age 14 and 20 years. Thyroid function did not differ between ET and FET, and no correlation between pE2 and fT4 was reported. LIMITATIONS, REASONS FOR CAUTION: The observational nature of the study limits the ability to prove causation. Furthermore, the comparison of ET and FET offspring at age 20 years may be lacking power. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI) owing to the low number of ICSI cycles at the time of study. As ART laboratory and clinic data were collected contemporaneously with the time of treatment, no other data pertaining to the ART cycles were sought retrospectively; hence, some factors could not be accounted for. WIDER IMPLICATIONS OF THE FINDINGS: This study does not support previous findings of clinically relevant differences in thyroid function when comparing a cohort of adolescents conceived after ART to counterparts conceived without ART. The minor differences detected in fT3 and fT4 were considered not biologically relevant. Although these findings appear reassuring, they warrant reinvestigation in adulthood. STUDY FUNDING/COMPETING INTERESTS: This project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director and a shareholder of PIVET Medical Centre, Perth, Western Australia. TRIAL REGISTRATION NUMBER: N/A.

Mental health and behavioural problems in adolescents conceived after ART.

STUDY QUESTION: Does mental health and behaviour differ between those conceived with and those conceived without ART? SUMMARY ANSWER: Our study observed less externalizing behaviour (delinquent/aggressive), and more parent-reported internalizing behaviour, as well as more (clinical) depression at age 14 years, in adolescents conceived after ART compared to their non-ART counterparts. WHAT IS KNOWN ALREADY: Health outcomes of ART-conceived offspring may differ from those conceived without ART, and previous studies have reported differences in behaviour and mental health, particularly in childhood. STUDY DESIGN, SIZE, DURATION: The Growing Up Healthy Study (GUHS) is a prospective cohort study, investigating the long-term health of offspring conceived after ART (aged 14, 17 and 20 years), in the two operational fertility clinics in Western Australia 1991-2001 (n = 303). Their long-term health outcomes were compared to those of offspring conceived without ART from the Raine Study Generation 2 (Gen2) born 1989-1991 (n = 2868). Both cohorts are representative of the local adolescent population. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mental health parameters and behaviour were assessed at ages 14 and 17 years, through the parent completed 'Child Behaviour Checklist' (CBCL; ART versus non-ART: age 14 years: N = 150 versus N = 1781, age 17 years: N = 160 versus N = 1351), and the adolescent completed equivalent 'Youth Self-Report' (YSR; age 14 years: by N = 151 versus N = 1557, age 17 years: N = 161 and N = 1232). Both tools generate a T-score (standardized for age and sex) for internalizing (withdrawn, somatic complaints, anxious/depressed), externalizing (delinquent/aggressive behaviour) and total behaviour. Adolescents also completed the 'Beck Depression Inventory for Youth' (BDI-Y; age 14 years: N = 151 versus N = 1563, age 17 years: N = 161 versus N = 1219). Higher scores indicate poorer mental health and behaviour on all the above tools. Parent-reported doctor-diagnosed conditions (anxiety, behavioural problems, attention problems and depression) were also univariately compared between the cohorts. In addition, univariate comparisons were conducted between the GUHS adolescents and Gen2 adolescents born to subfertile parents (time to pregnancy >12 months), as well as between offspring born to subfertile versus fertile parents within the Gen2 cohort. A subgroup analysis excluding offspring born preterm (<37 weeks' gestation) or at low birthweight (<2500 g) was also performed. Generalized estimating equations that account for correlated familial data were adjusted for the following covariates: non-singleton, primiparity, primary caregiver smoking, family financial problems, socio-economic status and both maternal and paternal ages at conception. MAIN RESULTS AND THE ROLE OF CHANCE: At both 14 and 17 years of age, ART versus non-ART-conceived adolescents reported lower mean T-scores for externalizing problems (age 14 years: 49 versus 51, P = 0.045, age 17 years: 49 versus 52, P < 0.001). A similar effect was reported by parents, although not significant (age 14 years: P = 0.293, age 17 years: P = 0.148). Fewer ART-conceived adolescents reported a T-score above the clinical cut-off for externalizing behaviour (≥60; age 14 years: 7.3% versus 16.3%, P = 0.003, age 17 years: 8.1% versus 19.7%, P < 0.001). At both ages, no differences in internalizing behaviour were reported by adolescents (age 14 years: P = 0.218, age 17 years: P = 0.717); however, higher mean scores were reported by parents of the ART-conceived adolescents than by parents of the non-ART conceived adolescents (age 14 years: 51 versus 48, P = 0.027, age 17 years: 50 versus 46, P < 0.001). No differences in internalizing behaviour above the clinical cut-off (T-score ≥ 60) were observed. At age 17 years, parents who conceived through ART reported higher total behaviour scores than those parents who conceived without ART (48 versus 45, P = 0.002). At age 14 years, ART versus non-ART-conceived adolescents reported significantly higher mean scores on the BDI-Y (9 versus 6, P = 0.005); a higher percentage of adolescents with a score indicating clinical depression (≥17; 12.6% versus 8.5%, aOR 2.37 (1.18-4.77), P = 0.016), as well as more moderate/severe depression (≥21; 9.3% versus 4.0%, P = 0.009). At age 17 years, no differences were reported on the BDI-Y. There was also a higher percentage of parent-reported doctor-diagnosed anxiety in the ART cohort (age 14 years: 8.6% versus 3.5%, P = 0.002, at age 17 years: 12.0% versus 4.5%, P < 0.001). Removing adolescents born preterm or at low birthweight did not alter the above results. Comparing outcomes between GUHS adolescents and Gen2 adolescents born to subfertile parents, as well as between those born to subfertile versus fertile parents within Gen2, did not alter results for CBCL and YSR outcomes. Those born to subfertile parents showed higher rates of clinical depression than those born to fertile parents at age 14 years (13.7% versus 6.9%, P = 0.035). LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study is the time difference between the GUHS and Gen2 assessments. Even though we have adjusted for covariates, additional socio-economic and lifestyle factors affecting behaviour and mental well-being could have changed. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI), owing to the low number of ICSI cycles at the time of study. Fertility sub-analyses need to be replicated in larger cohorts to increase power, potentially using siblingship designs. Lastly, selection bias may be present. WIDER IMPLICATIONS OF THE FINDINGS: The reported lower prevalence of externalizing behaviour (delinquent/aggressive), and higher prevalence of internalizing behaviour, as well as more (clinical) depression at age 14 years, in ART versus non-ART-conceived adolescents, is in line with some previous studies, mostly conducted in childhood. It is reassuring that differences in the rates of depression were not observed at age 17 years, however, these findings require replication. As the use of ART is common, and mental health disorders are increasing, knowledge about a potential association is important for parents and healthcare providers alike. STUDY FUNDING/COMPETING INTEREST(S): This project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. TRIAL REGISTRATION NUMBER: N/A.

Comparison of the cardiometabolic profiles of adolescents conceived through ART with those of a non-ART cohort.

STUDY QUESTION: Is the cardiometabolic health of adolescents conceived through ART worse than that of their counterparts conceived without ART? SUMMARY ANSWER: The majority of cardiometabolic and vascular health parameters of adolescents conceived through ART are similar or more favourable, than those of their counterparts of similar age and conceived without ART. WHAT IS KNOWN ALREADY: It has been proposed that the cardiometabolic health of offspring conceived with ART may be unfavourable compared to that of their counterparts conceived without ART. The literature pertaining to cardiometabolic health of offspring conceived after ART is contradictory, but generally suggests unfavourable cardiometabolic health parameters, such as an increase in blood pressure (BP), vascular dysfunction and adiposity, as well as unfavourable glucose and lipid profiles. With over 8 million children and adults born through ART worldwide, it is important to investigate whether these early signs of adverse cardiometabolic differences persist into adolescence and beyond. STUDY DESIGN, SIZE, DURATION: The Growing Up Healthy Study (GUHS) is a prospective cohort study that recruited 303 adolescents and young adults conceived after ART (aged 13-21 years) and born between 1991 and 2001 in Western Australia. Their health parameters, including cardiometabolic factors, were assessed and compared with counterparts from the Raine Study Generation 2 (Gen2). The 2868 Gen2 participants were born 1989-1992 and are representative of the Western Australian adolescent population. At ∼17 years of age (2013-2017), 163 GUHS participants replicated assessments previously completed by Gen2 at a similar age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cardiometabolic parameters were compared between a total of 163 GUHS and 1457 Gen2 adolescents. Separate male (GUHS n = 81, Gen2 n = 735) and female (GUHS n = 82, Gen2 n = 722) analyses were conducted. Assessments consisted of a detailed questionnaire including health, lifestyle and demographic parameters, anthropometric assessments (height, weight, BMI, waist circumference and skinfold thickness), fasting serum biochemistry, arterial stiffness and BP (assessed using applanation tonometry). Abdominal ultrasonography was used to assess the presence and severity of hepatic steatosis, and thickness of abdominal fat compartments. Non-alcoholic fatty liver disease (NAFLD) was diagnosed if there was sonographic fatty liver in the absence of significant alcohol consumption. Chi2, Fisher's exact and Mann-Whitney U tests, performed in SPSS V25, examined cohort differences and generalized estimating equations adjusted for the following covariates: singleton vs non-singleton pregnancy, birthweight (z-score), gestational age, BMI, smoking, alcohol consumption in the past 6 months and parent cardiovascular status. Arterial stiffness measures and waist circumference were additionally adjusted for height, and female analyses were additionally adjusted for use of oral contraceptives in the preceding 6 months. MAIN RESULTS AND THE ROLE OF CHANCE: In adjusted analyses, GUHS females had a lower BMI (22.1 vs 23.3 kg/m2, P = 0.014), and thinner skinfolds (triceps, subscapular, mid-abdominal; 16.9 vs 18.7 mm, P = 0.021, 13.4 vs 15.0 mm, P = 0.027, 19.7 vs 23.2 mm, P < 0.001, respectively), whereas males were not significantly different. Waist circumference was lower in GUHS adolescents (males: 78.1 vs 81.3 cm, P = 0.008, females: 76.7 vs 83.3 cm, P = 0.007). There were no significant differences between the two groups in glucose, insulin, homeostatic model assessment for insulin resistance, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), alanine aminotransferase and high-sensitivity C-reactive protein in both sexes. In females, serum triglycerides were lower in GUHS adolescents (1.0 vs 1.2 mmol/l, P = 0.029). GUHS males had higher serum HDL-C (1.1 vs 1.0 mmol/l, P = 0.004) and a lower TC/HDL-C ratio (3.2 vs 3.6, P = 0.036). There were no significant differences in the prevalence of NAFLD or steatosis severity scores between the cohorts in males and females. GUHS females had less subcutaneous adipose tissue (9.4 vs 17.9 mm, P < 0.001), whereas GUHS males had greater visceral adipose thickness (44.7 vs 36.3 mm, P < 0.001). There was no significant difference in pre-peritoneal adipose thickness. Pulse wave velocity was lower in GUHS males (5.8 vs 6.3 m/s, P < 0.001) and heart rate corrected augmentation index was lower in GUHS females (-8.4 vs -2.7%, P = 0.048). There were no significant differences in BP or heart rate in males or females between the two groups. LIMITATIONS, REASONS FOR CAUTION: Despite the substantial study size and the unique study design of the ART cohort, we were unable to differentiate between different types of ART, due to the low number of ICSI cycles (e.g. IVF vs ICSI), draw definite conclusions, or relate the outcomes to the cause of infertility. Considering the differences in time points when both cohorts were studied, external factors could have changed, which could not be accounted for. Given the observational nature of this study, causation cannot be proven. WIDER IMPLICATIONS OF THE FINDINGS: Contrary to our hypothesis and previous findings focussing mainly on childhood, this study reports mostly similar or favourable cardiometabolic markers in adolescents conceived with ART compared to those conceived without ART. The greater visceral adipose thickness, particularly present in males, requires further investigation. While these findings are generally reassuring, future well-designed and appropriately powered studies are required to definitively address the issue of cardiometabolic health in ART adults. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by NHMRC project grant number 1042269 and R.J.H. received education grant funding support from Ferring Pharmaceuticals. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. TRIAL REGISTRATION NUMBER: N/A.

DNA methylation patterns within whole blood of adolescents born from assisted reproductive technology are not different from adolescents born from natural conception.

STUDY QUESTION: Do the epigenome-wide DNA methylation profiles of adolescents born from ART differ from the epigenome of naturally conceived counterparts? SUMMARY ANSWER: No significant differences in the DNA methylation profiles of adolescents born from ART [IVF or ICSI] were observed when compared to their naturally conceived, similar aged counterparts. WHAT IS KNOWN ALREADY: Short-term and longer-term studies have investigated the general health outcomes of children born from IVF treatment, albeit without common agreement as to the cause and underlying mechanisms of these adverse health findings. Growing evidence suggests that the reported adverse health outcomes in IVF-born offspring might have underlying epigenetic mechanisms. STUDY DESIGN, SIZE, DURATION: The Growing Up Healthy Study (GUHS) is a prospective study that recruited 303 adolescents and young adults, conceived through ART, to compare various long-term health outcomes and DNA methylation profiles with similar aged counterparts from Generation 2 from the Raine Study. GUHS assessments were conducted between 2013 and 2017. The effect of ART on DNA methylation levels of 231 adolescents mean age 15.96 ± 1.59 years (52.8% male) was compared to 1188 naturally conceived counterparts, 17.25 ± 0.58 years (50.9% male) from the Raine Study. PARTICIPANTS/MATERIALS, SETTING, METHODS: DNA methylation profiles from a subset of 231 adolescents (13-19.9 years) from the GUHS, generated using the Infinium Methylation Epic Bead Chip (EPIC) array were compared to 1188 profiles from the Raine Study previously measured using the Illumina 450K array. We conducted epigenome-wide association approach (EWAS) and tested for an association between the cohorts applying Firth's bias reduced logistic regression against the outcome of ART versus naturally conceived offspring. Additionally, within the GUHS cohort, we investigated differences in methylation status in fresh versus frozen embryo transfers, cause of infertility as well as IVF versus ICSI conceived offspring. Following the EWAS analysis we investigated nominally significant probes using Gene Set Enrichment Analysis (GSEA) to identify enriched biological pathways. Finally, within GUHS we compared four estimates (Horvath, Hanuum, PhenoAge [Levine], and skin Horvath) of epigenetic age and their correlation with chronological age. MAIN RESULTS AND THE ROLE OF CHANCE: Between the two cohorts, we did not identify any DNA methylation probes that reached a Bonferroni corrected P-value < 1.24E-0.7. When comparing IVF versus ICSI conceived adolescents within the GUHS cohort, after adjustment for participant age, sex, maternal smoking, multiple births, and batch effect, three methylation probes (cg15016734, cg26744878 and cg20233073) reached a Bonferroni correction of 6.31E-08. After correcting for cell count heterogeneity, two of the aforementioned probes remained significant and an additional two probes (cg 0331628 and cg 20235051) were identified. A general trend towards hypomethylation in the ICSI offspring was observed. All four measures of epigenetic age were highly correlated with chronological age and showed no evidence of accelerated epigenetic aging within their whole blood. LIMITATIONS, REASONS FOR CAUTION: The small sample size coupled with the use of whole blood, where epigenetic differences may occur in other tissue. This was corrected by the utilized statistical method that accounts for imbalanced sample size between groups and adjusting for cell count heterogeneity. Only a small portion of the methylome was analysed and rare individual differences may be missed. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide further reassurance that the effects of the ART manipulations occurring during early embryogenesis, existing in the neonatal period are indeed of a transient nature and do not persist into adolescence. However, we have not excluded that alternative epigenetic mechanisms may be at play. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by NHMRC project Grant no. 1042269 and R.J.H. received funding support from Ferring Pharmaceuticals Pty Ltd. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from Merck Sharp & Dohme Corp.- Australia, Merck-Serono Australia Pty Ltd and Ferring Pharmaceuticals Pty Ltd. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. The remaining authors have no conflicts of interest.

Associations between maternal physical activity in early and late pregnancy and offspring birth size: remote federated individual level meta-analysis from eight cohort studies.

OBJECTIVE: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes. DESIGN: Individual level meta-analysis, which reduces heterogeneity across studies. SETTING: A consortium of eight population-based studies (seven European and one US) comprising 72 694 participants. METHODS: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self-reported LTPA at either early (8-18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta-analyses. MAIN OUTCOME MEASURES: Birth weight, large-for-gestational age (LGA), macrosomia, small-for-gestational age (SGA), % body fat, and ponderal index at birth. RESULTS: Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2  = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA. CONCLUSIONS: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA. TWEETABLE ABSTRACT: In an individual participant meta-analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.

Weight loss after laparoscopic adjustable gastric band and resolution of the metabolic syndrome and its components.

BACKGROUND: Substantial weight loss in the setting of obesity has considerable metabolic benefits. Yet some studies have shown improvements in obesity-related metabolic comorbidities with more modest weight loss. By closely monitoring patients undergoing bariatric surgery, we aimed to determine the effects of weight loss on the metabolic syndrome and its components and determine the weight loss required for their resolution. METHODS: We performed a prospective observational study of obese participants with metabolic syndrome (Adult Treatment Panel III criteria) who underwent laparoscopic adjustable gastric banding. Participants were assessed for all criteria of the metabolic syndrome monthly for the first 9 months, then 3-monthly until 24 months. RESULTS: There were 89 participants with adequate longitudinal data. Baseline body mass index was 42.4±6.2 kg m-2 with an average age was 48.2±10.7 years. There were 56 (63%) women. Resolution of the metabolic syndrome occurred in 60 of the 89 participants (67%) at 12 months and 60 of the 75 participants (80%) at 24 months. The mean weight loss when metabolic syndrome resolved was 10.9±7.7% total body weight loss (TBWL). The median weight loss at which prevalence of disease halved was 7.0% TBWL (17.5% excess weight loss (EWL)) for hypertriglyceridaemia; 11% TBWL (26.1-28% EWL) for high-density lipoprotein cholesterol and hyperglycaemia; 20% TBWL (59.5% EWL) for hypertension and 29% TBWL (73.3% EWL) for waist circumference. The odds ratio for resolution of the metabolic syndrome with 10-12.5% TBWL was 2.09 (P=0.025), with increasing probability of resolution with more substantial weight loss. CONCLUSIONS: In obese participants with metabolic syndrome, a weight loss target of 10-12.5% TBWL (25-30% EWL) is a reasonable initial goal associated with significant odds of having metabolic benefits. If minimal improvements are seen with this initial target, additional weight loss substantially increases the probability of resolution.

Engaging the public in healthcare decision-making: results from a Citizens' Jury on emergency care services.

BACKGROUND: Policies addressing ED crowding have failed to incorporate the public's perspectives; engaging the public in such policies is needed. OBJECTIVE: This study aimed at determining the public's recommendations related to alternative models of care intended to reduce crowding, optimising access to and provision of emergency care. METHODS: A Citizens' Jury was convened in Queensland, Australia, to consider priority setting and resource allocation to address ED crowding. Twenty-two jurors were recruited from the electoral roll, who were interested and available to attend the jury from 15 to 17 June 2012. Juror feedback was collected via a survey immediately following the end of the jury. RESULTS: The jury considered that all patients attending the ED should be assessed with a minority of cases diverted for assistance elsewhere. Jurors strongly supported enabling ambulance staff to treat patients in their homes without transporting them to the ED, and allowing non-medical staff to treat some patients without seeing a doctor. Jurors supported (in principle) patient choice over aspects of their treatment (when, where and type of health professional) with some support for patients paying towards treatment but unanimous opposition for patients paying to be prioritised. Most of the jurors were satisfied with their experience of the Citizens' Jury process, but some jurors perceived the time allocated for deliberations as insufficient. CONCLUSIONS: These findings suggest that the general public may be open to flexible models of emergency care. The jury provided clear recommendations for direct public input to guide health policy to tackle ED crowding.

Understanding administrative abdominal aortic aneurysm mortality data.

OBJECTIVE: Administrative data in the form of Hospital Episode Statistics (HES) and the Scottish Morbidity Record (SMR) have been used to describe surgical activity. These data have also been used to compare outcomes from different hospitals and regions, and to corroborate data submitted to national audits and registries. The aim of this observational study was to examine the completeness and accuracy of administrative data relating to abdominal aortic aneurysm (AAA) repair. METHODS: Administrative data (SMR-01 returns) from a single health board relating to AAA repair were requested (September 2007 to August 2012). A complete list of validated procedures; termed the reference data set was compiled from all available sources (clinical and administrative). For each patient episode electronic health records were scrutinised to confirm urgency of admission, diagnosis, and operative repair. The 30-day mortality was recorded. The reference data set was used to systematically validate the SMR-01 returns. RESULTS: The reference data set contained 608 verified procedures. SMR-01 returns identified 2433 episodes of care (1724 patients) in which a discharge diagnosis included AAA. This included 574 operative repairs. There were 34 missing cases (5.6%) from SMR-01 returns; nine of these patients died within 30 days of the index procedure. Omission of these cases made a statistically significant improvement to perceived 30-day mortality (p < .05, chi-square test). If inconsistent SMR-01 data (in terms of ICD-10 and OPCS-4 codes) were excluded only 81.9% of operative repairs were correctly identified and only 30.9% of deaths were captured. DISCUSSION: The SMR-01 returns contain multiple errors. There also appears to be a systematic bias that reduces apparent 30-day mortality. Using these data alone to describe or compare activity or outcomes must be done with caution.

Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy - A focus on energy expenditure.

OBJECTIVE: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. METHODS: Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. RESULTS: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. CONCLUSIONS: Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.

The mechanism of weight loss with laparoscopic adjustable gastric banding: induction of satiety not restriction.

Laparoscopic adjustable gastric banding (LAGB) has rapidly emerged as a popular bariatric procedure because of its safety, efficacy, durability and adjustability. Despite widespread use, there is limited understanding of how it induces weight loss. Previously, it has been classified as a restrictive procedure, physically limiting the patient to a small meal that subsequently slowly empties into the distal stomach. However, the tiny pouch of stomach created above the LAGB appears to be unable to accommodate even the smallest of meals. Therefore, the key mechanism has been hypothesized to be the induction of satiety via, as yet, undefined pathways. The critical question remains: what are the key physiological changes that lead to satiety and weight loss? In successful LAGB patients, a consistent intraluminal pressure at the level of the LAGB of 26.9 ± 19.8 mm Hg is observed. Studies using semi-solid swallows combined with intraluminal pressure recordings have demonstrated that semi-solid transit across the resistance of the LAGB is mediated by repeated esophageal peristaltic contractions (mean 4.5 ± 2.9) that produce episodic flow, interspersed by reflux events. Failed transit results in obstruction and regurgitation, whereas dilatation of the supraband stomach induces severe and intolerable reflux. Overall gastric emptying does not appear to be significantly altered following LAGB. Focused investigations have shown that the supraband stomach is empty of an ingested meal 1-2 min after intake ceases. Considerable progress has been made in understanding the mechanical physiological effects of the LAGB on esophageal and proximal gastric function. These have been correlated with patient outcomes and sensations. On the basis of recent data, it appears that the LAGB activates the peripheral satiety mechanism without physically restricting the meal size. Therefore, it should not be classified as a restrictive procedure. The precise mechanism of weight loss with the LAGB remains to be delineated.

Donor information considered important to donors, recipients and offspring: an Australian perspective.

Donor conception research supports open-identity donor programmes and disclosure to donor-conceived offspring. This study examines Australian donors', recipients' and donor-conceived offspring's views on the importance of different types of biographical information about the donor. Participants (125 recipients, 39 donors (known, identity-release and anonymous), 23 donor-conceived offspring) completed an online or paper self-administered anonymous questionnaire. Individuals rated the importance of 15 types of biographical information and subsequently chose the three they deemed most important. All groups included donor's health history and name as key variables to be available to donor-conceived offspring. Recipients viewed the donor's decision to donate as important, donors thought their feelings about being contacted were important and donor-conceived offspring expressed an interest in the donor's own family. Sperm donors were less inclined to view the provision of information as important compared with offspring. For recipients, the importance of information became apparent once they had disclosed to their children. This is the first study to gauge Australian stakeholders' attitudes to release of information in the donor conception process. The findings support the move to open-identity donation systems and emphasize the importance of considering the varying perspectives of all stakeholders by policy developers.

Association between infant correlates of impulsivity--surgency (extraversion)--and early infant growth.

Increasing evidence suggests that rapid postnatal weight gain is associated with increased risks of being overweight or obese later in life and of co-morbidities, such as diabetes, the metabolic syndrome and cardiovascular disease. In children as young as two years of age, as well as in adults, an appetitive system-linked impulsivity trait has been demonstrated to be linked with increased overweight, and postulated to act via increased food intake, through greater responsiveness to food and lower self-inhibitory control skills. In this study, we hypothesized that growth in infancy, a critical window for metabolic programming, would be predicted by measures of infant surgency/extraversion, assessed using the Rothbart Infant Behaviour Questionnaire (revised version). Anthropometry was measured at birth and at 3, 6 and 12 months, and weight gains expressed as increases in standardized scores, allowing for adjustment for gender and age, including gestational age. We used conditional weight (CW), a residual of current weight regressed on prior weights, to represent deviations from expected weight gains, from 0 to 3, 3 to 6 and 6 to 12 months. Controlling for significant sociodemographic correlations, multiple regression analyses showed significant prediction of CWs at 3 months but not of CWs at 6 or 12 months by surgency/extraversion. These pilot findings of association between infant growth, during a critical period, and surgency/extraversion, early correlates of impulsivity, warrant further investigation, to ascertain implications for childhood and later weight and body composition.

Sources of Revenue Loss and Recovery in Radiology Practices During the Coronavirus Disease 2019 (COVID-19) Pandemic.

RATIONALE AND OBJECTIVES: This study seeks to quantify the financial impact of COVID-19 on radiology departments, and to describe the structure of both volume and revenue recovery. MATERIALS AND METHODS: Radiology studies from a large academic health system were retrospectively studied from the first 33 weeks of 2020. Volume and work relative value unit (wRVU) data were aggregated on a weekly basis for three periods: Presurge (weeks 1-9), surge (10-19), and recovery (20-33), and analyzed compared to the pre-COVID baseline stratified by modality, specialty, patient service location, and facility type. Mean and median wRVU per study were used as a surrogate for case complexity. RESULTS: During the pandemic surge, case volumes fell 57%, while wRVUs fell by 69% relative to the pre-COVID-19 baseline. Mean wRVU per study was 1.13 in the presurge period, 1.03 during the surge, and 1.19 in the recovery. Categories with the greatest mean complexity declines were radiography (-14.7%), cardiothoracic imaging (-16.2%), and community hospitals overall (-15.9%). Breast imaging (+6.5%), interventional (+5.5%), and outpatient (+12.1%) complexity increased. During the recovery, significant increases in complexity were seen in cardiothoracic (0.46 to 0.49), abdominal (1.80 to 1.91), and neuroradiology (2.46 to 2.56) at stand-alone outpatient centers with similar changes at community hospitals. At academic hospitals, only breast imaging complexity remained elevated (1.32 from 1.17) during the recovery. CONCLUSION: Reliance on volume alone underestimates the financial impact of the COVID-19 pandemic as there was a disproportionate loss in high-RVU studies. However, increased complexity of outpatient cases has stabilized overall losses during the recovery.

Impact of COVID-19 social distancing regulations on outpatient diagnostic imaging volumes and no-show rates.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted outpatient radiology practices, necessitating change in practice infrastructure and workflow. OBJECTIVE: The purpose of this study was to assess the consequences of social distancing regulations on 1) outpatient imaging volume and 2) no-show rates per imaging modality. METHODS: Volume and no-show rates of a large, multicenter metropolitan healthcare system outpatient practice were retrospectively stratified by modality including radiography, CT, MRI, ultrasonography, PET, DEXA, and mammography from January 2 to July 21, 2020. Trends were assessed relative to timepoints of significant state and local social distancing regulatory changes. RESULTS: The decline in imaging volume and rise in no-show rates was first noted on March 10, 2020 following the declaration of a state of emergency in New York State (NYS). Total outpatient imaging volume declined 85% from baseline over the following 5 days. Decreases varied by modality: 88% for radiography, 75% for CT, 73% for MR, 61% for PET, 80% for ultrasonography, 90% for DEXA, and 85% for mammography. Imaging volume and no-show rate recovery preceded the mask mandate of April 15, 2020, and further trended along with New York City's reopening phases. No-show rates recovered within 2 months of the height of the pandemic, however, outpatient imaging volume has yet to recover to baseline after 3 months. CONCLUSION: The total outpatient imaging volume declined alongside an increase in the no-show rate following the declaration of a state of emergency in NYS. No-show rates recovered within 2 months of the height of the pandemic with imaging volume yet to recover after 3 months. CLINICAL IMPACT: Understanding the impact of social distancing regulations on outpatient imaging volume and no-show rates can potentially aid other outpatient radiology practices and healthcare systems in anticipating upcoming changes as the COVID-19 pandemic evolves.

Automated detection of critical findings in multi-parametric brain MRI using a system of 3D neural networks.

With the rapid growth and increasing use of brain MRI, there is an interest in automated image classification to aid human interpretation and improve workflow. We aimed to train a deep convolutional neural network and assess its performance in identifying abnormal brain MRIs and critical intracranial findings including acute infarction, acute hemorrhage and mass effect. A total of 13,215 clinical brain MRI studies were categorized to training (74%), validation (9%), internal testing (8%) and external testing (8%) datasets. Up to eight contrasts were included from each brain MRI and each image volume was reformatted to common resolution to accommodate for differences between scanners. Following reviewing the radiology reports, three neuroradiologists assigned each study to abnormal vs normal, and identified three critical findings including acute infarction, acute hemorrhage, and mass effect. A deep convolutional neural network was constructed by a combination of localization feature extraction (LFE) modules and global classifiers to identify the presence of 4 variables in brain MRIs including abnormal, acute infarction, acute hemorrhage and mass effect. Training, validation and testing sets were randomly defined on a patient basis. Training was performed on 9845 studies using balanced sampling to address class imbalance. Receiver operating characteristic (ROC) analysis was performed. The ROC analysis of our models for 1050 studies within our internal test data showed AUC/sensitivity/specificity of 0.91/83%/86% for normal versus abnormal brain MRI, 0.95/92%/88% for acute infarction, 0.90/89%/81% for acute hemorrhage, and 0.93/93%/85% for mass effect. For 1072 studies within our external test data, it showed AUC/sensitivity/specificity of 0.88/80%/80% for normal versus abnormal brain MRI, 0.97/90%/97% for acute infarction, 0.83/72%/88% for acute hemorrhage, and 0.87/79%/81% for mass effect. Our proposed deep convolutional network can accurately identify abnormal and critical intracranial findings on individual brain MRIs, while addressing the fact that some MR contrasts might not be available in individual studies.

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

BACKGROUND: Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. METHODS: In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. FINDINGS: Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). INTERPRETATION: The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. FUNDING: Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Nanostrain sensitivity in a wire torsion experiment.

The feasibility of a thin-wire torsion stress-strain experiment with nanostrain sensitivity is demonstrated. A gauge length of 50 m was made possible by using The Monument, London, thereby restoring it to its original purpose as a scientific instrument. A wire of 150 µm diameter was studied using the load-unload method, and data were recorded in the elastic regime and through the elastic-plastic transition. Analysis of this preliminary experiment suggested some necessary improvements to the equipment and methods. Progress towards definitive experiments is described together with difficulties still to be overcome.

Feasibility Trial of Thumb Taping by Parents in Infants with Cerebral Palsy: Brief Report.

Aim: To determine the feasibility and acceptability of parent-delivered elastic taping to the thumb and wrist in infants with cerebral palsy (CP).Design: Randomized cross-over feasibility trial.Participants: 20 infants (11 male; mean age 22 months) with CP.Intervention: Groups A and B received taping for 4 and 2 weeks, respectively.Outcomes: Primary: Recruitment and retention rates; adherence to protocol; Parent Satisfaction Questionnaire. Secondary: House Thumb score; Zancolli classification; Assisting Hand Assessment (AHA)/mini AHA. Exploratory: Duration of hand regard, thumb in palm, and open hand contact with toys during AHA/mini AHA.Results: Recruitment was feasible (95.2% uptake). Completion rates were 80% and 60% in Groups A and B. Questionnaire feedback was generally positive. Some parents reported increased awareness of the taped hand. Objective improvements were rare though one participant showed consistent improvement in thumb position.Conclusion: Taping proved feasible and acceptable; individual case benefit suggests further research is required.Trial registration: ISRCTN41918400.

Luminal material in microtubules of frog olfactory axons: structure and distribution.

The substructure and distribution of luminal material in microtubules of olfactory axons were studied in the bullfrog, Rana catesbeiana. By using numerous fixation methods, with and without osmium tetroxide, the luminal component was shown not to be an artifact of fixation. The material consists of globular elements 4-5 nm in diameter loosely arranged within the lumen in a discontinuous column. Counts of microtubules showing luminal material were obtained for axons in the proximal and distal ends of the olfactory nerve, and it was found that 16-18% more of the microtubules in the distal regions showed the luminal component. This raises the possibility that the material might be translocated within the microtubule lumen and tends to accumulate as it moves distally toward the axon terminal. In contrast to those of the olfactory axons, microtubules assembled in vitro from frog brain tubulin did not show luminal material. When microtubules in olfactory axons were depolymerized in situ by cold and calcium treatment and then induced to reassemble, most of those that were formed de novo showed empty lumina. Such evidence suggests that the luminal material is not an integral component of the microtubule. The hypothesis is discussed that material may be translocated within the lumina of microtubules. Furthermore, in the case of neuronal microtubules, the possibility is raised that they may serve as conduits for their own wall subunits.

Fine structure and replication of the kinetoplast of Trypanosoma lewisi.

The kinetoplastic DNA of Trypanosoma lewisi is described as a filamentous body lying within a mitochondrion, with the filaments oriented parallel to the long axis of the cell. The manner of fixation, the replicative state, and perhaps the physiological state of the cell, may result in slight morphological differences among such bodies. The kinetoplastic DNA replicates to form "left" and "right" rather than "upper" and "lower" members, and both the kinetoplast and nucleus incorporate radiothymidine as shown by radioautography. Radioautographic analyses suggest a random incorporation of radiothymidine by kinetoplasts. Silver grains were occasionally observed over centriolar elements. Finally, the observations are discussed with respect to the sequential replication of the aforementioned organelles by T. lewisi.