Benefits of routine probiotic supplementation in preterm infants.

AIM: We introduced routine probiotic supplementation (RPS) of preterm infants in June 2012. We previously reported that RPS reduced the incidence of necrotising enterocolitis (NEC) and mortality in such infants. In this study, we assessed if the benefits of RPS were sustained for infants in the current era. METHOD: We compared the outcomes of preterm infants in recent epoch 3 (RPS, 1st June 2014 to 31st December 2019) versus epoch 2 (RPS, 1st June 2012 to 31st May 2014) and epoch 1 (no RPS, 1st December 2008 to 30th November 2010). Multiple logistic and Cox regression models were used to compare the outcomes. RESULTS: There were 645 infants in epoch 1, 712 in epoch 2 and 1715 in epoch 3. Age at full feeds was significantly lower in epoch 3 vs. 2 and epoch 3 vs. 1 in infants <28 weeks of gestation. NEC and late-onset sepsis (LOS) were significantly lower in epoch 3 vs. 1 in infants <28 weeks. LOS and age at full feeds were significantly lower in epoch 3 vs. 2 and epoch 3 vs. 1 in infants with gestation 28 to 32 weeks. CONCLUSION: The benefits associated with RPS were sustained during epoch 3.

Facilitators and barriers to attending postpartum screening in women with a recent pregnancy complicated by gestational diabetes mellitus: a qualitative study.

OBJECTIVE: Pregnant women with gestational diabetes mellitus (GDM) are 50% more likely to develop type II diabetes (T2D) within 6 months to 2 years after giving birth. Therefore, international guidelines recommend it is best practice for women diagnosed with GDM to attend screening for T2D 6-12 weeks postpartum and every 1-3 years thereafter for life. However, uptake of postpartum screening is suboptimal. This study will explore the facilitators of and barriers to attending postpartum screening for T2D that women experience. STUDY DESIGN: This was a prospective qualitative cohort study using thematic analysis. METHODS: A total of 27 in-depth, semistructured interviews were conducted over the telephone with women who had recent GDM. Interviews were recorded and transcribed, and data were analysed using thematic analysis. RESULTS: Facilitators of and barriers to attending postpartum screening were identified at three different levels: personal, intervention, and healthcare systems level. The most common facilitators identified were concern for their own health and having the importance of screening explained to them by a health professional. The most common barriers identified were confusion over the test and COVID-19. CONCLUSION: This study identified several facilitators of and barriers to attending postpartum screening. These findings will help to inform research and interventions for improving rates of attendance at postpartum screening to reduce the subsequent risk of developing T2D.

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.

Prenatal exposure to maternal stressful life events and earlier age at menarche: the Raine Study.

STUDY QUESTION: Is there an association between prenatal exposure to stressful life events and age at menarche, and does childhood BMI mediate this association? SUMMARY ANSWER: Girls exposed to prenatal stress had a slightly earlier age at menarche, but this association did not show a dose-response effect and was not mediated by childhood offspring BMI. WHAT IS ALREADY KNOWN: Prenatal stress may impact on reproductive function in females including age at menarche, but human data are very limited. High childhood BMI is known to be associated with earlier age at menarche. Only one small study has measured the association between maternal stress and age at menarche and reported that childhood BMI mediated the association between maternal stress and earlier age at menarche. However, neither maternal stress nor age at menarche was prospectively recorded and the study was limited to 31 mother-daughter pairs. STUDY DESIGN, SIZE, DURATION: The Raine Study is a large prospective population-based pregnancy cohort study (n = 1414 mother-daughter pairs) continuously followed from prenatal life through to adolescence. In the present study, we examined the association between exposure to maternal stressful life events during early, late and total gestation and age at menarche in offspring using 753 mother-daughter pairs with complete case information. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mothers prospectively reported stressful life events during pregnancy at 18 and 34 weeks using a standardized 10-point questionnaire. Exact date of menarche was assessed using a purpose-designed questionnaire at 8, 10, 14 and 17 years of age. Complete information on exposure, outcome and confounding variables was obtained from 753 mothers-daughter pairs. Multivariate linear regression complete case analysis was used to examine associations between maternal stressful life event exposure and age at menarche. Potential selection bias was evaluated using multiple imputations (50 datasets). The mediating effects of offspring childhood BMI (ages 5, 8, or 10 years) on these associations were measured in separate sub-analyses. MAIN RESULTS AND ROLE OF CHANCE: Most (580/753, 77%) daughters were exposed to at least one prenatal stressful life event. Exposure to maternal stressful life events during the entire pregnancy was associated with a non-linear earlier age at menarche. Exposure to one event and two or more psychological stressful events was associated with a 3.5 and 1.7-month earlier onset of puberty, respectively when compared to the reference group with no exposure maternal stressful life events. The estimates from multiple imputation with 50 datasets were comparable with complete case analysis confirming the existence of an underlying effect. No separate significant effects were observed for exposure during early or late gestation. The association between prenatal stressful events and age at menarche was not mediated by childhood BMI in the offspring. LIMITATIONS, REASONS FOR CAUTION: Stressful life events may have affected pregnant women in different ways and self-perceived maternal stress severity may have provided a more precise estimate of gestational psychological stress. The observed non-linear U-shape of the association between maternal psychological stress and age at menarche did not reflect a dose-response. This suggests that the first exposure to prenatal stress exerts a greater effect on fetal reproductive development. A potential mechanism is via dramatic initial activation of the hypothalamic-pituitary-adrenal (HPA) axis following the first stressful life event which is greater than that observed following subsequent exposure to two or more maternal stressful life events. Whilst we adjusted for a priori chosen confounders, we cannot exclude residual confounding or confounding by factors we did not include. Maternal age at menarche was not available so the effects of familial history/genetics could not be assessed. There was a large loss due to the number of girls with no information on date of menarche and missing confounder information implying risk of selection bias and multiple imputation analyses did not fully exclude this risk (similar direction but slightly weaker estimate magnitude). WIDER IMPLICATIONS OF THE FINDINGS: Menarche is a sentinel reproductive event and earlier age at menarche carries implications for psychological, social and reproductive health and for long-term risk of common non-communicable diseases. Understanding the factors regulating age at menarche has extensive health implications. This is the first population-based cohort study in humans to demonstrate that prenatal psychological stress might directly modify age at menarche. STUDY FUNDING/COMPETING INTEREST(S): Dr. Bräuner and Trine Koch's salaries were supported by Doctor Sofus Carl Emil Friis and spouse Olga Doris Friis foundation, The Danish Cancer Society (Kræftens Bekæmpelse, RP15468, R204-A12636, Denmark) and The Danish Health Foundation (Helsefonden, F-22181-23, Denmark). Martha Hickey was funded by NHMRC Practitioner Fellowships. The funding bodies played no role in the design, collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Dr. Hart has received personal fees in his function as the Medical Director of Fertility Specialists of Western Australia and received educational sponsorship grants from MSD, Merck-Serono and from Ferring Pharmaceuticals. Dr Hart has also received personal fees from Shareholders in Western IVF outside the submitted work. TRIAL REGISTRATION NUMBER: NA.

Solving the Puzzles of the Decay of the Heaviest Known Proton-Emitting Nucleus

Two long-standing puzzles in the decay of ^{185}Bi, the heaviest known proton-emitting nucleus are revisited. These are the nonobservation of the 9/2^{-} state, which is the ground state of all heavier odd-A Bi isotopes, and the hindered nature of proton and α decays of its presumed 60-µs 1/2^{+} ground state. The ^{185}Bi nucleus has now been studied with the ^{95}Mo(^{93}Nb,3n) reaction in complementary experiments using the Fragment Mass Analyzer and Argonne Gas-Filled Analyzer at Argonne National Laboratory's ATLAS facility. The experiments have established the existence of two states in ^{185}Bi; the short-lived T_{1/2}=2.8_{-1.0}^{+2.3} µs, proton- and α-decaying ground state, and a 58(2)-µs γ-decaying isomer, the half-life of which was previously attributed to the ground state. The reassignment of the ground-state lifetime results in a proton-decay spectroscopic factor close to unity and represents the only known example of a ground-state proton decay to a daughter nucleus (^{184}Pb) with a major shell closure. The data also demonstrate that the ordering of low- and high-spin states in ^{185}Bi is reversed relative to the heavier odd-A Bi isotopes, with the intruder-based 1/2^{+} configuration becoming the ground, similar to the lightest At nuclides.

Exploiting Isospin Symmetry to Study the Role of Isomers in Stellar Environments.

Proton capture on the excited isomeric state of ^{26}Al strongly influences the abundance of ^{26}Mg ejected in explosive astronomical events and, as such, plays a critical role in determining the initial content of radiogenic ^{26}Al in presolar grains. This reaction also affects the temperature range for thermal equilibrium between the ground and isomeric levels. We present a novel technique, which exploits the isospin symmetry of the nuclear force, to address the long-standing challenge of determining proton-capture rates on excited nuclear levels. Such a technique has in-built tests that strongly support its veracity and, for the first time, we have experimentally constrained the strengths of resonances that dominate the astrophysical ^{26m}Al(p,γ)^{27}Si reaction. These constraints demonstrate that the rate is at least a factor ∼8 lower than previously expected, indicating an increase in the stellar production of ^{26}Mg and a possible need to reinvestigate sensitivity studies involving the thermal equilibration of ^{26}Al.

Shape Changes in the Mirror Nuclei

We studied the proton-rich T_{z}=-1 nucleus ^{70}Kr through inelastic scattering at intermediate energies in order to extract the reduced transition probability, B(E2;0^{+}→2^{+}). Comparison with the other members of the A=70 isospin triplet, ^{70}Br and ^{70}Se, studied in the same experiment, shows a 3σ deviation from the expected linearity of the electromagnetic matrix elements as a function of T_{z}. At present, no established nuclear structure theory can describe this observed deviation quantitatively. This is the first violation of isospin symmetry at this level observed in the transition matrix elements. A heuristic approach may explain the anomaly by a shape change between the mirror nuclei ^{70}Kr and ^{70}Se contrary to the model predictions.

First Direct Measurement of an Astrophysical p-Process Reaction Cross Section Using a Radioactive Ion Beam.

We have performed the first direct measurement of the ^{83}Rb(p,γ) radiative capture reaction cross section in inverse kinematics using a radioactive beam of ^{83}Rb at incident energies of 2.4 and 2.7A MeV. The measured cross section at an effective relative kinetic energy of E_{cm}=2.393 MeV, which lies within the relevant energy window for core collapse supernovae, is smaller than the prediction of statistical model calculations. This leads to the abundance of ^{84}Sr produced in the astrophysical p process being higher than previously calculated. Moreover, the discrepancy of the present data with theoretical predictions indicates that further experimental investigation of p-process reactions involving unstable projectiles is clearly warranted.

Search for Nova Presolar Grains: γ-Ray Spectroscopy of

The discovery of presolar grains in primitive meteorites has initiated a new era of research in the study of stellar nucleosynthesis. However, the accurate classification of presolar grains as being of specific stellar origins is particularly challenging. Recently, it has been suggested that sulfur isotopic abundances may hold the key to definitively identifying presolar grains with being of nova origins and, in this regard, the astrophysical ^{33}Cl(p,γ)^{34}Ar reaction is expected to play a decisive role. As such, we have performed a detailed γ-ray spectroscopy study of ^{34}Ar. Excitation energies have been measured with high precision and spin-parity assignments for resonant states, located above the proton threshold in ^{34}Ar, have been made for the first time. Uncertainties in the ^{33}Cl(p,γ) reaction have been dramatically reduced and the results indicate that a newly identified ℓ=0 resonance at E_{r}=396.9(13) keV dominates the entire rate for T=0.25-0.40 GK. Furthermore, nova hydrodynamic simulations based on the present work indicate an ejected ^{32}S/^{33}S abundance ratio distinctive from type-II supernovae and potentially compatible with recent measurements of a presolar grain.

The association between in-utero exposure to stressful life events during pregnancy and male reproductive function in a cohort of 20-year-old offspring: The Raine Study.

STUDY QUESTION: Is exposure to gestational stress in the critical time window for the normal differentiation and growth of male reproductive tissue associated with male reproductive function in offspring in later life? SUMMARY ANSWER: Exposure to stressful life events (SLEs) in early, but not late gestation, are associated with reduced adult male reproductive function, consistent with the hypothesis that events during early prenatal life programme adult male reproductive function. WHAT IS ALREADY KNOWN: Animal studies suggest that gestational stress may impact on the reproductive function of male offspring, but human evidence is sparse. STUDY DESIGN, SIZE, DURATION: Using a prospective longitudinal cohort, we examined the association between number and type of maternal stressors during pregnancy in both early and late gestation and reproductive function in 643 male Generation 2 (offspring) at age 20 years. Mothers and their male Generation 2 (offspring) from The Raine Study participated. Mothers prospectively reported SLEs during pregnancy recorded at gestational weeks 18 and 34 using a standardized 10-point questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 643 male Generation 2 (offspring) underwent testicular ultrasound examination and semen analysis and provided serum for reproductive hormone analysis. Multivariate linear regression analysis was used to examine associations. MAIN RESULTS AND ROLE OF CHANCE: Of 643 recruited males, 407 (63%) were exposed to at least one SLE in early gestation. Fewer SLEs were reported in late gestation (n = 343, 53%). Maternal SLE exposure in early gestation was negatively associated with total sperm count (ß = -0.31, 95% CI -0.58; -0.03), number of progressive motile sperm (ß = -0.15, 95% CI -0.31; 0.00) and morning serum testosterone concentration (ß = -0.04, 95% CI -0.09; -0.00). No similar effects of maternal SLE exposure in late pregnancy were detected. The large sample size and an objective detailed direct assessment of adult male reproductive function with strict external quality control for sperm quality, as well as detailed prospectively collected information on prenatal SLEs in two distinct time windows of pregnancy reported by the women in early and late gestation along with other risk factors, imply minimal possibility of recall, information bias and selection bias. When assessing our results, we adjusted for a priori chosen confounders, but residual confounding or confounding by factors unbeknown to us cannot be ruled out. LIMITATIONS, REASONS FOR CAUTION: It is not possible to measure how SLEs impacted differently on the mother's experience or perception of stress. Resilience (coping) gradients may alter cortisol levels and thus modify the associations we observed and the mothers' own perception of stress severity may have provided a more precise estimate of her exposure. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that exposure to SLEs in early, but not late gestation, are associated with reduced adult male reproductive function. Improved support for women with exposure to SLEs during pregnancy, particularly during the first trimester, may improve the reproductive health of their male offspring in later life. Intervention studies of improved pregnancy support could provide more insight into this association and more information is needed about the potential specific epigenetic mechanisms underlying this association. STUDY FUNDING/COMPETING INTEREST(S): The male fertility sub-study was funded by NHMRC Grant 634 457. The core management of the Raine Study is funded by University of Western Australia, Curtin University, Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia and Raine Medical Research foundation. Dr Bräuner's salary was supported by Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis foundation in Denmark. All authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Features of the metabolic syndrome in late adolescence are associated with impaired testicular function at 20 years of age.

STUDY QUESTION: Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood? SUMMARY ANSWER: Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder. WHAT IS KNOWN ALREADY: Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function. STUDY DESIGN, SIZE, DURATION: The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989-1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years; 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectrometry.At 17 years of age, a liver ultrasound examination was performed to determine the presence of non-alcoholic fatty liver disease (NAFLD), and serum analysed for the cytokines interleukin-18 and soluble tumour necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2).At 17 and 20 years of age, fasting blood samples were analysed for serum liver enzymes, insulin, glucose, triglycerides (TG), total cholesterol, high density lipoprotein and low density lipoprotein cholesterol, high sensitivity C-reactive protein and uric acid. The homoeostatic model assessment (HOMA) was calculated and approximated IR was defined by a HOMA >4. Anthropometric data was collected and dual energy X-ray absorptiometry measurement performed for lean and total fat mass. As at this young age the prevalence of metabolic syndrome was expected to be low, a two-step cluster analysis was used using waist circumference, TGs, insulin, and systolic blood pressure to derive a distinct high-risk group with features consistent with the metabolic syndrome and increased cardiometabolic risk. MAIN RESULTS AND THE ROLE OF CHANCE: Men at age 17 years with increased cardiometabolic risk had lower concentrations of serum testosterone (medians: 4.0 versus 4.9 ng/mL) and inhB (193.2 versus 221.9 pg/mL) (P < 0.001 for both) compared to those within the low risk metabolic cluster. Men with ultrasound evidence of NAFLD (n = 45, 9.8%) had reduced total sperm output (medians: 68.0 versus 126.00 million, P = 0.044), testosterone (4.0 versus 4.7 ng/mL, P = 0.005) and inhB (209.1 versus 218.4 pg/mL, P = 0.032) compared to men without NAFLD.Men with higher concentrations of sTNFR1 at 17 years of age had a lower sperm output and serum concentration of inhB, with an increase in LH and FSH (all P < 0.05 after adjustment for age, BMI, abstinence and a history of cryptorchidism, varicocele, cigarette smoking, alcohol and drug use), compared to those without an elevated sTNFR1. Multivariable regression analysis, adjusting for confounders, demonstrated that men in the high-risk metabolic cluster at 20 years had a lower serum testosterone and inhB (P = 0.003 and P = 0.001, respectively). A HOMA-IR > 4 was associated with a lower serum testosterone (P = <0.001) and inhB (P = 0.010) and an increase in serum FSH (P = 0.015). LIMITATIONS, REASONS FOR CAUTION: This study is limited by the sample size and multiple comparisons, and causality cannot be proven from an observational study. Due to a 3-year interval between some metabolic assessments and assessment of testicular function, we cannot exclude the introduction of a bias into the study, as some of the participants and their testicular function will not have been fully mature at the 17-year assessment. WIDER IMPLICATIONS OF THE FINDINGS: Irrespective of a proven causation, our study findings are important in that a significant minority of the men, prior to seeking parenthood, presented co-existent features of metabolic disorder and signs of testicular impairment. Of particular note is that the presence of NAFLD at 17 years of age, although only present in a minority of men, was associated with an almost 50% reduction in sperm output at 20 years of age, and that the presence of IR at 20 years was associated with a 20% reduction in testicular volume. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Australian NHMRC (Grant Numbers 634457, 35351417 and 403981) and received support from the Raine Medical Research Foundation, The Telethon Kids Institute, University of Western Australia, Women and Infants Research Foundation, Curtin University and Edith Cowan University. D.A.D., J.E.D., N.M., L.A.A., R.-C.H., T.A.M., J.K.O., L.J.B. have nothing to declare. R.J.H. is Medical Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals. RMcL has equity interests in the Monash IVF Group. R.J.N. has equity interests in FertilitySA, and has received grant support from Merck Serono and Ferring Pharmaceuticals. D.J.H. has received institutional grant funding (but no personal income) for investigator-initiated testosterone pharmacology studies from Lawley and Besins Healthcare and has provided expert testimony to anti-doping tribunals and for testosterone litigation.This abstract was awarded the Fertility Society of Australia clinical exchange award for the oral presentation at ESHRE, Barcelona, in 2018.

Alterations in circulating lymphoid cell populations in systemic small vessel vasculitis are non-specific manifestations of renal injury.

Innate lymphocyte populations, such as innate lymphoid cells (ILCs), γδ T cells, invariant natural killer T (iNK T) cells and mucosal-associated invariant T (MAIT) cells are emerging as important effectors of innate immunity and are involved in various inflammatory and autoimmune diseases. The aim of this study was to assess the frequencies and absolute numbers of innate lymphocytes as well as conventional lymphocytes and monocytes in peripheral blood from a cohort of anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV) patients. Thirty-eight AAV patients and 24 healthy and disease controls were included in the study. Patients with AAV were sampled both with and without immunosuppressive treatment, and in the setting of both active disease and remission. The frequencies of MAIT and ILC2 cells were significantly lower in patients with AAV and in the disease control group compared to healthy controls. These reductions in the AAV patients remained during remission. B cell count and frequencies were significantly lower in AAV in remission compared to patients with active disease and disease controls. Despite the strong T helper type 2 (Th) preponderance of eosinophilic granulomatosis with polyangiitis, we did not observe increased ILC2 frequency in this cohort of patients. The frequencies of other cell types were similar in all groups studied. Reductions in circulating ILC2 and MAIT cells reported previously in patients with AAV are not specific for AAV, but are more likely to be due to non-specific manifestations of renal impairment and chronic illness. Reduction in B cell numbers in AAV patients experiencing remission is probably therapy-related.

Superallowed α Decay to Doubly Magic

We report the first observation of the ^{108}Xe→^{104}Te→^{100}Sn α-decay chain. The α emitters, ^{108}Xe [E_{α}=4.4(2) MeV, T_{1/2}=58_{-23}^{+106} µs] and ^{104}Te [E_{α}=4.9(2) MeV, T_{1/2}<18 ns], decaying into doubly magic ^{100}Sn were produced using a fusion-evaporation reaction ^{54}Fe(^{58}Ni,4n)^{108}Xe, and identified with a recoil mass separator and an implantation-decay correlation technique. This is the first time α radioactivity has been observed to a heavy self-conjugate nucleus. A previous benchmark for study of this fundamental decay mode has been the decay of ^{212}Po into doubly magic ^{208}Pb. Enhanced proton-neutron interactions in the N=Z parent nuclei may result in superallowed α decays with reduced α-decay widths significantly greater than that for ^{212}Po. From the decay chain, we deduce that the α-reduced width for ^{108}Xe or ^{104}Te is more than a factor of 5 larger than that for ^{212}Po.

First Accurate Normalization of the ß-delayed α Decay of

The ^{12}C(α,γ)^{16}O reaction plays a central role in astrophysics, but its cross section at energies relevant for astrophysical applications is only poorly constrained by laboratory data. The reduced α width, γ_{11}, of the bound 1^{-} level in ^{16}O is particularly important to determine the cross section. The magnitude of γ_{11} is determined via sub-Coulomb α-transfer reactions or the ß-delayed α decay of ^{16}N, but the latter approach is presently hampered by the lack of sufficiently precise data on the ß-decay branching ratios. Here we report improved branching ratios for the bound 1^{-} level [b_{ß,11}=(5.02±0.10)×10^{-2}] and for ß-delayed α emission [b_{ßα}=(1.59±0.06)×10^{-5}]. Our value for b_{ßα} is 33% larger than previously held, leading to a substantial increase in γ_{11}. Our revised value for γ_{11} is in good agreement with the value obtained in α-transfer studies and the weighted average of the two gives a robust and precise determination of γ_{11}, which provides significantly improved constraints on the ^{12}C(α,γ) cross section in the energy range relevant to hydrostatic He burning.

Anomalies in the Charge Yields of Fission Fragments from the

Fast-neutron-induced fission of ^{238}U at an energy just above the fission threshold is studied with a novel technique which involves the coupling of a high-efficiency γ-ray spectrometer (MINIBALL) to an inverse-kinematics neutron source (LICORNE) to extract charge yields of fission fragments via γ-γ coincidence spectroscopy. Experimental data and fission models are compared and found to be in reasonable agreement for many nuclei; however, significant discrepancies of up to 600% are observed, particularly for isotopes of Sn and Mo. This indicates that these models significantly overestimate the standard 1 fission mode and suggests that spherical shell effects in the nascent fission fragments are less important for low-energy fast-neutron-induced fission than for thermal neutron-induced fission. This has consequences for understanding and modeling the fission process, for experimental nuclear structure studies of the most neutron-rich nuclei, for future energy applications (e.g., Generation IV reactors which use fast-neutron spectra), and for the reactor antineutrino anomaly.

Spectroscopic Quadrupole Moments in {96,98}Sr: Evidence for Shape Coexistence in Neutron-Rich Strontium Isotopes at N=60.

Neutron-rich {96,98}Sr isotopes have been investigated by safe Coulomb excitation of radioactive beams at the REX-ISOLDE facility. Reduced transition probabilities and spectroscopic quadrupole moments have been extracted from the differential Coulomb excitation cross sections. These results allow, for the first time, the drawing of definite conclusions about the shape coexistence of highly deformed prolate and spherical configurations. In particular, a very small mixing between the coexisting states is observed, contrary to other mass regions where strong mixing is present. Experimental results have been compared to beyond-mean-field calculations using the Gogny D1S interaction in a five-dimensional collective Hamiltonian formalism, which reproduce the shape change at N=60.

Erratum: Spectroscopic Quadrupole Moments in

This corrects the article DOI: 10.1103/PhysRevLett.116.022701.