Optimizing care for children with difficult-to-treat and severe asthma through specialist paediatric asthma centres: expert practical experience and advice.

Severe asthma in children carries an unacceptable treatment burden, yet its rarity means clinical experience in treating it is limited, even among specialists. Practical guidance is needed to support clinical decision-making to optimize treatment for children with this condition.This modified Delphi convened 16 paediatric pulmonologists and allergologists from northern Europe, all experienced in treating children with severe asthma. Informed by interviews with stakeholders involved in the care of children with severe asthma (including paediatricians, nurses and carers), and an analysis of European guidelines, the experts built a consensus focused on the gaps in existing guidance. Explored were considerations for optimizing care for patients needing biologic treatment, and for selecting home or hospital delivery of biologics. This consensus is aimed at clinicians in specialist centres, as well as general paediatricians, paediatric allergologists and paediatric pulmonologists who refer children with the most severe asthma to specialist care. Consensus is based on expert opinion and is intended for use alongside published guidelines.Our discussions revealed three key facets to optimizing care. Firstly, early asthma detection in children presenting with wheezing and/or dyspnoea is vital, with a low threshold for referral from primary to specialist care. Secondly, children who may need biologics should be referred to and managed by specialist paediatric asthma centres; we define principles for the specialist team members, tests, and expertise necessary at such centres, as well as guidance on when homecare biologics delivery is and is not appropriate. Thirdly, shared decision-making is essential at all stages of the patient's journey: clear, concise treatment plans are vital for patient/carer self-management, and structured processes for transition from paediatric to adult services are valuable. The experts identified the potential for specialist paediatric asthma nurses to play a significant role in facilitating multidisciplinary working.Through this project is agreed a framework of practical advice to optimize the care of children with severe asthma. We encourage clinicians and policymakers to implement this practical advice to enhance patient care.

Positional obstructive sleep apnea in children: prevalence and risk factors.

PURPOSE: Positional (supine dependent) obstructive sleep apnea (POSA) affects about 55% of adults with obstructive sleep apnea (OSA). We aimed to study the prevalence and risk factors for POSA in children. METHODS: Cross-sectional analysis of data obtained in 171 children with moderate to severe OSA confirmed by polysomnography (PSG) performed over a 2-year period. POSA is defined by an obstructive apnea-hypopnea index (oAHI) in the supine position ≥ 2× oAHI in the non-supine position. RESULTS: The overall prevalence of POSA was 18.7%. Children with POSA were significantly older (p < 0.001), had a higher prevalence of obesity (p = 0.04), a lower tonsil score (p = 0.049), and less severe OSA (lower oAHI) (p = 0.02) compared to children without POSA, while age was the only significant independent predictor of POSA. The ratio AHI supine to AHI non-supine was not significantly higher during REM than during NREM sleep in children with POSA. CONCLUSIONS: POSA is less common in children compared to adults and the prevalence of POSA increases with age. Although OSA worsens during REM sleep, this was not observed for POSA. Future studies should investigate the prevalence of POSA in specific subgroups and upper airway characteristics of POSA in children.

Sleep disorders during childhood: a practical review.

Sleep disorders are a common problem during childhood. The consequences are variable, and sleep disorders can influence medical, psychological and developmental aspects of the growing child. It is important to recognize sleep disorders and to treat them correctly. We discuss common sleep disorders during childhood using the 3rd edition of the International Classification of Sleep Disorders. We analyze the different sleep disorders from a clinical approach and provide an overview of adequate treatment options.Conlusion: This review discusses common sleep disorders during childhood using the 3rd edition of the International Classification of Sleep Disorders. We analyze the different sleep disorders from a clinical approach and provide an overview of adequate treatment options. What is known: • Sleep disorders are a common problem during childhood. • The consequences are variable, and sleep disorders can influence medical, psychological, and developmental aspects of the growing child. What is new: • Pediatricians should routinely screen for sleep and sleep disorders. • It is important to recognize sleep disorders and to treat them correctly.

Drug-induced sedation endoscopy in surgically naïve infants and children with obstructive sleep apnea: impact on treatment decision and outcome.

PURPOSE: Adenotonsillectomy (AT) is the first-line treatment for obstructive sleep apnea (OSA) in children irrespective of clinical upper airway (UA) findings. We aimed to investigate whether drug-induced sedation endoscopy (DISE) changes treatment decision and outcome in otherwise healthy children and infants with OSA. METHODS: Retrospective analysis of prospectively collected data on polysomnography, DISE, and treatment in surgically naïve, otherwise healthy infants (n = 34) and children (n = 75) with OSA. Treatment success is defined as post-treatment obstructive apnea/hypopnea index (oAHI) < 5 h-5-1, and cure is defined as oAHI < 2 h-1. RESULTS: Based upon UA findings during DISE, AT was performed in 22 infants and 57 children. oAHI improved from 16.5 h-1 (8.1-28.3) to 0.8 h-1 (0.3-4.2) (p = 0.01) in infants and from 28.6 h-1 (23.4-34.9) to 0.7 h-1 (0.4-1.8) (p < 0.001) in children. AT was successful in 84.2% of infants and 91.4% of children. A cure was obtained in 68.4% of infants and 78.7% of children. DISE changed the treatment decision in 1/3rd of infants and 1/4th of children, and they did not undergo AT. In the non-AT group, isolated adenoidectomy/tonsillectomy or non-surgical treatment was successful in 86.6% of children and in 100% of infants. Cure was achieved in 66.6% of children and 75% of infants. CONCLUSIONS: DISE performed in otherwise healthy and surgically naïve infants and children with OSA altered the therapeutic decision making in up to 1/3rd to 1/4th of the cases and resulted in comparable treatment outcomes as standard treatment by AT. The present data suggest that DISE may provide individually tailored treatment of OSA in otherwise healthy infants and children.

Telomere attrition and growth: a life-history framework and case study in common terns.

The relationship between growth and age-specific telomere length, as a proxy of somatic state, is increasingly investigated, but observed patterns vary and a predictive framework is lacking. We outline expectations based on the assumption that telomere maintenance is costly and argue that individual heterogeneity in resource acquisition is predicted to lead to positive covariance between growth and telomere length. However, canalization of resource allocation to the trait with a larger effect on fitness, rendering that trait relatively invariant, can cause the absence of covariance. In a case study of common tern (Sterna hirundo) chicks, in which hatching order is the main determinant of variation in resource acquisition within broods, we find that body mass, but not telomere length or attrition, varies with hatching order. Moreover, body mass and growth positively predict survival to fledging, whereas telomere length and attrition do not. Using a novel statistical method to quantify standardized variance in plasticity, we estimate between-individual variation in telomere attrition to be only 12% of that of growth. Consistent with the relative invariance of telomere attrition, we find no correlation between age-specific body mass or growth and telomere attrition. We suggest that common tern chicks prioritize investment in long-term somatic state (as indicated by canalization of telomere maintenance) over immediate survival benefits of growth as part of an efficient brood reduction strategy that benefits the parents. As such, interspecific variation in the growth-telomere length relationship may be explained by the extent to which parents benefit from rapid mortality of excess offspring.

Drug-induced sedation endoscopy in children <2 years with obstructive sleep apnea syndrome: upper airway findings and treatment outcomes.

Few data are available about the pattern of upper airway (UA) obstruction in children <2 years with obstructive sleep apnea syndrome (OSAS). Also, the role of adenoidectomy versus adenotonsillectomy (AT) is poorly defined in this age group. We performed drug-induced sedation endoscopy (DISE) in young OSAS children to investigate the pattern of UA obstruction and the value of DISE in therapeutic decision making. Retrospective analysis of ≤2-year-old children undergoing DISE-directed UA surgery. OSAS severity and the treatment outcomes were documented by polysomnography. Data are available for 28 patients, age 1.5 years (1.3-1.8), BMI-z score 0.5 (-0.7 to 1.3) with severe OSAS, obstructive apnea/hypopnea index (oAHI) 13.8/hr (7.5-28.3). All but 3 had (>50%) obstruction at the level of the adenoids, and all but 5 had (>50%) tonsillar obstruction. DISE-directed treatment consisted of adenoidectomy (n = 4), tonsillectomy (n = 1), and AT (n = 23). There was a significant improvement in respiratory parameters. Twenty children (71.4%) had a postoperative oAHI <2/hr. None had palatal or tongue base obstruction. Five children had a circumferential UA narrowing (hypotonia), 2 of them had residual OSAS. DISE showed a collapse of the epiglottis in 6 and late-onset laryngomalacia in 4. These findings did not affect surgical outcome. Adenotonsillar hypertrophy is the major cause of UA obstruction, and DISE-directed UA surgery was curative in 71,4% of children ≤2 years. We suggest that DISE may be helpful in surgical decision making. Circumferential UA narrowing may result in less favorable surgical outcomes.

Stabilizing survival selection on presenescent expression of a sexual ornament followed by a terminal decline.

Senescence is a decrease in functional capacity, increasing mortality rate with age. Sexual signals indicate functional capacity, because costs of ornamentation ensure signal honesty, and are therefore expected to senesce, tracking physiological deterioration and mortality. For sexual traits, mixed associations with age and positive associations with life expectancy have been reported. However, whether these associations are caused by selective disappearance and/or within-individual senescence of sexual signals, respectively, is not known. We previously reported that zebra finches with redder bills had greater life expectancy, based on a single bill colour measurement per individual. We here extend this analysis using longitudinal data and show that this finding is attributable to terminal declines in bill redness in the year before death, with no detectable change in presenescent redness. Additionally, there was a quadratic relationship between presenescent bill colouration and survival: individuals with intermediate bill redness have maximum survival prospects. This may reflect that redder individuals overinvest in colouration and/or associated physiological changes, while below-average bill redness probably reflects poorer phenotypic quality. Together, this pattern suggests that bill colouration is defended against physiological deterioration, because of mate attraction benefits, or that physiological deterioration is not a gradual process, but accelerates sharply prior to death. We discuss these possibilities in the context of the reliability theory of ageing and sexual selection.

Rasch analysis of professional behavior in medical education.

The use of students' "consumer feedback" to assess faculty behavior and improve the process of medical education is a significant challenge. We used quantitative Rasch measurement to analyze pre-categorized student comments listed by 385 graduating medical students. We found that students differed little with respect to the number of comments they provided and that their comments indeed form a probabilistic Rasch hierarchy. However, different hierarchies were found across medical departments and faculty. An analysis of these interactions provides valuable, detailed, and quantitative information that can augment qualitative research approaches. In addition, we suggest how the Rasch scaling of student comments can assist researchers in the design and implementation of new faculty evaluation instruments. Finally, the interactions between student and department identified a subset of behaviors that appear to guide and possibly elicit students' comments.

Mutation screen of the SIM1 gene in pediatric patients with early-onset obesity.

BACKGROUND: The transcription factor SIM1 (Single-minded 1) is involved in the control of food intake and in the pathogenesis of obesity. In mice, Sim1 is involved in the development of the paraventricular nucleus, and Sim1 deficiency leads to severe obesity and hyperphagia. In humans, chromosomal abnormalities in the SIM1 gene region have been reported in obese individuals. Furthermore, recent data also suggest that loss-of-function point mutations in SIM1 are responsible for SIM1 haplo-insufficiency that is involved in causing human obesity. In this study, we therefore wanted to expand the evidence regarding the involvement of SIM1 mutations in the pathogenesis of severe early-onset obesity. METHODS: We screened 561 severely overweight and obese children and adolescents and 453 lean adults for mutations in the coding region of the SIM1 gene. Mutation screening in all patients and lean individuals was performed by high-resolution melting curve analysis combined with direct sequencing. To evaluate the effect of the mutations on SIM1 transcriptional activity, luciferase reporter assays were performed. RESULTS: Mutation analysis identified four novel nonsynonymous coding variants in SIM1 in four unrelated obese individuals: p.L242V, p.T481K, p.A517V and p.D590E. Five synonymous variants, p.P57P, p.F93F, p.I183I, p.V208V and p.T653T, were also identified. Screening of the lean control population revealed the occurrence of four other rare SIM1 variants: p.G408R, p.R471P, p.S492P and p.S622F. For variants p.T481K and p.A517V, which were found in obese individuals, a decrease in SIM1 transcriptional activity was observed, whereas the transcriptional activity of all variants found in lean individuals resembled wild type. CONCLUSIONS: In this study, we have demonstrated the presence of rare SIM1 variants in both an obese pediatric population and a population of lean adult controls. Further, we have shown that functional in vitro analysis of SIM1 variants may help in distinguishing benign variants of no pathogenic significance from variants which contribute to the obesity phenotype.

Preconception predictors of gestational diabetes: a multicentre prospective cohort study on the predominant complication of pregnancy in polycystic ovary syndrome.

STUDY QUESTION: Can we develop an adequate preconception prediction model to identify those women with polycystic ovary syndrome (PCOS) who have an increased risk of developing gestational diabetes mellitus (GDM) during subsequent pregnancy? STUDY ANSWER: The risk of developing GDM in women with PCOS can be adequately predicted prior to conception by a prediction model. WHAT IS KNOWN ALREADY: Women with PCOS are at increased risk of pregnancy complications, especially GDM. GDM has serious short-term and long-term effects on mother and baby. STUDY DESIGN, SIZE, DURATION: This study is a part of a multicentre prospective cohort study, which was conducted between April 2008 and April 2012. A total of 326 women with PCOS were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS and a wish to conceive were included prior to conception and followed until 6 weeks after delivery. Maternal, neonatal and birth complications were reported. A multivariate model was developed to predict the most common pregnancy complication, GDM, by using univariate and multivariate logistic regression of preconception patient characteristics. The area under the curve (AUC) of the receiver-operating characteristic was used to test the performance of the model. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 189 women (58%) achieved an ongoing pregnancy (8% multiples) and delivered a live-born neonate. One or two maternal complications occurred in 62 (33%) pregnant women, mainly GDM (n = 41; 22%) and pregnancy-induced hypertension (n = 14; 7%). In children, one or two complications were observed in 49 (26%) of 206 children born, e.g. premature delivery (n = 23; 12%) and small for gestational age (n = 15; 8%). The preconception prediction model for GDM performed well (AUC 0.87, 95% CI 0.81-0.93). First-degree relatives with type 2 diabetes mellitus, serum levels of fasting glucose, fasting insulin, androstenedione and sex hormone-binding globulin before conception were identified as predictors. LIMITATIONS, REASONS FOR CAUTIONS: The prediction model has not yet been externally validated in another group of patients. Also, there were missing data for some of the determinants, which were accounted for by multiple imputation. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS who achieve a pregnancy have an increased risk of GDM. The prediction model can be used to identify women particularly at risk for GDM who should be monitored closely to enable preventative measures that may reduce the risk of developing GDM and its adverse consequences. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for the study. M.A.W., S.M.V.V., A.J.G., A.F. and M.P.H.K. have nothing to disclose. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, European Society of Human Reproduction and Embryology and MSD. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, Merck-Serono, MSD, Organon, Schering Plough, Sharp & Dome and Serono. M.J.C. has received grant support from the following companies (in alphabetic order): Illumina and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Ferring, Ova-Science, PregLem SA, Roche and Watson Laboratories. TRIAL REGISTRATION NUMBER: NCT00821379 [Clinicaltrials.gov].

Aminoglycoside-induced sensorineural hearing loss in pediatric cystic fibrosis patients: A retrospective cohort study.

Background: Pulmonary infections by gram-negative organisms are important in cystic fibrosis (CF). Aminoglycosides (AG) are often part of the treatment regimen. However, they are a well-known cause of ototoxicity. Even minimal hearing impairment in children could have a future impact on functional well-being.We aimed to investigate the progression of sensorineural hearing loss (SNHL) over several years in pediatric CF patients, and to identify risk factors, such as the use of AG, including both intravenous (IV) and inhaled AG. Methods: Retrospective analyses of patient records from children and adolescents followed up at the CF clinic of the Antwerp University Hospital, Belgium, were performed. We collected data on age, sex, pure-tone audiometry, and the use of AG. Descriptive and binary logistic regression analyses, and if indicated generalized estimating equations (GEE) analyses were performed. Results: Forty pediatric patients were enrolled in the study taking part from 2013 to 2020. Pure-tone audiometry revealed an important rate of SNHL over several years, with a prevalence of 29 % for high-frequency SNHL (i.e. 8 kHz). Increasing age was identified as a significant risk factor for the development of SNHL at 8 kHz if 5 or more IV AG courses (p = 0.01) were reported or when IV AG were combined with inhaled AG (p = 0.002). Conclusions: Age combined with the use of IV AG (≥5 courses or in combination with inhaled AG) are predictive for developing high-frequency SNHL (i.e. 8 kHz). We suggest routine annual hearing screening (incl. high-frequency thresholds) in CF patients, starting from childhood.

Expression of CXCR3 and its ligands CXCL9, -10 and -11 in paediatric opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder associated with remote cancer. To understand more clearly the role of inflammatory mediators, the concentration of CXCR3 ligands CXCL10, CXCL9 and CXCL11 was measured in 245 children with OMS and 81 paediatric controls using enzyme-linked immunosorbent assay (ELISA), and CXCR3 expression on CD4(+) T cells was measured by flow cytometry. Mean cerebrospinal fluid (CSF) CXCL10 was 2·7-fold higher in untreated OMS than controls. Intrathecal production was demonstrated by significantly different CXCL10 CSF : serum ratios. The dichotomized 'high' CSF CXCL10 group had higher CSF leucocyte count (P = 0·0007) and B cell activating factor (BAFF) and CXCL13 concentrations (P < 0·0001). CSF CXCL10 did not correlate with clinical severity or relapse using grouped data, although it did in some patients. Among seven types of immunotherapy, including rituximab or chemotherapy, only adrenocorticotrophic hormone (ACTH) monotherapy showed reduced CSF CXCL10, but prospective longitudinal studies of ACTH combination therapies indicated no reduction in CXCL10 despite clinical improvement (P < 0·0001). CXCL10 concentrations were 11-fold higher in CSF and twofold higher in serum by multiplexed fluorescent bead-based immunoassay than enzyme-linked immunosorbent assay, but the two correlated (r = 0·7 and 0·83). In serum, no group differences for CXCL9 or CXCL11 were found. CXCR3 expression on CD4(+) T cells was fivefold higher in those from CSF than blood, but was not increased in OMS or altered by conventional immunotherapy. These data suggest alternative roles for CXCL10 in OMS. Over-expression of CXCL10 was not reduced by clinical immunotherapies as a whole, indicating the need for better therapeutic approaches.

Specific medical and surgical treatment for chronic inflammatory diseases in children.

Treatment for chronic inflammatory conditions in children should take into account the specific pathophysiological and clinical processes underlying these disorders. These guidelines provide a framework for both the medical and surgical treatment of chronic inflammatory diseases such as otitis media, allergic rhinitis and chronic rhinosinusitis, chronic inflammation of tonsils and adenoids, and laryngitis. In addition, the role of vaccinations and immunomodulatory therapies is discussed. Whenever possible, the evidence levels for specific treatments comply with the Oxford Levels of Evidence.

Unintentional combining enzalutamide with a moderate CYP2C8 inhibitor in a patient with metastatic castration-resistant prostate cancer: a case report.

BACKGROUND: Enzalutamide, registered for the treatment of metastatic castration-resistant prostate cancer (mCRPC), is an inducer of multiple CYP-enzymes. Enzalutamide itself is mainly converted by CYP2C8 to the active metabolite N-desmethylenzalutamide (NDME). Due to a pharmacokinetic interaction, combining enzalutamide with a moderate CYP2C8 inhibitor might result in higher enzalutamide concentrations. Addressing this interaction is challenging since pharmacokinetic data are missing. CASE PRESENTATION: We present a case of a Caucasian male with mCRPC who was treated with enzalutamide and a moderate CYP2C8 inhibitor, clopidogrel, concomitantly. Plasma trough levels (Ctrough) of enzalutamide and its active metabolite N-desmethylenzalutamide (NDME) were determined and compared when treated with and without clopidogrel. The sum concentration of enzalutamide and NDME was not affected by coadministration of a moderate CYP2C8 inhibitor. Both treatments were well tolerated and no major side effect were observed. CONCLUSION: This case report shows that enzalutamide can be safely prescribed while cotreated with a moderate CYP2C8-inhibitor, without reducing the dose. More research is warranted to make a statement about the effect of enzalutamide on clopidogrel.

Hippo signaling instructs ectopic but not normal organ growth.

The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.

Stochastic modeling of length-dependent telomere shortening in Corvus monedula.

It was recently shown that, within individuals, longer telomeres shorten at a higher rate. This explorative study deals with a mathematical model of this process. It is a nonlinear differential equation describing length-dependent decrease that can be linked to a Poisson process. The model also takes in account telomere shortening due to the end replication problem. Parameters are fitted using data from samples of red blood cells of free-living juvenile corvids. The Poisson process can be related to oxidative stress causing DNA strand breaks. The shortest telomeres in a genome are the best predictors of survival, and one can therefore hypothesize on functional grounds that short telomeres should be better protected by some control mechanism in the cellular system. However, the present study shows that such a mechanism is not required to explain length-dependent telomere shortening: agents of telomere shortening such as oxidative stress with a certain strength modeled by a Poisson process with an appropriately chosen parameter suffice to generate the observed pattern.

Effect of body weight on upper airway findings and treatment outcome in children with obstructive sleep apnea.

OBJECTIVE/BACKGROUND: Surgical interventions for obstructive sleep apnea (OSA) are less effective in obese than in normal-weight children. However, the mechanisms that underpin this relationship are not fully understood. Therefore, this study aimed to explore how body weight influences upper airway collapse and treatment outcome in children with OSA. METHODS: We conducted a retrospective analysis of prospectively collected data on polysomnography, drug-induced sleep endoscopy (DISE), and treatment outcome in otherwise healthy children with OSA. Associations between body mass index (BMI) z-score and upper airway collapse during DISE were assessed using logistic regression modelling. Treatment success was defined as obstructive apnea-hypopnea index (oAHI) < 5 events/hour and cure as oAHI < 2 events/hour with obstructive apnea index < 1 event/hour. RESULTS: A total of 139 children were included [median (Q1─Q3); age 4.5 (3.1─8.4) years; BMI z-score 0.3 (-0.8 to 1.4); oAHI 10.8 (6.8─18.0) events/hour]. Twenty-five of them were overweight and 21 were obese. After adjusting for age and history of upper airway surgery, BMI z-score was significantly correlated with circumferential upper airway collapse during DISE (odds ratio 1.67; 95% confidence interval 1.12─2.65; P = 0.011). Outcome of DISE-directed treatment was similar in normal-weight (success: 91.4%; cure: 78.5%), overweight (success: 88.0%; cure: 80.0%), and obese (success: 90.5%; cure: 76.5%) children. Children with circumferential collapse responded better to continuous positive airway pressure than to (adeno)tonsillectomy. CONCLUSION: Increasing body weight is associated with circumferential upper airway collapse during DISE and, accordingly, may require treatment strategies other than (adeno)tonsillectomy.

Sex hormone-binding globulin concentrations before conception as a predictor for gestational diabetes in women with polycystic ovary syndrome.

BACKGROUND: Low plasma sex hormone-binding globulin (SHBG) concentrations during pregnancy have been associated with the risk of developing gestational diabetes mellitus (GDM). Women presenting with polycystic ovary syndrome (PCOS) often exhibit low plasma SHBG concentration and are at increased risk of developing GDM. In this study, we investigate whether SHBG levels before conception are predictive of GDM in women with PCOS. METHODS: A total of 50 women with PCOS were enrolled and followed up during pregnancy. Initial endocrine, metabolic and physical features were assessed according to a standardized preconception screening program. At 24-26 weeks of gestational age a 100-g glucose tolerance test was performed to screen for GDM. RESULTS: Of the 50 women, 21 (42%) were diagnosed with GDM by a 100-g glucose tolerance test. Waist circumference, BMI, blood pressure, plasma glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) and SHBG levels before conception were significantly different between women who did and did not develop GDM. Stepwise logistic regression analysis showed that SHBG was the most significant predictive parameter for GDM (odds ratio 0.92; 95% confidence interval 0.87-0.97), without significant contribution of waist circumference and HOMA-IR. Receiver operator characteristic (ROC) analysis indicated that plasma SHBG (area under the curve 0.86) had the highest predictive value for subsequent development of GDM, however, the limited group size did not allow for calculation of a threshold value of SHBG. CONCLUSIONS: In women with PCOS, preconception SHBG levels are strongly associated with subsequent development of GDM. Regression and ROC analysis show that preconception SHBG levels may be a better predictor for GDM in PCOS women compared with waist circumference or HOMA-IR. CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379.

Trans-generational effects on ageing in a wild bird population.

Ageing, long thought to be too infrequent to study effectively in natural populations, has recently been shown to be ubiquitous, even in the wild. A major challenge now is to explain variation in the rates of ageing within populations. Here, using 49 years of data from a population of great tits (Parus major), we show that offspring life-history trajectories vary with maternal age. Offspring hatched from older mothers perform better early in life, but suffer from an earlier onset, and stronger rate, of reproductive senescence later in life. Offspring reproductive lifespan is, however, unaffected by maternal age, and the different life-history trajectories result in a similar fitness payoff, measured as lifetime reproductive success. This study therefore identifies maternal age as a new factor underlying variation in rates of ageing, and, given the delayed trans-generational nature of this effect, poses the question as to proximate mechanisms linking age-effects across generations.