Delayed effects of alcohol consumption on the association between serum BDNF levels and post-traumatic stress disorder development over two-years.

BACKGROUNDS: This study aimed to examine the individual and combined effects of serum BDNF (sBDNF) levels and alcohol consumption status, assessed shortly after a physical injury, on the development of post-traumatic stress disorder (PTSD) over two years. METHODS: Participants were consecutively recruited from a trauma center and followed prospectively for two years. At baseline, sBDNF levels and alcohol consumption history were assessed. A range of socio-demographic and clinical covariates were also collected. PTSD diagnosis during follow-up (3, 6, 12, and 24 months post-injury) was established using the Clinician-Administered PTSD Scale for DSM-5. Binary and multinomial logistic regression analyses were employed to investigate the relationships between sBDNF levels, alcohol consumption status, and PTSD onset. RESULTS: Out of 923 participants analyzed, 112 (12.1%) developed PTSD at some point during the study, with prevalence rates of 8.8% at 3 months, 7.6% at 6 months, 4.8% at 12 months, and 3.7% at 24 months. The study found no individual associations between sBDNF levels or alcohol consumption status and PTSD development. However, lower sBDNF levels significantly predicted PTSD in individuals who consumed alcohol, a relationship not observed in non-drinkers, with significant interaction terms. This pattern was consistent at later follow-up points from 12 to 24 months, but not at earlier assessments at 3 and 6 months. LIMITATIONS: The study's reliance on participants from a single trauma center with moderate to severe injuries may limit the generalizability of the findings. CONCLUSIONS: A significant interaction between sBDNF levels and alcohol consumption in relation to PTSD development was observed, particularly in the long term. These findings highlight the necessity of considering both sBDNF levels and alcohol consumption in strategies aimed at preventing PTSD among individuals with physical injuries, underscoring the need for tailored approaches based on these factors.

Effects of microgravity on neural crest stem cells.

Exposure to microgravity (µg) results in a range of systemic changes in the organism, but may also have beneficial cellular effects. In a previous study we detected increased proliferation capacity and upregulation of genes related to proliferation and survival in boundary cap neural crest stem cells (BC) after MASER14 sounding rocket flight compared to ground-based controls. However, whether these changes were due to µg or hypergravity was not clarified. In the current MASER15 experiment BCs were exposed simultaneously to µg and 1 g conditions provided by an onboard centrifuge. BCs exposed to µg displayed a markedly increased proliferation capacity compared to 1 g on board controls, and genetic analysis of BCs harvested 5 h after flight revealed an upregulation, specifically in µg-exposed BCs, of Zfp462 transcription factor, a key regulator of cell pluripotency and neuronal fate. This was associated with alterations in exosome microRNA content between µg and 1 g exposed MASER15 specimens. Since the specimens from MASER14 were obtained for analysis with 1 week's delay, we examined whether gene expression and exosome content were different compared to the current MASER15 experiments, in which specimens were harvested 5 h after flight. The overall pattern of gene expression was different and Zfp462 expression was down-regulated in MASER14 BC µg compared to directly harvested specimens (MASER15). MicroRNA exosome content was markedly altered in medium harvested with delay compared to directly collected samples. In conclusion, our analysis indicates that even short exposure to µg alters gene expression, leading to increased BC capacity for proliferation and survival, lasting for a long time after µg exposure. With delayed harvest of specimens, a situation which may occur due to special post-flight circumstances, the exosome microRNA content is modified compared to fast specimen harvest, and the direct effects from µg exposure may be partially attenuated, whereas other effects can last for a long time after return to ground conditions.

Effects of the prenatal and postnatal nurturing environment on the phenotype and gut microbiota of mice with polycystic ovary syndrome induced by prenatal androgen exposure: a cross-fostering study.

The gut microbiome is implicated in the pathogenesis of polycystic ovary syndrome (PCOS), and prenatal androgen exposure is involved in the development of PCOS in later life. Our previous study of a mouse model of PCOS induced by prenatal dihydrotestosterone (DHT) exposure showed that the reproductive phenotype of PCOS appears from puberty, followed by the appearance of the metabolic phenotype after young adulthood, while changes in the gut microbiota was already apparent before puberty. To determine whether the prenatal or postnatal nurturing environment primarily contributes to these changes that characterize prenatally androgenized (PNA) offspring, we used a cross-fostering model to evaluate the effects of changes in the postnatal early-life environment of PNA offspring on the development of PCOS-like phenotypes and alterations in the gut microbiota in later life. Female PNA offspring fostered by normal dams (exposed to an abnormal prenatal environment only, fostered PNA) exhibited less marked PCOS-like phenotypes than PNA offspring, especially with respect to the metabolic phenotype. The gut microbiota of the fostered PNA offspring was similar to that of controls before adolescence, but differences between the fostered PNA and control groups became apparent after young adulthood. In conclusion, both prenatal androgen exposure and the postnatal early-life environment created by the DHT injection of mothers contribute to the development of PCOS-like phenotypes and the alterations in the gut microbiota that characterize PNA offspring. Thus, both the pre- and postnatal environments represent targets for the prevention of PCOS and the associated alteration in the gut microbiota in later life.

Determining the late effect parameter in the Fleming-Harrington test using asymptotic relative efficiency in cancer immunotherapy clinical trials.

The delayed treatment effect, which manifests as a separation of survival curves after a change point, has often been observed in immunotherapy clinical trials. A late effect of this kind may violate the proportional hazards assumption, resulting in the non-negligible loss of statistical power of an ordinary log-rank test when comparing survival curves. The Fleming-Harrington (FH) test, a weighted log-rank test, is configured to mitigate the loss of power by incorporating a weight function with two parameters, one each for early and late treatment effects. The two parameters need to be appropriately determined, but no helpful guides have been fully established. Since the late effect is expected in immunotherapy trials, we focus on the late effect parameter in this study. We consider parameterizing the late effect in a readily interpretable fashion and determining the optimal late effect parameter in the FH test to maintain statistical power in reference to the asymptotic relative efficiency (ARE). The optimization is carried out under three lag models (i.e. linear, threshold, and generalized linear lag), where the optimal weights are proportional to the lag functions characterized by the change points. Extensive simulation studies showed that the FH test with the selected late parameter reliably provided sufficient power even when the change points in the lag models were misspecified. This finding suggests that the FH test with the ARE-guided late parameter may be a reasonable and practical choice for the primary analysis in immunotherapy clinical trials.

The delayed, durable effect of expressive writing on depression, anxiety and stress: A meta-analytic review of studies with long-term follow-ups.

BACKGROUND: Expressive writing is a promising tool to heal the wounds with words. AIMS: This meta-analysis evaluated the current state of efficacy of expressive writing on depression, anxiety and stress symptoms among healthy and subclinical samples. MATERIALS AND METHODS: Thirty-one experimental studies (N = 4012) with randomized controlled trials and follow-up assessments were analysed. RESULTS: Results showed that expressive writing had an overall small but significant effect (Hedges' g = -0.12, 95% CI [-0.21, -0.04]) on reducing symptoms of depression, anxiety and stress. Change score analyses suggested that the intervention effect emerged after a delay, as evidenced by assessments at follow-up periods. Moderator analyses indicated that the effect sizes varied as a function of one intervention feature: interval. Studies that implemented short intervals (1-3 days) between writing sessions yielded stronger effects (Gdiff  = -0.18, p = .01) relative to studies that implemented medium intervals (4-7 days) or long intervals (>7 days). The effects of expressive writing remained consistent across other intervention features including focus, instruction, number of sessions, topic repetition and delivery mode. DISCUSSION: Together, these findings provide evidence for the delayed, durable effect of expressive writing and underscore the importance of scheduling writing sessions at short intervals. CONCLUSION: Implications for incorporating expressive writing into clinical practice and daily life are discussed.

From single to multivariable exposure models to translate climatic and air pollution effects into mortality risk. A customized application to the city of Rome, Italy.

This study presents an approach developed to derive a Delayed-Multivariate Exposure-Response Model (D-MERF) useful to assess the short-term influence of temperature on mortality, accounting also for the effect of air pollution (O3 and PM10). By using Distributed, lag non-linear models (DLNM) we explain how city-specific exposure-response functions are derived for the municipality of Rome, which is taken as an example. The steps illustrated can be replicated to other cities while the statistical model presented here can be further extended to other exposure variables. We derive the mortality relative-risk (RR) curve averaged over the period 2004-2015, which accounts for city-specific climate and pollution conditions. Key aspects of customization are as follows: This study reports the steps followed to derive a combined, multivariate exposure-response model aimed at translating climatic and air pollution effects into mortality risk. Integration of climate and air pollution parameters to derive RR values. A specific interest is devoted to the investigation of delayed effects on mortality in the presence of different exposure factors.

Stock market fluctuation and stroke incidence: A time series study in Eastern China.

OBJECTIVE: To explore the association between daily change of Shanghai Stock Exchange (SSE) Composite Index and stroke incidence in Zhejiang, China. METHODS: Data on daily stock index change and stroke incidence during 2009-2016 were collected to form the time series. Data were analyzed using distributed lag non-linear model (DLNM) with quasi-Poisson as link function, controlling for long-term and seasonal trends, day of the week, public holiday, meteorological factors, and economic conditions. RESULTS: Large changes in daily stock index were associated with increased risk of stroke. Rise of stock index was significantly related to higher stroke incidence without delay. The relative risks (RRs) of stroke on the lag0 day were 1.040 (95% CI 1.011-1.071) for 100 index increase, and 1.111 (95% CI 1.000-1.235) for 200 index increase. Additionally, fall of stock index was associated with higher stroke incidence at lag of 5 and 6 days. The relative risks (RRs) of stroke for -200 index decline on the lag5 and lag6 day were 1.058 (95% CI 1.025-1.093) and 1.061 (95% CI 1.019-1.104) respectively. The association was relatively consistent across subgroups stratified by the subtype of stroke, gender, and age groups. CONCLUSION: Both rise and fall of stock index were associated with an elevated occurrence of stroke.

Complex survival trial design by the product integration method.

Nonproportional hazards (NPHs) are often observed in survival trials such as the immunotherapy cancer trials. Under NPH, the classical log-rank test can be inefficient, and the estimated hazards ratio from the Cox model is difficult to interpret. The weighted log-rank test, and the tests for comparing the restricted mean survival time or the milestone survival become increasingly popular in handling NPH. The sample size calculation for these tests may require high-dimensional numerical integration. We present a sample size determination method for survival trials via product integration on the basis of a continuous-time multistate Markov model. The main challenge of the method lies in the design of the multistate model under a complex NPH pattern, and this is illustrated for NPH induced by delayed effect with individual heterogeneity in the lag duration, cure fractions, and treatment switching due to disease progression or noncompliance. Numerical examples are presented to demonstrate the accuracy of the proposed method. We obtain the following findings. The powers of the tests for milestone survival and RMST depend on both the trial duration and milestone timepoint, and may not increase as the milestone timepoint increases. If the milestone timepoint is appropriately chosen, the RMST test can be more powerful than the conventional log-rank test in the presence of diminishing treatment effect or in the proportional hazards cure model. In general, the RMST test yields lower power than a proper Fleming-Harrington weighted log-rank test.

Ghrelin treatment induces rapid and delayed increments of food intake: a heuristic model to explain ghrelin's orexigenic effects.

Ghrelin is a stomach-derived peptide hormone with salient roles in the regulation of energy balance and metabolism. Notably, ghrelin is recognized as the most powerful known circulating orexigenic hormone. Here, we systematically investigated the effects of ghrelin on energy homeostasis and found that ghrelin primarily induces a biphasic effect on food intake that has indirect consequences on energy expenditure and nutrient partitioning. We also found that ghrelin-induced biphasic effect on food intake requires the integrity of Agouti-related peptide/neuropeptide Y-producing neurons of the hypothalamic arcuate nucleus, which seem to display a long-lasting activation after a single systemic injection of ghrelin. Finally, we found that different autonomic, hormonal and metabolic satiation signals transiently counteract ghrelin-induced food intake. Based on our observations, we propose a heuristic model to describe how the orexigenic effect of ghrelin and the anorectic food intake-induced rebound sculpt a timely constrain feeding response to ghrelin.

Immediate and Delayed Effects of Cupping Therapy on Reducing Neuromuscular Fatigue.

Cupping therapy has been popular in elite athletes in recent years. However, the effect of cupping therapy on reducing muscle fatigue has not been investigated. The purpose of this study was to investigate the immediate and delayed effects of cupping therapy on reducing biceps brachii fatigue during biceps curls. Twelve healthy untrained participants were recruited for this repeated-measures study. Cupping therapy (-300 mmHg pressure for 5 min) and sham control (no negative pressure for 5 min) were applied after biceps fatigue induced by performing repeated biceps curls at 75% of the 10 repetitions of maximum of the non-dominant hand. Surface electromyography (EMG) with spectral analyses [mean frequency (MNF), median frequency (MDF), and spectral moments ratio (SMR)] were used to assess muscle fatigue during the fatigue task. EMG signals during the first 10 repetitions and the last 10 repetitions of biceps curls were used to assess neuromuscular fatigue. There were significant decreases in MNF and MDF and a significant increase in SMR immediately and 24 h after the sham control (no intervention). When comparing the MNF, MDF, and SMR after cupping therapy to the sham control, there was no significant immediate effect on reducing muscle fatigue. However, there was a significant delayed effect on improving recovery following fatigue for the cupping therapy compared to the sham control (MNF changes: sham 0.87 ± 0.02 vs. cupping 0.91 ± 0.02, p < 0.05; MDF changes sham: 0.85 ± 0.03 vs. cupping: 0.91 ± 0.02, p < 0.05; SMR changes: sham 1.89 ± 0.15 vs. cupping 1.58 ± 0.13, p < 0.05). The findings of this study demonstrate that there is a time effect of cupping therapy for reducing muscle fatigue. Cupping therapy is effective on reducing biceps brachii muscle fatigue after 24 h.

Behavioural effects in mice orally exposed to domoic acid or ibotenic acid are influenced by developmental stages and sex differences.

The structure of the brain is dramatically altered during the critical period. Physiological substances (neurotransmitters, hormones, etc.) in the body fluctuate significantly before and after sexual maturation. Therefore, the effect of chemical exposure on the central nervous system often differs depending on the developmental stage and sex. We aimed to compare the behavioural effects that emerged from the administration of chemicals to mice of different life stages (immature or mature) and different sex (male or female). We administered mice with domoic acid (DA), a marine poison, and ibotenic acid (IA), found in poisonous mushrooms. These excitatory amino acids act as agonists for glutamate and are potent neurotoxins. Interestingly, the behavioural effects of these chemicals were completely different. Following DA administration, we observed memory deficits only in groups of male mice treated at maturity. Following IA administration, we observed deviations in emotional behaviour in groups of male mice treated at both immaturity and maturity. In contrast, few characteristic changes were detected in all groups of females. Our results support the theory that the behavioural effects of chemical administration vary considerably with developmental stages and sex. In conclusion, our findings promote better understanding of individual differences in excitatory chemical-induced neurotoxicity and provide evidence for future risk strategies and treatments.

A unified approach to power and sample size determination for log-rank tests under proportional and nonproportional hazards.

Log-rank tests have been widely used to compare two survival curves in biomedical research. We describe a unified approach to power and sample size calculation for the unweighted and weighted log-rank tests in superiority, noninferiority and equivalence trials. It is suitable for both time-driven and event-driven trials. A numerical algorithm is suggested. It allows flexible specification of the patient accrual distribution, baseline hazards, and proportional or nonproportional hazards patterns, and enables efficient sample size calculation when there are a range of choices for the patient accrual pattern and trial duration. A confidence interval method is proposed for the trial duration of an event-driven trial. We point out potential issues with several popular sample size formulae. Under proportional hazards, the power of a survival trial is commonly believed to be determined by the number of observed events. The belief is roughly valid for noninferiority and equivalence trials with similar survival and censoring distributions between two groups, and for superiority trials with balanced group sizes. In unbalanced superiority trials, the power depends also on other factors such as data maturity. Surprisingly, the log-rank test usually yields slightly higher power than the Wald test from the Cox model under proportional hazards in simulations. We consider various nonproportional hazards patterns induced by delayed effects, cure fractions, and/or treatment switching. Explicit power formulae are derived for the combination test that takes the maximum of two or more weighted log-rank tests to handle uncertain nonproportional hazards patterns. Numerical examples are presented for illustration.

Immediate and delayed effects of climatic factors on hospital admissions for schizophrenia in Queensland Australia: A time series analysis.

BACKGROUND: Evidence of immediate and delayed effects of climatic drivers on hospital admissions for schizophrenia is limited and inconsistent. We aimed to assess the association between climatic factors and daily hospital admissions for schizophrenia in Queensland, Australia. METHODS: Daily hospital admissions for schizophrenia from January 1, 1996 to December 31, 2015 in all private and public hospitals of Queensland were obtained from Queensland Health. The association between climatic factors and hospital admissions for schizophrenia were analysed using Generalised Linear Models with Poisson distribution (GLM) and Distributed Lag non-linear Models (DLNM) across different climatic zones. RESULTS: In South East Queensland, only daily mean temperature showed an immediate negative effect on schizophrenia admissions (RR 0.93, 95%CI 0.90-0.98, p value < 0.001). For other regions, the adverse effect of temperature on hospital admissions was not significant, however, relative humidity (North: RR 1.01, 95%CI 1.00-1.02, p = 0.05) and air pressure (North: RR 1.03, 95%CI 1.00-1.05, p = 0.04; South West: RR 1.01, 95%CI 1.00-1.02, p = 0.05) had an immediate and positive effect on hospital admissions. Moreover, climatic factors had some delayed effects on schizophrenia admissions in different regions of Queensland, i.e. temperature over 0-4 lag days (South East: RR 0.97, 95%CI 0.94-0.98, p = 0.05; South West: RR 0.96, 95%CI 0.94-0.98, p = 0.01), relative humidity over 0-7 lag days (North: RR 0.95, 95%CI 0.92-0.98, p = 0.01; Central: RR 1.02, 95%CI 1.00-1.03, p = 0.05) and rainfall over 0-21 lag days (North: RR 1.03, 95%CI 1.01-1.04, p = 0.01). Meta-analysis showed significant pooled delayed effects of temperature (0-15 days lag: RR 0.95, 95% CI 0.93-0.98, p value < 0.001), relative humidity (0-7 days: RR 0.96, 95%CI 0.92-0.99, p < 0.001); rainfall (0-21 lag days: RR 1.03, 95%CI 1.01-1.04, p < 0.001) and air pressure (0-7 days lag: RR 1.02, 95%CI 1.00-1.04, p < 0.001) on schizophrenia admissions in Queensland. DISCUSSION: As this is the largest study from Australia and also internationally to extensively examine both short term and delayed association between climatic factors and daily admissions for schizophrenia, the results of the study indicate that climate plays an important role in the sudden exacerbation of acute episodes of schizophrenia. Thus, preventive measures could be taken to reduce the severity of symptoms as well as hospital admissions due to schizophrenia during vulnerable periods.

UKCTOCS update: applying insights of delayed effects in cancer screening trials to the long-term follow-up mortality analysis.

BACKGROUND: During trials that span decades, new evidence including progress in statistical methodology, may require revision of original assumptions. An example is the continued use of a constant-effect approach to analyse the mortality reduction which is often delayed in cancer-screening trials. The latter led us to re-examine our approach for the upcoming primary mortality analysis (2020) of long-term follow-up of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (LTFU UKCTOCS), having initially (2014) used the proportional hazards (PH) Cox model. METHODS: We wrote to 12 experts in statistics/epidemiology/screening trials, setting out current evidence, the importance of pre-specification, our previous mortality analysis (2014) and three possible choices for the follow-up analysis (2020) of the mortality outcome: (A) all data (2001-2020) using the Cox model (2014), (B) new data (2015-2020) only and (C) all data (2001-2020) using a test that allows for delayed effects. RESULTS: Of 11 respondents, eight supported changing the 2014 approach to allow for a potential delayed effect (option C), suggesting various tests while three favoured retaining the Cox model (option A). Consequently, we opted for the Versatile test introduced in 2016 which maintains good power for early, constant or delayed effects. We retained the Royston-Parmar model to estimate absolute differences in disease-specific mortality at 5, 10, 15 and 18 years. CONCLUSIONS: The decision to alter the follow-up analysis for the primary outcome on the basis of new evidence and using new statistical methodology for long-term follow-up is novel and has implications beyond UKCTOCS. There is an urgent need for consensus building on how best to design, test, estimate and report mortality outcomes from long-term randomised cancer screening trials. TRIAL REGISTRATION: ISRCTN22488978 . Registered on 6 April 2000.

Effect of Ambient Temperature on Daily Nebulized Asthma Hospital Visits in a Tropical City of Dhaka, Bangladesh.

The acute effect of temperature on asthma morbidity in Bangladesh is not well understood. As climate varies extensively in different parts of the world, the relation between temperature and asthma might also differ. We investigated the association between temperature and asthma-related hospital visits in the tropical city of Dhaka. We analyzed information from a total of 5989 asthma patients who received ambulatory care in the form of nebulized medication at the National Asthma Center in Mohakhali, Dhaka from February to November 2013. A time-stratified case-crossover study was conducted to estimate the effect of daily temperature, with consideration of delayed effects and possible confounders such as relative humidity and political strikes. An inverse association was observed between temperature and the number of hospital visits. The effect was delayed for approximately a week. A degree centigrade decrease in mean temperature (averaged across lags 0-6) was associated with an increase of approximately 4.5% (95% CI 1.5, 7.5) in all asthma visits. The association was evident in adult males but marginal in elderly males. A positive association (lag 0) was observed among adult females, whereas no association was observed among children. Strikes significantly modified the effect among the elderly. Findings suggest temperature declines affect asthma outcomes in a warm climate, and this effect can be delayed and vary by sex and age group.

Delayed association of acute particulate matter 2.5 air pollution exposure with loss of complexity in cardiac rhythm dynamics: insight from detrended fluctuation analysis.

There is a delayed (lag 1 to 2 days) correlation between acute PM 2.5 (particulate matter < 2.5 µm in aerodynamic diameter) exposure and cardiovascular events, but the underlying mechanism remained unclear. We aimed to investigate the delayed impact of acute PM 2.5 exposures on cardiac autonomics through linear and nonlinear heart rate variability (HRV) analyses. Among 6912 patients who had received 24-h Holter ECG between October 1, 2015, to October 31, 2016, 56 patients (31 males, 70.3 ± 12.7 years old) were enrolled. We classified the patients as high (> 35.4 µg/m3) or low (< 35.4 µg/m3) PM 2.5 groups according to their PM 2.5 exposures on the day of Holter recordings (day 0) lag 1 and lag 2 days. Linear and nonlinear HRV parameters〔Detrended fluctuation analysis (DFA) slopes 1 and 2〕were compared. Baseline characteristics were similar between groups. Linear and nonlinear HRV parameters were similar between high- and low-exposure groups on day 0 and lag 1 day, respectively. However, DFA slope 1 was significantly lower in the high-exposure group on lag 2 days (0.784 ± 0.201 vs. 0.964 ± 0.274, p = 0.021). DFA slope 1 of the high-exposure group was significantly lower on daytime periods (9 am to 9 pm, 8 am to 4 pm and 4 pm to 12 pm) but not on nighttime periods. High lag 2 days PM 2.5 exposure is associated with low DFA slope 1 and the relationship is diurnal. This suggests that air pollution might have a delayed impact on the cardiovascular autonomic system.

The same stress has divergent effects on social versus asocial manifestations of anxiety-like behavior over time.

Stress may lead to augmented anxiety, which may, with time culminate in some form of anxiety disorder. Behavioral alterations related to increased anxiety can be broadly classified into two types-social, affecting interactions between individuals, and self-oriented, affecting the anxious individual only. While a growing body of literature now exists describing the effects of stress-induced anxiety on self-oriented behavior in animal models of anxiety disorders, the effects of such aberrant anxiety on social behavior has largely remained uncharacterized in these models. This study aims to fill this gap in our understanding by examining changes in social behavior following a single 2-hour episode of immobilization stress, which has been shown to cause delayed structural and functional changes in the amygdala. To this end, we examined social behavior, measured as active social interactions, anogenital sniffing, nose-to-nose contacts, allogrooming, actively following and crawling under, as well as self-oriented asocial behavior, manifested as self-grooming and rearing, in adult male rats. Stressed animals showed reduced social interaction 1 day after immobilization stress and this decrease was persistent for at least 10 days after stress. In contrast, individualistic behaviors were impaired only 10 days, but not 1 day later. Together, these results not only show that the same single episode of stress can elicit divergent effects on social and asocial measures of anxiety in the same animal, but also suggest that enhanced social anxiety soon after stress may also serve as an early indicator of its delayed behavioral effects.

Maternal pre-pregnancy overweight and infertility in sons and daughters: A cohort study.

INTRODUCTION: Overweight and obesity in pregnancy is increasing worldwide and may harm the developing fetus, including its future reproductive health. We therefore studied the association between in utero exposure to maternal overweight and obesity and infertility in adulthood. No studies have previously assessed this association. MATERIAL AND METHODS: We performed a cohort study with 9232 adult sons and daughters whose mothers were enrolled in the Danish Healthy Habits for Two cohort during pregnancy in 1984-87. Participants were sons and daughters followed in the Danish In-Vitro-Fertilization-Register and Danish National Patient Register until February 2018 for diagnoses of infertility. RESULTS: In total, 1203 (13%) sons and daughters were born to mothers with a body mass index (BMI) >25 kg/m2 ; 871 (9.4%) of the participants were identified as being infertile during follow-up. Sons of overweight mothers had slightly increased odds of infertility compared with sons of mothers with normal body weight (BMI 18.5-24.9 kg/m2 , adjusted odds ratio 1.4, 95% confidence interval [CI] 1.0-1.9). Cubic spline analyses with continuous BMI levels showed increasing odds with higher levels of BMI; however, for BMI >29 kg/m2 the confidence intervals were too wide to draw conclusions. No association between maternal overweight and infertility was found among daughters (adjusted odds ratio 0.9, 95% CI 0.7-1.2)). CONCLUSIONS: Sons born to overweight mothers had higher odds of infertility compared with sons of normal weight mothers. No association between maternal overweight and infertility was observed in daughters. Prevention of overweight during pregnancy may be an important tool to preserve fecundity in future generations.

Statistical adaptation to oncology drug development evolution.

Cancer treatment started with surgery at least three thousand years ago. Radiation therapy was added in 1896 with chemotherapy started 50 years later. These "cut, burn, and poison" techniques try to kill cancer cells directly and have been the main approaches in treating cancer until recently. In the past few years, immunotherapies have revolutionized cancer treatment. Instead of treating the disease, immunotherapies treat the patient with the disease; more precisely, correct the patient's immune system so that it can fight cancer in a long term, which makes the cure of metastatic cancers a real possibility. To adapt to the evolution of oncology treatment, clinical trial designs and statistical analysis methodologies are required to change accordingly in order to efficiently bring novel oncology medicines to cancer patients. For example, one of the major differences between immunotherapies and chemotherapies is that immunotherapies may take longer to have an effect but generally last longer with some patients cured. Trial design assumptions and adaptation rules (if adaptive design is used) need to take account of this delayed effect and long-term cure effect phenomenon. At the same time, more efficient statistical tests such as Fleming-Harrington test and Zmax test can be used to improve statistical power over the conventional logrank test for the analyses of time-to-event data that often exhibit non-proportional hazards. This article intends to describe how oncology drug development evolves over time and how statistical methods change accordingly.

Time-course of changes in key catecholaminergic receptors and trophic systems in rat brain after antidepressant administration.

Several biochemical parameters within the brain are altered by antidepressants. However, it is still uncertain which parameters are important for the evaluation of the effectiveness of these drugs. What seems certain is that the response of the nervous system is dynamic. The dynamic nature of the nervous system is still poorly understood, although it has implications in clinical management. Criteria for evaluating treatment resistant depression are based on this temporal variability. The present study was designed to evaluate dynamic alterations in catecholaminergic receptors and calcyon (associated with monoaminergic theory of depression) in the rat brain as well as brain-derived neurotrophic factor (BDNF) and tyrosine kinase beta (TRKB; related to neurotrophin theory) induced by three antidepressant drugs (ADs) with various pharmacological profiles (imipramine, desipramine, and citalopram) administered for 21 days or acutely, followed by various drug-free periods. Receptor autoradiography and in situ hybridization studies allowed us to identify changes in various brain regions simultaneously in each rat. Repeated treatment with ADs induced biochemical alterations, which were in agreement with the results of previous studies. These alterations include the downregulation of ß1, ß2, and α1 adrenergic receptors, upregulation of α2-adrenergic receptors and dopamine D2 receptors, and increased expression of BDNF in the hippocampus. Additionally, we observed dynamic alterations in the measured parameters after acute drug administration, particularly at the level of dopamine receptors, which were extremely sensitive to a single dose of ADs followed by various drug-free periods. All three ADs induced the upregulation of dopamine D2 receptor mRNA levels in the nucleus accumbens. The same effect was induced by single doses of ADs followed by various drug-free periods. The obtained results indicate that alterations in the availability of neurotransmitters at synapses induced by ADs are strong enough to induce immediate and long-lasting adaptive changes in the neuronal network.