Deconstructing the smoking-preeclampsia paradox through a counterfactual framework.

Although smoking during pregnancy may lead to many adverse outcomes, numerous studies have reported a paradoxical inverse association between maternal cigarette smoking during pregnancy and preeclampsia. Using a counterfactual framework we aimed to explore the structure of this paradox as being a consequence of selection bias. Using a case-control study nested in the Icelandic Birth Registry (1309 women), we show how this selection bias can be explored and corrected for. Cases were defined as any case of pregnancy induced hypertension or preeclampsia occurring after 20 weeks' gestation and controls as normotensive mothers who gave birth in the same year. First, we used directed acyclic graphs to illustrate the common bias structure. Second, we used classical logistic regression and mediation analytic methods for dichotomous outcomes to explore the structure of the bias. Lastly, we performed both deterministic and probabilistic sensitivity analysis to estimate the amount of bias due to an uncontrolled confounder and corrected for it. The biased effect of smoking was estimated to reduce the odds of preeclampsia by 28 % (OR 0.72, 95 %CI 0.52, 0.99) and after stratification by gestational age at delivery ( 1, revealing the structure of the paradox. The bias-adjusted estimation of the smoking effect on preeclampsia showed an OR of 1.22 (95 %CI 0.41, 6.53). The smoking-preeclampsia paradox appears to be an example of (1) selection bias most likely caused by studying cases prevalent at birth rather than all incident cases from conception in a pregnancy cohort, (2) omitting important confounders associated with both smoking and preeclampsia (preventing the outcome to develop) and (3) controlling for a collider (gestation weeks at delivery). Future studies need to consider these aspects when studying and interpreting the association between smoking and pregnancy outcomes

The TGF beta family in human placental development at the fetal-maternal interface

Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGF beta) family as it has been shown that the TGF beta family has an important role in human placental development and disease.Stem cells & developmental biolog

Smad7 and protein phosphatase 1α are critical determinants in the duration of TGF-β/ALK1 signaling in endothelial cells

BACKGROUND: In endothelial cells (EC), transforming growth factor-β (TGF-β) can bind to and transduce signals through ALK1 and ALK5. The TGF-β/ALK5 and TGF-β/ALK1 pathways have opposite effects on EC behaviour. Besides differential receptor binding, the duration of TGF-β signaling is an important specificity determinant for signaling responses. TGF-β/ALK1-induced Smad1/5 phosphorylation in ECs occurs transiently. RESULTS: The temporal activation of TGF-β-induced Smad1/5 phosphorylation in ECs was found to be affected by de novo protein synthesis, and ALK1 and Smad5 expression levels determined signal strength of TGF-β/ALK1 signaling pathway. Smad7 and protein phosphatase 1α (PP1α) mRNA expression levels were found to be specifically upregulated by TGF-β/ALK1. Ectopic expression of Smad7 or PP1α potently inhibited TGF-β/ALK1-induced Smad1/5 phosphorylation in ECs. Conversely, siRNA-mediated knockdown of Smad7 or PP1α enhanced TGF-β/ALK1-induced signaling responses. PP1α interacted with ALK1 and this association was further potentiated by Smad7. Dephosphorylation of the ALK1, immunoprecipitated from cell lysates, was attenuated by a specific PP1 inhibitor. CONCLUSION: Our results suggest that upon its induction by the TGF-β/ALK1 pathway, Smad7 may recruit PP1α to ALK1, and thereby control TGF-β/ALK1-induced Smad1/5 phosphorylation

Cumulative risk over the early life course and its relation to academic achievement in childhood and early adolescence

Early-life risk factors, such as family disruption, maltreatment, and poverty, can negatively impact children's scholastic abilities; however, most previous studies have relied on cross-sectional designs and retrospective measurement. This study investigated the relation between cumulative risk factors during the early life course and subsequent academic achievement in a cohort of children and adolescents. Data for this study were based on registry-data material from the LIFECOURSE study of 1151 children from the 2000 birth cohort in Reykjavik, Iceland, assembled in 2014-2016. Multiple lifetime risk factors, including maternal smoking during pregnancy, parent's disability status, being born to a young mother, number of children in the household, family income, number of visits to school nurses, and reports of maltreatment, were assessed. Latent class analysis and Analysis of Covariance (ANCOVA) were used to predict academic achievement in the 4th and 7th grades. Individuals with no risk factors reported the highest average academic achievement in the 4th (M=66 points, SD=17) and 7th grades (M=67 points, SD=15). There was a significant main effect for 4th-grade risk factors and academic achievement (F [7, 1146]=12.06, p<0.001) and a similar relationship between the risk factor profile and achievement scores in 7th grade (F [7, 1146]=15.08, p<0.001). Each additional risk factor was associated with a drop in academic achievement at both grade levels. We conclude that academic achievement declines in proportion to the number of risk factors in early life

Waiting time for cancer treatment and mental health among patients with newly diagnosed esophageal or gastric cancer: a nationwide cohort study

Background Except for overall survival, whether or not waiting time for treatment could influences other domains of cancer patients’ overall well-being is to a large extent unknown. Therefore, we performed this study to determine the effect of waiting time for cancer treatment on the mental health of patients with esophageal or gastric cancer. Methods Based on the Swedish National Quality Register for Esophageal and Gastric Cancers (NREV), we followed 7,080 patients diagnosed 2006–2012 from the time of treatment decision. Waiting time for treatment was defined as the interval between diagnosis and treatment decision, and was classified into quartiles. Mental disorders were identified by either clinical diagnosis through hospital visit or prescription of psychiatric medications. For patients without any mental disorder before treatment, the association between waiting time and subsequent onset of mental disorders was assessed by hazard ratios (HRs) with 95% confidence interval (CI), derived from multivariable-adjusted Cox model. For patients with a preexisting mental disorder, we compared the rate of psychiatric care by different waiting times, allowing for repeated events. Results Among 4,120 patients without any preexisting mental disorder, lower risk of new onset mental disorders was noted for patients with longer waiting times, i.e. 18–29 days (HR 0.86; 95% CI 0.74-1.00) and 30–60 days (HR 0.79; 95% CI 0.67-0.93) as compared with 9–17 days. Among 2,312 patients with preexisting mental disorders, longer waiting time was associated with more frequent psychiatric hospital care during the first year after treatment (37.5% higher rate per quartile increase in waiting time; p for trend = 0.0002). However, no such association was observed beyond one year nor for the prescription of psychiatric medications. Conclusions These data suggest that waiting time to treatment for esophageal or gastric cancer may have different mental health consequences for patients depending on their past psychiatric vulnerabilities. Our study sheds further light on the complexity of waiting time management, and calls for a comprehensive strategy that takes into account different domains of patient well-being in addition to the overall survival.This study was partly supported by the Swedish Cancer Society (grant No: CAN 2014/417).Peer Reviewe

Mental disorders around cancer diagnosis and increased hospital admission rate - a nationwide cohort study of Swedish cancer patients

Background: Whether the emotional distress around cancer diagnosis is associated with the long-term outcomes and care utilization is unknown. We aimed to examine the association of mental disorders around cancer diagnosis with the hospital admission rates of cancer patients thereafter. Methods: We conducted a nationwide cohort study including 218,508 cancer patients diagnosed in Sweden during 2004–2009 and followed them from 90 days after cancer through 2010. We used a clinical diagnosis of stress-related mental disorders from 90 days before to 90 days after cancer diagnosis as the exposure. We studied first all hospital admissions and then separately three common admissions, including external injuries, infections, and cardiovascular diseases. The Cox model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Four thousand one hundred five patients received a diagnosis of stress-related mental disorders around the cancer diagnosis, and experienced a 35% increased rate of any hospital admission during follow-up (HR: 1.35, 95%CI: 1.28–1.41) as well as hospital admissions for external injuries (HR: 1.89, 95%CI: 1.67–2.14), infections (HR: 1.28, 95%CI: 1.08–1.52), and cardiovascular diseases (HR: 1.16, 95%CI: 1.03–1.30). Similar association was noted for most common cancer types. Conclusions: These data suggest that cancer patients diagnosed with a stress-related mental disorder immediately before or after cancer diagnosis are subsequently at increased risk of hospital admissions for major comorbidities of cancer. Electronic supplementary material The online version of this article (10.1186/s12885-018-4270-4) contains supplementary material, which is available to authorized users

Childhood injury after a parental cancer diagnosis

A parental cancer diagnosis is psychologically straining for the whole family. We investigated whether a parental cancer diagnosis is associated with a higher-than-expected risk of injury among children by using a Swedish nationwide register-based cohort study. Compared to children without parental cancer, children with parental cancer had a higher rate of hospital contact for injury during the first year after parental cancer diagnosis (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 1.22-1.33), especially when the parent had a comorbid psychiatric disorder after cancer diagnosis (HR = 1.41, 95% CI = 1.08-1.85). The rate increment declined during the second and third year after parental cancer diagnosis (HR = 1.10, 95% CI = 1.07-1.14) and became null afterwards (HR = 1.01, 95% CI = 0.99-1.03). Children with parental cancer also had a higher rate of repeated injuries than the other children (HR = 1.13, 95% CI = 1.12-1.15). Given the high rate of injury among children in the general population, our findings may have important public health implications.NonePublishe

How Much Information Do Icelandic Men Receive on Pros and Cons of Prostate-Specific Antigen Testing Prior to Undergoing Testing?

Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Traditional Chinese Medical Science and Technology Project of Zhejiang Province (Grant No. 2022ZB130), and the National Famous Old Chinese Medicine Experts SONG Xinwei Inheritance Studio Project (G.TCM.R.J.H.[2018]134). Funding Information: The authors acknowledge the important work done at the Icelandic Cancer Registry that made this study possible and thank their staff for invaluable guidance. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Icelandic Center for Research (grant no. 141490) and the Research Fund of the Icelandic Cancer Society (grant no. 2017-05). Publisher Copyright: © The Author(s) 2022.Prostate-specific antigen (PSA) testing for asymptomatic men is neither encouraged nor discouraged in most countries; however, shared decision-making is emphasized prior to PSA testing. The objective of this study was to examine to what extent Icelandic men receive information about the pros and cons of PSA testing. Furthermore, to explore if patient–provider communication about pros and cons of PSA testing has improved in the last decade during which time more emphasis has been placed on shared decision-making. All Icelandic men diagnosed with prostate cancer in the years 2015 to 2020 were invited to participate, and a total of 471 out of 1002 men participated (response rate 47.0%). Participants’ age ranged from 51 to 95 years (M = 71.9, SD = 7.3). Only half of the men received information about the pros and cons of PSA testing, a third did not receive any information prior to testing and, alarmingly, 22.2% of the men did not even know that they were being tested. A majority of the participants lacked knowledge about the testing with half of the men reporting that they had no knowledge about pros and cons of PSA testing prior to testing. The findings have major public health relevance as they indicate that information provided prior to PSA testing continue to be deficient and that there is a pressing need for interventions that educate men about the benefits and limitations of PSA testing before men undergo medical procedures that can seriously affect their quality of life.Peer reviewe

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

Publisher's version (útgefin grein)Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease.M.S.A. is supported by the “Göngum saman” cancer fund and the Helga Jonsdottir and Sigurlidi Kristjansson memorial fund; G.V. is supported by the University of Iceland research fund, the Icelandic cancer association, and the Watanabe trust fund at the University of Iceland.Peer Reviewe

Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries

Objective: To assess whether maternal use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of persistent pulmonary hypertension in the newborn, and whether such an effect might differ between specific SSRIs. Design: Population based cohort study using data from the national health registers. Setting: Denmark, Finland, Iceland, Norway, and Sweden, 1996-2007. Participants: More than 1.6 million infants born after gestational week 33. Main outcome measures: Risks of persistent pulmonary hypertension of the newborn associated with early and late exposure to SSRIs during pregnancy and adjusted for important maternal and pregnancy characteristics. Comparisons were made between infants exposed and not exposed to SSRIs. Results: Around 30 000 women had used SSRIs during pregnancy and 11 014 had been dispensed an SSRI later than gestational week 20. Exposure to SSRIs in late pregnancy was associated with an increased risk of persistent pulmonary hypertension in the newborn: 33 of 11 014 exposed infants (absolute risk 3 per 1000 liveborn infants compared with the background incidence of 1.2 per 1000); adjusted odds ratio 2.1 (95% confidence interval 1.5 to 3.0). The increased risks of persistent pulmonary hypertension in the newborn for each of the specific SSRIs (sertraline, citalopram, paroxetine, and fluoxetine) were of similar magnitude. Filling a prescription with SSRIs before gestational week 8 yielded slightly increased risks: adjusted odds ratio 1.4 (95% confidence interval 1.0 to 2.0). Conclusions: The risk of persistent pulmonary hypertension of the newborn is low, but use of SSRIs in late pregnancy increases that risk more than twofold. The increased risk seems to be a class effect.publishedVersio