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Introduction: Transverse relaxation time (T2*) is related to tissue oxygenation and morphology. We aimed to describe T2* weighted MRI in selected fetal organs in normal pregnancies, and to investigate the correlation between fetal organ T2* and placental T2*, birthweight (BW) deviation, and redistribution of fetal blood flow. Methods: T2*-weighted MRI was performed in 126 singleton pregnancies between 23+6- and 41+3-weeks’ gestation. The T2* value was obtained from the placenta and fetal organs (brain, lungs, heart, liver, kidneys, and spleen). In normal BW pregnancies (BW > 10th centile), the correlation between the T2* value and gestational age (GA) at MRI was estimated by linear regression. The correlation between fetal organ Z-score and BW group was demonstrated by boxplots and investigated by analysis of variance (ANOVA) for each organ. Results: In normal BW pregnancies fetal organ T2* was negatively correlated with GA. We found a significant correlation between BW group and fetal organ T2* z-score in the fetal heart, kidney, lung and spleen. A positive linear correlation was demonstrated between fetal organ T2* and outcomes related to placental function such as BW deviation and placenta T2* in all investigated fetal organs except for the fetal liver. In the fetal heart, kidneys, and spleen the T2* value showed a significant correlation with fetal redistribution of blood flow (Middle cerebral artery Pulsatility Index) before delivery. Discussion: Fetal T2* is correlated with BW, placental function, and redistribution of fetal blood flow, suggesting that fetal organ T2* reflects fetal oxygenation and morphological changes related to placental dysfunction.

STUDY QUESTION Is the chance of childbirth, and risk of infertility, pregnancy loss and need for assisted reproduction different for women with asthma compared to women without asthma? SUMMARY ANSWER Women with asthma had comparable chances of giving birth compared to the reference population, however, their risk of both infertility and pregnancy loss, as well their need for medically assisted reproduction, was higher. WHAT IS KNOWN ALREADY Reproductive dysfunction has been reported among women with asthma, including longer time to pregnancy, increased risk of pregnancy loss and a higher need of medically assisted reproduction, but their risk of clinical infertility is unknown. STUDY DESIGN, SIZE, DURATION This longitudinal register-based cohort study included all women with a healthcare visit for delivery, infertility, pregnancy loss or induced abortion in the southernmost county in Sweden, over the last 20 years. PARTICIPANTS/MATERIALS, SETTING, METHODS Using the Skåne Healthcare Register, we identified all women aged 15–45 between 1998 and 2019, who received a diagnosis of asthma before their first reproductive outcome (n = 6445). Chance of childbirth and risk of infertility, pregnancy loss and assisted reproduction were compared to a healthcare seeking population of women without any asthma (n = 200 248), using modified Poisson regressions. MAIN RESULTS AND THE ROLE OF CHANCE The chance of childbirth was not different between women with asthma versus those without, adjusted risk ratio (aRR) = 1.02, 95% CI: 1.01–1.03. The risk of seeking care for infertility was increased, aRR = 1.29, 95% CI: 1.21–1.39, and women with asthma more often needed assisted reproduction aRR = 1.34 95% CI: 1.18–1.52. The risk of suffering a pregnancy loss was higher, aRR = 1.21, 95% CI: 1.15–1.28, and induced abortions were more common, aRR = 1.15, 95% CI: 1.11–1.20, among women with asthma. LIMITATIONS, REASONS FOR CAUTION The study was an observational study based on healthcare visits and lacked detailed anthropometric data, thus residual confounding cannot be excluded. Only women with a healthcare visit for a reproductive outcome were included, which cannot be translated into pregnancy intention. A misclassification, presumed to be non-differential, may arise from an incorrect or missing diagnosis of asthma or female infertility, biasing the results towards the null. WIDER IMPLICATIONS OF THE FINDINGS This study points towards reproductive dysfunction associated with asthma, specifically in regards to the ability to maintain a pregnancy and the risk of needing medically assisted reproduction following clinical infertility, but reassuringly the chance of subsequently giving birth was not lower for these women. STUDY FUNDING/COMPETING INTEREST(S) This article is part of the ReproUnion collaborative study, co-financed by EU Interreg ÖKS, Capital Region of Denmark, Region Skåne and Ferring Pharmaceuticals. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER N/A.

INTRODUCTION: We identified risk factors and outcomes associated with SARS-CoV-2 infection in pregnancy in a universally tested population according to disease severity and validated information on SARS-CoV-2 during pregnancy in national health registers in Denmark.MATERIAL AND METHODS: Cohort study using data from national registers and medical records including all pregnancies between March 1, 2020 and February 28, 2021. We compared women with a validated positive SARS-CoV-2 test during pregnancy with non-infected pregnant women. Risk factors and pregnancy outcomes were assessed by Poisson and Cox regression models and stratified according to disease severity defined by hospital admission status and admission reason (COVID-19 symptoms or other). Using medical record data on actual period of pregnancy, we calculated predictive values of the SARS-CoV-2 diagnosis in pregnancy in the registers.RESULTS: SARS-CoV-2 infection was detected in 1819 (1.6%) of 111 185 pregnancies. Asthma was associated with infection (relative risk [RR] 1.63, 95% confidence interval [CI] 1.28-2.07). Risk factors for severe COVID-19 disease requiring hospital admission were high body mass index (median ratio 1.06, 95% CI 1.04-1.09), asthma (RR 7.47, 95% CI 3.51-15.90) and gestational age at the time of infection (gestational age 28-36 vs CONCLUSIONS: Women infected with SARS-CoV-2 during pregnancy were at increased risk of hypertensive disorders in pregnancy, early pregnancy loss, preterm delivery and having children small for gestational age. The validity of Danish national registers was acceptable for identification of SARS-CoV-2 infection during pregnancy.

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cells11244079/s1, Figure S1: UA kills MCF7 cells partly through apoptosis; Figure S2: UA causes LC3 puncta formation in MCF7 and HCT15 cells; Figure S3: UA causes LMP prior to MOMP and alters lysosomal localization in HeLa cells; Figure S4: Additional lipidomics data; Table S1: List of resources; Table S2: Internal lipid and drug standards; Table S3: Precursor ion, fragment ion, and neutral loss for lipid identification; Table S4: All experiments., Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms. In this report, we identify lysosomes as the essential targets of the anti-cancer activity of ursolic acid. The treatment of MCF7 breast cancer cells with ursolic acid elevates lysosomal pH, alters the cellular lipid profile, and causes lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol. Lysosomal membrane permeabilization precedes the essential hallmarks of apoptosis placing it as an initial event in the cascade of effects induced by ursolic acid. The disruption of the lysosomal function impairs the autophagic pathway and likely partakes in the mechanism by which ursolic acid kills cancer cells. Furthermore, we find that combining treatment with ursolic acid and cationic amphiphilic drugs can significantly enhance the degree of lysosomal membrane permeabilization and cell death in breast cancer cells., This work was supported by grants from the Danish National Research Foundation (DNRF125), European Research Council (AdG340751), Danish Cancer Society (R167-A11061) and, Novo Nordisk Foundation (NNF19OC0054296), to M.J., K.M. was supported by the Independent Research Fund Denmark (6108–00542B) and Novo Nordisk Foundation (NNF17OC0029432)., info:eu-repo/semantics/publishedVersion

Background Sex differences in brain structure and neurodevelopment occur in non-clinical populations. We investigated whether sex had a similar effect on developmental domains amongst boys and girls with a familial risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and controls. Methods Through Danish registries, we identified 522 7-year-old children (242 girls) with FHR-SZ, FHR-BP, and controls. We assessed their performance within the domains of neurocognition, motor function, language, social cognition, social behavior, psychopathology, and home environment. Results FHR-SZ boys compared with FHR-SZ girls had a higher proportion of disruptive behavior and attention-deficit hyperactivity disorder (ADHD) and exhibited lower performance in manual dexterity, balance, and emotion recognition. No sex differences were found between boys and girls within FHR-BP group. Compared with controls, both FHR-SZ boys and FHR-SZ girls showed impaired processing speed and working memory, had lower levels of global functioning, and were more likely to live in an inadequate home environment. Compared with control boys, FHR-SZ boys showed impaired manual dexterity, social behavior, and social responsiveness, and had a higher proportion of ADHD and disruptive behavior disorder diagnoses. Stress and adjustment disorders were more common in FHR-BP boys compared with control boys. We found no differences between FHR-BP girls and control girls. Conclusions Impairment within neurodevelopmental domains associated within FHR-SZ boys v. FHR-SZ girls was most evident among boys, whereas no sex differences were found within the FHR-BP group (FHR-BP boys v. FHR-BP girls). FHR-SZ boys exhibited the highest proportion of early developmental impairments.

Background Exposure to inadequate home environment may put the healthy development of familial high-risk children at risk. This study aimed to investigate associations between risk factors and an adequate home environment of children having a parent diagnosed with schizophrenia or bipolar disorder. Methods From a cohort of 522 children, data from 463 7-year-old children was included. Of these 172 children had familial risk for schizophrenia, 109 children had familial risk for bipolar disorder, and 190 were population-based controls. As part of a comprehensive battery, all participants were assessed with the Middle Childhood-Home Observation for Measurement of the Environment Inventory (MC-HOME Inventory) measuring the quality of the home environment. Results When analyzing all families together, we found that having a parent diagnosed with schizophrenia would have a negative impact on the home environment (ß = -1.08; 95% CI (-2.16;-0.01); p = 0.05), while familial risk for bipolar disorder did not show significant predictive value. Being a single caregiver and child having experienced severe life events from ages 4 to 7 showed significant negative impact, while child having a mental illness diagnosis did not. Being a female caregiver, good social functioning of the caregiver, high child IQ and not being a single caregiver were found to predict positive values for the home environment. We found similar results when analyzing caregivers with and without a diagnosis separately. Conclusions Knowledge of what predicts good home environment should be used to inform development of early interventions for families at risk.

Objective: To study childbirth and the risk of miscarriage and infertility among women who have received a diagnosis of type 2 diabetes before the start of their reproductive journey.Design: Register-based cohort study using the Skane Healthcare Register.Setting: All healthcare visits for the whole population of the southernmost region in Sweden over the past 20 years.Patient(s): All women who were aged 18-45 years between January 1, 1998 and December 31, 2019 and who received a clinical diagnosis of type 2 diabetes before their first childbirth, miscarriage, or infertility diagnosis (n = 230) were compared with a healthcareseeking population of women without any type of diabetes, matched for calendar year and age (n = 179,434).Intervention(s): None.Main Outcome Measure(s): Childbirth, miscarriage, and infertility diagnosis.Result(s): The birthrate was lower among women with type 2 diabetes (62.6% vs. 83.8%), and they were less likely to give birth (crude risk ratio [RR] = 0.73, 95% confidence interval [CI]: 0.66-0.81). They had a higher risk of experiencing a miscarriage (RR = 1.88, 95% CI: 1.50-2.36). The risk of infertility was increased (RR = 3.44, 95% CI: 2.88-4.10) as was the risk of having infertility and not giving birth (RR = 4.47, 95% CI: 3.44-5.82). All results remained the same after adjustment for polycystic ovary syndrome and obesity.Conclusion(s): Women with type 2 diabetes with onset before their reproductive journey were more often childless compared with women without diabetes and had a higher risk of experiencing both miscarriage and infertility. This patient group may be in need of targeted information regarding potential fertility issues as part of their clinical treatment. ((c) 2021 by American Society for Reproductive Medicine.) El resumen esta disponible en Espanol al final del articulo.

To examine whether children's acquisition of perspective-marking language supports development in their ability to reason about mental states, we conducted a longitudinal study testing whether proficiency with complement clauses around age 3 explained variance in false-belief reasoning 6 months later. Forty-five English-speaking 2- and 3-year-olds (23 female, Time 1 age range = 33-41 months) from middle-class families in the North-West of England took part in the study, which addresses a series of uncertainties in previous studies. We avoided the confound of using complement clauses in the false-belief tests, assessed complement-clause proficiency with a new comprehensive test designed to capture gradual development, and controlled for individual differences in executive functioning that could affect both linguistic and sociocognitive performance. Further, we aimed to disentangle the influence of two aspects of complement-clause acquisition: proficiency with the perspective-marking syntactic structure itself and understanding of the specific mental verbs used in this syntactic structure. To investigate direction of causality, we also tested whether early false-belief reasoning predicted later complement-clause proficiency. The results provide strong support for the hypothesis that complement-clause acquisition promotes development in false-belief reasoning. Proficiency with the general structure of complement-clause constructions and understanding of the specific mental verbs "think" and "know" in third-person complements at Time 1 both contributed uniquely to predicting false-belief performance at Time 2. However, false-belief performance at Time 1 also contributed uniquely to predicting complement-clause proficiency at Time 2. Together, these results indicate a bidirectional relationship between linguistic and sociocognitive development. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background Infertility affects 15-25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques available, approximately 30% of infertile couples do not obtain a live birth after fertility treatment. For these couples, there are no further options to increase their chances of a successful pregnancy and live birth. Objectives Three overall questions will be studied: 1) What are the risk factors and natural life courses of infertility, early embryonic loss, and adverse pregnancy outcomes? 2) Can we develop new diagnostic and prognostic biomarkers for fecundity and treatment success? And 3) what are the health characteristics of women and men in infertile couples at the time of fertility treatment and during long-term follow-up? Material and methods ReproUnion Biobank and Infertility Cohort (RUBIC) is established as an add-on to the routine fertility management at Copenhagen University Hospital Departments in the Capital Region of Denmark and Reproductive Medicine Centre at Skane University Hospital in Sweden. The aim is to include a total of 5000 couples equally distributed between Denmark and Sweden. The first patients were enrolled in June 2020. All eligible infertile couples are prospectively asked to participate in the project. Participants complete an extensive questionnaire and undergo a physical examination and collection of bio-specimens (blood, urine, hair, saliva, rectal swabs, feces, semen, endometrial biopsies, and vaginal swabs). After the cohort is established, the couples will be linked to the Danish and Swedish national registers to obtain information on parental, perinatal, childhood, and adult life histories, including disease and medication history. This will enable us to understand the causes of infertility and identify novel therapeutic options for this important societal problem. This article is protected by copyright. All rights reserved.

AIM Objective and reproducible quality measures of complete mesocolic excision (CME) for colon cancer are not currently available. This study aimed to measure the inferior mesenteric stump length following CME for sigmoid colon cancer and explore surgical, pathological and oncological outcomes in patients with a stump length of

Background People living with HIV have increased risk of depression compared with uninfected controls. The determinants of this association are unclear. Alterations in kynurenine (Kyn) metabolism have been associated with depression in uninfected individuals, but whether they are involved in the development of depression in the context of HIV infection is unknown. Methods A total of 909 people living with HIV were recruited from the Copenhagen Comorbidity in HIV infection study. Information regarding demographics and depression was obtained from questionnaires. HIV-related variables and use of antidepressant medication were collected from patient records. Logistic regression models before and after adjustment for confounders were used to test our hypotheses. Results The prevalence of depression was 11%. Among traditional risk factors, only being unmarried was associated with greater odds of depression. Higher levels of quinolinic-to-kynurenic acid ratio (P = 0.018) and higher concentrations of quinolinic acid (P = 0.048) were found in individuals with depression than in those without. After adjusting for confounders, high levels of quinolinic-to-kynurenic acid ratio and high concentrations of quinolinic acid remained associated with depression [adjusted odds ratio 1.61 (1.01; 2.59) and adjusted odds ratio 1.68 (1.02; 2.77), respectively]. Conclusions The results from this study suggest that alterations in the kynurenine pathway of tryptophan metabolism are associated with the presence of depression in the context of HIV infection.

Our aim was to investigate whether echocardiography may aid in identifying patients, specifically men, at risk of bradycardia as detected by implantable loop recorders (ILR) in patients evaluated for syncope and palpitations.We included ambulatory patients undergoing ILR implantation for syncope (84%), presyncope (9%), and palpitations (8%). Echocardiographic examination was performed prior to implantation (2.9 months [IQR 1.0-6.0 months]). Echocardiograms were analyzed for conventional and speckle tracking parameters. We examined time to first event of bradycardia, defined as (a) heart rate30 beats/min and (b) ≥4 beats, including sinus arrest, asystole, sinoatrial block, and second- and third-degree atrioventricular nodal block. We applied Cox proportional hazards models.A total of 285 patients we enrolled, and during a median time of 2.7 years [IQR 1.0, 3.3 years] of continuous heart rhythm monitoring, 84 (29%) had bradycardia detected by ILR. Patients with bradycardia were older (61 ± 19 years vs 55 ± 18 years, P = .01) and more frequently men (62% vs 44%, P = .01). Sex modified the association between echocardiographic parameters and bradycardia (P interaction0.05 for all), such that left ventricular LV mass index (HR: 1.02 per 1g/mEchocardiographic parameters of LV structure and function may potentially be more useful for predicting bradycardia in men than women, among patients undergoing ILR implantation for syncope, presyncope, and palpations.

Introduction: Maternal near miss is a major global health issue; approximately 7 million women worldwide experience it each year. Maternal near miss can have several different health consequences and can affect the women’s quality of life, yet little is known about the size and magnitude of this association. The aim of this study was to assess the evidence of the association between women who have experienced maternal near miss and quality of life and women who had an uncomplicated pregnancy and delivery. Material and methods: Cochrane library, Embase, CINAHL, Web of Science, MEDLINE, Scopus and PubMed were searched for published studies. Studies were selected according to the PECO model (population, exposure, control and outcome) and were included if they investigated quality of life as an outcome after maternal near miss among women of all ages with no limitation on country or time (up to June 2020). Maternal near miss was defined as a life-threatening condition arising from complications related to pregnancy and/or childbirth. The quality of the studies was assessed according to the Newcastle-Ottawa scale and a Forest plot was constructed based on quality of life outcomes and study quality. PROSPERO registration number: CRD42020169232. Results: Fifteen studies were included in the review with a total of 31 558 women. Quality of life was reported in various ways, and 25 different confounders were controlled for. Compared with women who did not experience maternal near miss, women exposed to maternal near miss had an overall lower quality of life (n = 2/2), had poorer mental (n = 6/10) and social health (n = 2/3), and maternal near miss had negative economic consequences (n = 4/4). Maternal near miss was not associated with sexual dysfunction (n = 1/5). Ten of 15 studies were assessed as being of poor quality. Conclusions: Evidence shows that maternal near miss is negatively associated with various aspects of quality of life. This highlights the importance of addressing the adverse effects associated with maternal near miss and follow up maternal near miss after discharge. Quality of life is a multidimensional concept that is assessed in various ways, and the literature on the field is heterogeneous. More high-quality studies are needed.

HIV-related stigma has been shown to negatively affect the health-related quality of life (HRQoL) in people living with HIV. Women living with HIV (WLWH) suffer greater consequences from stigma on multiple health outcomes when compared to men. The objective of this review was to examine the association between HIV-related stigma and HRQoL in WLWH in developed countries. A systematic search was conducted in three medical databases. The PRISMA guideline was used as a methodical frame of reference, and the STROBE checklist as a quality assessment tool. Eight studies on a total of 2903 WLWH were included. All studies were cross-sectional of design and published between 2011-2019. All studies found a negative and statistically significant association between HIV-related stigma and HRQoL. The association was found to be weak to moderate in strength when examined using correlations statistics. Heterogeneity across the choice of measures and variables examined in the included studies made comparison difficult. Risk of bias was deemed present in majority of studies. Thus, this review reveals a negative association between HIV-related stigma and HRQoL in WLWH in developed countries. The association appears to be influenced by a range of complex factors, such as psychosocial variables and sociodemographic determinants.

Objective To investigate (1) if antidepressant use among women in assisted reproductive technology (ART) treatment and among women without ART treatment influences cumulative live birth rates (CLBR) and number of initiated treatment cycles per woman, (2) whether women undergoing ART treatment are at higher risk of initiating use of antidepressants compared to women not having undergone ART, (3) if mothers after ART treatment have higher risk for postpartum use of antidepressants after ART treatment compared to mothers not having used ART treatment. Study design A Danish nation-wide register-based cohort study including all women in ART treatment between 1995 through 2009 and an age-matched comparison group of women not having initiated ART treatment. In both groups, women had no previous children before study entry. The women were followed from time of initiating first ART treatment until time of permanent emigration (> 6 months), date of death, or end of follow-up by 31st of December 2009. Chi-square test was used to assess whether observed differences in CLBR between groups were significant. Adjusted incidence rates (IR) and incidence rate ratio (IRR) with 95 % confidence interval (CI) were calculated using Poisson regression analysis. The main outcome measures were: CLBR, number of initiated ART treatment cycles and IRR of initiating antidepressant use. Results Women using antidepressants before, during or after ART treatment were significantly older, had a lower CLBR and a lower mean number of initiated ART treatment cycles compared to women in ART treatment with no use of antidepressants. No significant difference was found in the incidence of initiating antidepressant use between women in ART treatment and the comparison group. However, when comparing only women with a live birth, significantly more women in ART treatment initiated antidepressant use in the postpartum period (adjusted incidence rate ratio (IRR) = 2.56 (95 % CI 1.98−3.30; p Conclusion Generally, women undergoing ART treatment are not at higher risk of initiating use of antidepressants compared with an age-matched comparison group not treated with ART. However, women with antidepressant medication use prior to ART initiate fewer ART treatments and have lower CLBR. Even though it has not been possible to adjust for all relevant confounders and our follow-up period only runs until the end of 2009, we still believe the results of this study to be highly relevant. According to our study, clinicians should be aware that women conceiving after ART treatment might experience an increased level of psychological strain during the postpartum period compared to mothers who conceived without ART.

Background: Nocturnal enuresis (bedwetting) is a common disorder affecting 10–16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology. Methods: We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis. Findings: The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p−8). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135–1·267; p=9·91 × 10−11), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095–1·205; p=1·21 × 10−8). All associated variants in the chromosome 6 locus were replicated (p−3) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9–30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01–1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target. Interpretation: This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets. Funding: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex co-occurring neurodevelopmental conditions. Their genetic architectures reveal striking similarities but also differences, including strong, discordant polygenic associations with educational attainment (EA). To study genetic mechanisms that present as ASD-related positive and ADHD-related negative genetic correlations with EA, we carry out multivariable regression analyses using genome-wide summary statistics (N = 10,610–766,345). Our results show that EA-related genetic variation is shared across ASD and ADHD architectures, involving identical marker alleles. However, the polygenic association profile with EA, across shared marker alleles, is discordant for ASD versus ADHD risk, indicating independent effects. At the single-variant level, our results suggest either biological pleiotropy or co-localisation of different risk variants, implicating MIR19A/19B microRNA mechanisms. At the polygenic level, they point to a polygenic form of pleiotropy that contributes to the detectable genome-wide correlation between ASD and ADHD and is consistent with effect cancellation across EA-related regions., Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder are co-occurring neurodevelopmental conditions displaying strong, discordant polygenic associations with educational attainment. Here, the authors study genetic mechanisms underlying genome-wide correlation patterns across these traits.

Language is one of the cognitive domains often impaired across many neurodevelopmental disorders. While for some disorders the linguistic deficit is the primary impairment (e.g., specific language impairment, SLI), for others it may accompany broader behavioral problems (e.g., autism). The precise nature of this phenotypic overlap has been the subject of debate. Moreover, several studies have found genetic overlaps across neurodevelopmental disorders. This raises the question of whether these genetic overlaps may correlate with phenotypic overlaps and, if so, in what manner. Here, we apply a genome‐wide approach to the study of the linguistic deficit in SLI, autism spectrum disorder (ASD), and attention deficit/hyperactivity disorder (ADHD). Using a discovery genome‐wide association study of SLI, we generate polygenic risk scores (PRS) in an independent sample which includes children with language impairment, SLI, ASD or ADHD and age‐matched controls and perform regression analyses across groups. The SLI‐trained PRS significantly predicted risk in the SLI case–control group (adjusted R 2 = 6.24%; P = 0.024) but not in the ASD or ADHD case‐control groups (adjusted R 2 = 0.0004%, 0.01%; P = 0.984, 0.889, respectively) nor for height, used as a negative control (R 2 = 0.2%; P = 0.452). Additionally, there was a significant difference in the normalized PRS between children with SLI and children with ASD (common language effect size = 0.66; P = 0.044). Our study suggests no additive common‐variant genetic overlap between SLI and ASD and ADHD. This is discussed in the context of phenotypic studies of SLI and related disorders. Autism Res 2020, 13: 369–381. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. Lay Summary Language deficits are characteristic of specific language impairment (SLI), but may also be found in other neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Many studies examined the overlaps and differences across the language deficits in these disorders, but few studies have examined the genetic aspect thereof. In this study, we use a genome‐wide approach to evaluate whether common genetic variants increasing risk of SLI may also be associated with ASD and ADHD in the same manner. Our results suggest that this is not the case, and we discuss this finding in the context of theories concerning the etiologies of these disorders.

To describe the extent of participation and engagement in family activities and explore variables potentially impacting on these factors in family activities among girls and young women with Rett syndrome (RTT) under the age of 21.The Child Participation in Family Activities (Child-PFA) questionnaire was sent to parents in the target group (23 families participated. Highest degrees of participation and engagement were seen in social and stationary family activities.Therapists working with this target group may benefit from focusing on engagement in routine activities and modification of family activities.IMPLICATIONS FOR REHABILITATIONTherapists may benefit from focusing on engagement in routine activities in the goal setting process and intervention as they occur on a daily basis, giving the opportunity for development of new skills.Therapists may benefit from focusing on assistive devices or other compensatory strategies for outdoor activities and activities that require a certain amount of hand function.Therapists may benefit from modifying the family's activities so that they require more social and mental participation and focus on experiencing different types of sensory input e.g., sound, tactile, visual or vestibular input rather than taking part in the activity by using their hands.

Patients with breast cancer‐related lymphedema (BCRL) have reduced quality of life and arm function. Current treatments are palliative, and treatments improving lymphedema are lacking. Preclinical studies have suggested that adipose‐derived regenerative cells (ADRCs) can alleviate lymphedema. We, therefore, aimed to assess whether ADRCs can alleviate lymphedema in clinical reality with long‐term follow‐up. We treated 10 patients with BCRL using ADRCs and a scar‐releasing lipotransfer to the axillary region, and all patients were followed 1, 3, 6, 12, and 48 months after treatment. The primary endpoint was change in arm volume. Secondary endpoints were safety, change in lymphedema symptoms, quality of life, lymphedema‐associated cellulitis, and conservative treatment use. There was no significant decrease in BCRL volume after treatment. However, self‐reported upper extremity disability and arm heaviness and tension improved. Six patients reduced their use of conservative BCRL treatment. Five patients felt that their BCRL had improved substantially, and four of these would redo the treatment. We did not observe any cases of locoregional breast cancer recurrence. In this phase I study with 4 years of follow‐up, axillary delivered ADRCs and lipotransfer were safe and feasible and improved BCRL symptoms and upper extremity function. Randomized controlled trials are needed to confirm the results of this study., This graphical abstract shows the improvements in patients self‐reported lymphedema symptoms and arm function. P = P value

A decreased glomerular filtration rate (GFR) is a risk factor for cardiovascular disease even after adjustment for conventional risk factors. The myocardial performance index (MPI) is defined as (isovolumetric relaxation time (IVRT) + isovolumetric contraction time (IVCT))/ejection time (ET). It has been shown to be an independent predictor of cardiovascular events. We hypothesized the MPI could prove valuable for assessing cardiac risk in subjects of the general population with decreased estimated GFR (eGFR). MPI was measured in 1915 subjects from a large general population prospective cohort study using color tissue Doppler imaging (TDI) M-mode through the mitral valve. We compared the prognostic capabilities of the MPI between subjects with eGFR ≥ 75 mL/min/1.73 m2 and subjects with eGFR < 75 mL/min/1.73 m2 using multivariable adjusted Cox regression models. The composite endpoint was heart failure, myocardial infarction or cardiovascular death. Mean age was 58 years (SD 16.2), 58% were women, 42% had hypertension and 8.3% diabetes. During a median follow-up time of 12.4 years [IQR 10.6–12.7 years] 269 participants reached the combined endpoint. eGFR modified the prognostic capability of MPI (p-value for interaction < 0.001): After multivariable adjustment, MPI remained an independent predictor of the composite endpoint only in participants with eGFR < 75 mL/min/1.73 m2: HR 1.18 (95% CI 1.02–1.38), p = 0.03, vs. in subjects with eGFR ≥ 75 mL/min/1.73 m2: HR 1.14 (95% CI 0.94–1.39), p = 0.17. These results suggest the MPI could be particularly valuable for identifying elevated cardiac risk in individuals from the general population with decreased eGFR.

Tetracyclines and clindamycin plus rifampicin combination therapy are both considered first-line therapy in current Hidradenitis Suppurativa (HS) guidelines. However, evidence for their efficacy is drawn from small studies, often without validated outcomes., info:eu-repo/semantics/published

Introduction: Placental transverse relaxation time (T2) assessed by MRI may have the potential to improve the antenatal identification of small for gestational age. The aims of this study were to provide normal values of placental T2 in relation to gestational age at the time of MRI and to explore the correlation between placental T2 and birthweight. Material and methods: A mixed cohort of 112 singleton pregnancies was retrieved from our placental MRI research database. MRI was performed at 23.6-41.3 weeks of gestation in a 1.5T system (TE (8): 50-440 ms, TR: 4000 ms). Normal pregnancies were defined by uncomplicated pregnancies with normal obstetric outcome and birthweight deviation within ±1 SD of the expected for gestational age. The correlation between placental T2 and birthweight was investigated using the following outcomes; small for gestational age (birthweight ≤−2 SD of the expected for gestational age) and birthweight deviation (birthweight Z-scores). Results: In normal pregnancies (n = 27), placenta T2 showed a significant negative linear correlation with gestational age (r = −.91, P =.0001) being 184 ms ± 15.94 ms (mean ± SD) at 20 weeks of gestation and 89 ms ± 15.94 ms at 40 weeks of gestation. Placental T2 was significantly reduced among small-for-gestational-age pregnancies (mean Z-score −1.95, P 2 =.26, P =.0001). Conclusions: This study provides normal values of placental T2 to be used in future studies on placental MRI. Placental T2 is closely related to birthweight and may improve the antenatal identification of small-for-gestational-age pregnancies.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease of the intertriginous areas. HS affects hair follicles causing perifollicular inflammation, resulting in the formation of nodules and painful abscesses. Intense pulsed light (IPL) uses selective photothermolysis to destroy the hair follicles. To evaluate the effect of IPL hair removal as treatment for mild-to-moderate HS. We conducted a single-blinded, clinical randomized trial with patients with Hurley Stage I-II. Patients with symmetrical disease were randomized to monthly unilateral treatment of the axilla or groin. The contralateral side served as internal control. Concomitant treatment modalities for HS were not permitted throughout the study. Efficacy was assessed using Hidradenitis Suppurativa Clinical Response (HiSCR), modified Sartorius score (MSS) and patient-reported outcomes. A total of 17 patients completed the trial and were included in the analysis. HiSCR was not evaluated in patients without abscesses or inflammatory nodules pre-treatment. HiSCR was insignificantly different between the intervention side (8/12) and control side (4/10), P=0.467. There was, however, a significant reduction in regional MSS on the intervention side with a median score decreasing from 8.5 (IQR: 6.3–13.5) to 4.5 (IQR 1.8–8.0) post-treatment, P=0.006, and an insignificant score reduction in the control side from 6.0 (IQR: 4.5–8.3) to 5.0 (IQR: 2.5–9.0), post-treatment P=0.492. IPL hair removal resulted in a significant reduction on MSS on the treated area with no significant reduction on the control side. Our study suggests that IPL may be an effective treatment for mild-to-moderate HS.

In human papillomavirus (HPV) cervical cancer screening, cytology is used as triage to counter the low specificity of HPV testing. VALID‐SCREEN is a EU‐multicenter, retrospective study conducted to evaluate the clinical performance of the FAM19A4/miR124‐2 methylation‐based molecular triage test as a substitute or addition to cytology as reflex testing of HPV screen positive women. FAM19A4/miR124‐2 methylation test (QIAsure Methylation Test) was evaluated in 2384 HPV‐positive cervical screening samples, from women 29‐76 years of age, derived from four EU countries. Specimens were collected in ThinPrep or SurePath media, HPV‐status, concurrent cytology, and histology diagnosis were provided by the parent institutes. The control population consisted of women with no evidence of disease within 2 years of follow‐up. A total of 899 histologies were retrieved; 527 showed no disease, 124 CIN2 (5.2%), 228 CIN3 (9.6%) and 20 cervical cancers (0.8%); 19 of 20 screen‐detected cervical cancers were found methylation‐positive (sensitivity 95%). Overall specificity of FAM19A4/miR124‐2 methylation test was 78.3% (n = 2013; 95%CI: 76‐80). The negative predictive value of hrHPV positive, methylation‐negative outcomes were 99.9% for cervical cancer (N = 1694; 95%CI: 99.6‐99.99), 96.9% for ≥CIN3 (95%CI: 96‐98), and 93.0% for ≥CIN2 (95%CI: 92‐94). Overall sensitivity for CIN3 using FAM19A4/miR124‐2 methylation test was 77% (n = 228; 95%CI: 71‐82). CIN3 sensitivity was uniform between centers independent of sample collection medias, DNA extraction methods and HPV screening tests. Being objectively reported compared to the subjectivity of cytology, equally performing across settings and screening methods, the FAM19A4/miR124‐2 methylation constitute an alternative/supplement to cytology as triage method to be investigated in real‐life pilot implementation., What's new? In HPV screening for cervical cancer, cytology has been used to triage those women who are hrHPV‐positive. However, cytology is subjective, and skilled cytologists are often in short supply. A molecular test using specific biomarkers might offer better results. In this large European study, the authors found that a new standardized test for the methylation biomarker combination FAM19A4/miR124‐2 did indeed yield results that were equal to or better than triage by cytology, in determining which hrHPV‐positive women should be referred for colposcopy.

DICER is a key enzyme in microRNA (miRNA) biogenesis. Here we show that aerobic exercise training up-regulates DICER in adipose tissue of mice and humans. This can be mimicked by infusion of serum from exercised mice into sedentary mice and depends on AMPK-mediated signaling in both muscle and adipocytes. Adipocyte DICER is required for whole-body metabolic adaptations to aerobic exercise training, in part, by allowing controlled substrate utilization in adipose tissue, which, in turn, supports skeletal muscle function. Exercise training increases overall miRNA expression in adipose tissue, and up-regulation of miR-203-3p limits glycolysis in adipose under conditions of metabolic stress. We propose that exercise training-induced DICER-miR-203-3p up-regulation in adipocytes is a key adaptive response that coordinates signals from working muscle to promote whole-body metabolic adaptations.

Denmark implemented early widespread social distancing to reduce pressure on the healthcare system from the coronavirus disease 2019 (COVID-19) pandemic, with the aims to reduce mortality. Unintended consequences might be delays in treatment for other diseases and subsequent mortality. We examined national all-cause mortality comparing weeks 1–27 in 2020 and 2015–2019. This registry-based study used Danish national registry data until 5 July 2020. We examined all-cause mortality rates among all deaths recorded from 2015 to 2020 and among chronic conditions (cardiovascular (cardiac & circulatory), chronic pulmonary, chronic kidney disease, cancer, and diabetes), comparing each week in 2020 to weeks in 2015–2019. In 2020, there were 28,363 deaths in weeks 1–27 (30 December 2019–5 July 2020), the mean deaths in 2015–2019 were 28,630 deaths (standard deviation 784). Compared to previous years, the mortality rate in weeks 3–10 of 2020 was low, peaking in week 14 (17.6 per 100,000 persons in week 9, 19.9 per 100,000 in week 14). Comorbidity prevalence among deceased individuals was similar in 2020 and 2015–2019: 71.1% of all deceased had a prior cardiovascular diagnosis, 30.0% of all deceased had a prior cardiac diagnosis. There were 493 deaths with COVID-19 in weeks 11–27, (59.8% male), and 75.1% had a prior cardiovascular diagnosis. Weekly mortality rates for pre-existing chronic conditions peaked in week 14, and then declined. During the COVID-19 pandemic, due to timely lockdown measures, the mortality rate in Denmark has not increased compared to the mortality rates in the same period during 2015–2019. Electronic supplementary material The online version of this article (10.1007/s10654-020-00680-x) contains supplementary material, which is available to authorized users.

Background People with human immunodeficiency virus (PWH) may be at risk of nonalcoholic fatty liver disease. We compared the prevalence of moderate-to-severe hepatic steatosis (M-HS) in PWH with human immunodeficiency virus (HIV)-uninfected controls and determined risk factors for M-HS in PWH. Methods The Copenhagen Co-Morbidity in HIV Infection study included 453 participants, and the Copenhagen General Population Study included 765 participants. None had prior or current viral hepatitis or excessive alcohol intake. Moderate-to-severe hepatic steatosis was assessed by unenhanced computed tomography liver scan defined by liver attenuation ≤48 Hounsfield units. Adjusted odds ratios (aORs) were computed by adjusted logistic regression. Results The prevalence of M-HS was lower in PWH compared with uninfected controls (8.6% vs 14.2%, P Conclusions Moderate-to-severe hepatic steatosis is less common in PWH compared with demographically comparable uninfected controls. Besides BMI and ALT, integrase inhibitor exposure was associated with higher prevalence of steatosis in PWH.

Introduction The Glasgow Coma Scale (GCS) and visual inspection of pupillary function are routine measures to monitor patients with impaired consciousness and predict their outcome in the neurointensive care unit (neuro-ICU). Our aim was to compare more recent measures, i.e. FOUR score and automated pupillometry, to standard monitoring with the GCS and visual inspection of pupils. Methods Supervised trained nursing staff examined a consecutive sample of patients admitted to the neuro-ICU of a tertiary referral centre using GCS and FOUR score and assessing pupillary function first by visual inspection and then by automated pupillometry. Clinical outcome was evaluated 6 months after admission using the Glasgow Outcome Scale-Extended. Results Fifty-six consecutive patients (median age 63 years) were assessed a total of 234 times. Of the 36 patients with at least one GCS score of 3, 13 had a favourable outcome. All seven patients with at least one FOUR score of ≤ 3 had an unfavourable outcome, which was best predicted by a low “brainstem” sub-score. Compared to automated pupillometry, visual assessment underestimated pupillary diameters (median difference, 0.4 mm; P = 0.006). Automated pupillometry detected a preserved pupillary light reflex in 10 patients, in whom visual inspection had missed pupillary constriction. Discussion Training of nursing staff to implement frequent monitoring of patients in the neuro-ICU with FOUR score and automated pupillometry is feasible. Both measures provide additional clinical information compared to the GCS and visual assessment of pupillary function, most importantly a more granular classification of patients with low levels of consciousness by the FOUR score.

Objectives: Bipolar disorder (BD) is a debilitating illness that often starts at an early age. Prevention of first and subsequent mood episodes, which are usually preceded by a period characterized by subthreshold symptoms is important. We compared demographic and clinical characteristics including severity and duration of subsyndromal symptoms across adolescents with three different bipolar-spectrum disorders. Methods: Syndromal and subsyndromal psychopathology were assessed in adolescent inpatients (age = 12-18 years) with a clinical mood disorder diagnosis. Assessments included the validated Bipolar Prodrome Symptom Interview and Scale - Prospective (BPSS-P). We compared phenomenology across patients with a research consensus conference-confirmed DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnoses of BD-I, BD - not otherwise specified (NOS), or mood disorder (MD) NOS. Results: Seventy-six adolescents (age = 15.6 ± 1.4 years, females = 59.2%) were included (BD-I = 24; BD-NOS = 29; MD-NOS = 23) in this study. Median baseline global assessment of functioning scale score was 21 (interquartile range = 17-40; between-group p = 0.31). Comorbidity was frequent, and similar across groups, including disruptive behavior disorders (55.5%, p = 0.27), anxiety disorders (40.8%, p = 0.98), and personality disorder traits (25.0%, p = 0.21). Mania symptoms (most frequent: irritability = 93.4%, p = 0.82) and depressive symptoms (most frequent: depressed mood = 81.6%, p = 0.14) were common in all three BD-spectrum groups. Manic and depressive symptoms were more severe in both BD-I and BD-NOS versus MD-NOS (p < 0.0001). Median duration of subthreshold manic symptoms was shorter in MD-NOS versus BD-NOS (11.7 vs. 20.4 weeks, p = 0.002) and substantial in both groups. The most used psychotropics upon discharge were antipsychotics (65.8%; BD-I = 79.2%; BD-NOS = 62.1%; MD-NOS = 56.5%, p = 0.227), followed by mood stabilizers (43.4%; BD-I = 66.7%; BD-NOS = 31.0%; MD-NOS = 34.8%, p = 0.02) and antidepressants (19.7%; BD-I = 20.8%; BD-NOS = 10.3%; MD-NOS = 30.4%). Conclusions: Youth with BD-I, BD-NOS, and MD-NOS experience considerable symptomatology and are functionally impaired, with few differences observed in psychiatric comorbidity and clinical severity. Moreover, youth with BD-NOS and MD-NOS undergo a period with subthreshold manic symptoms, enabling identification and, possibly, preventive intervention of those at risk for developing BD or other affective episodes requiring hospitalization.

Objective To investigate plasma glucose changes during the ictal state of migraine compared to the interictal state. Background Previous studies suggest abnormal glucose metabolism in migraine patients during and outside of attacks. It is not known if plasma glucose levels change during spontaneous migraine attacks. Methods Plasma glucose levels were measured during and outside of spontaneous migraine attacks with and without aura. Plasma glucose values were corrected for diurnal variation of plasma glucose by subtracting the difference between the moving average (intervals of 2 hours) and overall mean from the plasma glucose values. Results This was a sub-study of a larger study conducted at Rigshospitalet Glostrup in the Capital Region of Denmark. Thirty-one patients (24 F, 7 M, 13 with aura, 18 without aura) were included in the study. Mean time from attack onset to blood sampling was 7.6 hours. Mean pain at the time of investigation was 6 on a 0-10 verbal rating scale. Plasma glucose was higher ictally compared to the interictal phase (interictal mean: 88.63 mg/dL, SD 11.70 mg/dL; ictal mean: 98.83 mg/dL, SD 13.16 mg/dL, difference 10.20 mg/dL, 95% CI = [4.30; 16.10]), P = .0014). The ictal increase was highest in patients investigated early during attacks and decreased linearly with time from onset of migraine (-1.57 mg/dL/hour from onset of attack, P = .020). The attack-related increase in blood glucose was not affected by pain intensity or presence of aura symptoms. Conclusions We demonstrated higher plasma glucose values during spontaneous migraine attacks, independent of the presence of aura symptoms and not related to pain intensity, peaking in the early phase of attacks. Additional studies are necessary to confirm our findings and explore the possible underlying mechanisms.

Background: Environmental factors are associated with acquiring multiple sclerosis (MS) particularly in adolescence. Objective: To test for association between MS and exposure to passive smoking at the age of 10–19. Methods: A total of 919 patients from the Danish MS Registry and Biobank and 3419 healthy blood donors who had not smoked before the age of 19 were targeted. We analyzed separately for each sex and for those never-smokers (cohort 1) and active smokers above the age of 19 (cohort 2). All participants completed standardized questionnaires about smoking and lifestyle. We matched cases and controls in the ratio of 1:2 by propensity scores discarding unmatchable individuals and used logistic regression adjusted for all covariates and interactions. Results: After matching, we included 110/213 male cases/controls and 232/377 female case/controls in cohort 1. In cohort 2, the numbers were 160/320 and 417/760, respectively. Among women in cohort 1, the odds ratio (OR) for MS by passive smoking at the age of 10–19 was 1.432 ( p = 0.037) but in men it was 1.232 ( p = 0.39). Among men in cohort 2, OR was 1.593 ( p = 0.022) but among women it was only 1.102 ( p = 0.44). Conclusion: Among never smokers, female MS cases were more often than female controls reported with passive smoking between the age of 10 and 19, and among smokers above the age of 19, male MS patients were more often than male controls reported with passive smoking.

BackgroundThe typical onset of schizophrenia coincides with the maturational peak in cognition; however, for a significant proportion of patients the onset is before age 18 and after age 30 years. While cognitive deficits are considered core features of schizophrenia, few studies have directly examined the impact of age of illness onset on cognition.MethodsThe aim of the study was to examine if the effects of age on cognition differ between healthy controls (HCs) and patients with schizophrenia at illness onset. We examined 156 first-episode antipsychotic-naïve patients across a wide age span (12–43 years), and 161 age- and sex-matched HCs. Diagnoses were made according to ICD-10 criteria. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), and IQ was estimated using subtests from the Wechsler adult- or child-intelligence scales. Multivariate analysis of covariance (MANCOVA) was used to examine linear and quadratic effects of age on cognitive scores and interactions by group, including sex and parental socioeconomic status as covariates.ResultsThere was a significant overall effect of age on BACS and IQ (p < 0.001). Significant group-by-age interactions for verbal memory (for age-squared, p = 0.009), and digit sequencing (for age, p = 0.01; age-squared, p < 0.001), indicated differential age-related trajectories between patients and HCs.ConclusionsCognitive functions showing protracted maturation into adulthood, such as verbal memory and verbal working memory, may be particularly impaired in both early- and late-schizophrenia onset. Our findings indicate a potential interaction between the timing of neurodevelopmental maturation and a possible premature age effect in late-onset schizophrenia.

Treatment guidelines for type 2 diabetes (T2D) recommend avoidance of hypoglycemia and less stringent glycemic control in older patients. We examined the relation of glycemic control to glucose-lowering medications use in a cohort of patients aged>80 years with a diagnosis of T2D and a hospital admission in the Capital Region of Denmark in 2012–2016. We extracted data on medication use, diagnoses, and biochemistry from the hospitals’ records. We identified 5,172 T2D patients with high degree of co-morbidity and where 17% had an HbA1c in the range recommended for frail, comorbid, older patients with type 2 diabetes (58–75 mmol/mol (7.5–9%)). Half of the patients (n = 2,575) had an HbA1c 1c-values 1c values 1c within the generally recommended glycemic targets. One third of patients did not meet the diagnostic criteria for T2D, and of the patients who were treated with glucose-lowering medications, one-fifth had HbA1c-values suggesting overtreatment.

ObjectiveTo assess the evidence of the association between exposure to intimate partner violence (IPV) and postpartum depression. IPV during pregnancy can have immediate and long-term physical and mental health consequences for the family. Therefore, it has been hypothesised that IPV may affect the risk of developing postpartum depression.MethodsA systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Global Health Library, Scopus and Google scholar were searched for published studies without restrictions on language, time or study design (up to May 2020). Studies were included if they assessed postpartum depression using the Edinburg Postnatal Depression Scale (cut-off≥10), among women who had been exposed to IPV (emotional, physical and/or sexual abuse). The quality of studies was judged according to the Newcastle-Ottawa scale.ResultsA total of 33 studies were included in the review (participants n=131 131). The majority of studies found an association between exposure to IPV and the development of signs of postpartum depression. Overall, studies measured both exposure and outcome in various ways and controlled for a vast number of different confounders. Thirty percent of the studies were set in low-income and lower-middle-income countries while the rest were set in upper-middle-income and high-income countries and the association did not differ across settings. Among the studies reporting adjusted OR (aOR) (n=26), the significant aOR ranged between 1.18 and 6.87 (95% CI 1.12 to 11.78). The majority of the studies were judged as ‘good quality’ (n=20/33).ConclusionWe found evidence of an association between exposure to IPV and the development of signs of postpartum depression. Meta-analysis or individual patient data meta-analysis is required to quantify the magnitude of the association between IPV and postpartum depression.PROSPERO registration numberCRD42020209435.

BACKGROUND: The antenatal identification of placental dysfunction in small-for-gestational-age fetuses with normal fetal Doppler flows remains an obstetrical challenge. In a significant fraction of such pregnancies, placental dysfunction is revealed by clinical manifestations such as preeclampsia, preterm delivery, or severe small-for-gestational-age at birth or by abnormal findings in the postnatal placental histologic examination. Therefore, new methods to identify placental function directly in pregnancy at the time of small-for-gestational-age diagnosis is highly needed. T2*-weighted placental magnetic resonance imaging is sensitive to changes in placental morphology and oxygenation and is thereby related to placental function. Previous studies have demonstrated that pregnancies complicated by low birthweight and preeclampsia are characterized by low placental T2* values. However, the specific performance of placental T2* in the prediction of placenta-related outcomes in small-for-gestational-age pregnancies with normal fetal Doppler flows remains to be explored. OBJECTIVE: In small-for-gestational-age pregnancies with normal fetal Doppler flows, we aimed to evaluate T2*-weighted placental magnetic resonance imaging as an antenatal biomarker of placental dysfunction. In addition, we aimed to investigate the correlation between placental T2* and Doppler flow measurements of fetal and uterine arteries at the time of magnetic resonance imaging. STUDY DESIGN: In this prospective cohort study, the inclusion criterion was suspected small-for-gestational-age (ultrasound estimated fetal weight Z-score ≤−2.0 [2.3rd centile]) with normal fetal Doppler flows (middle cerebral artery pulsatility index Z-score > −2.0 and umbilical artery pulsatility index Z-score

This review summarises the current knowledge of electroconvulsive therapy (ECT) which is still the most potent and fast-acting antidepressant intervention. The modern procedure is safe when general precautions are taken. Cognitive side effects are transient in most patients, and concerns about side effects should not prevent relevant use. Due to the prognostic benefits of rapid remission, ECT should, in relevant patients, be considered early in the treatment course. Patients should be offered maintenance pharmacotherapy, and, in high-risk cases, tapering of the acute ECT course or maintenance ECT, in order to reduce the risk of relapse.

This review summarises the current knowledge of electroconvulsive therapy (ECT) which is still the most potent and fast-acting antidepressant intervention. The modern procedure is safe when general precautions are taken. Cognitive side effects are transient in most patients, and concerns about side effects should not prevent relevant use. Due to the prognostic benefits of rapid remission, ECT should, in relevant patients, be considered early in the treatment course. Patients should be offered maintenance pharmacotherapy, and, in high-risk cases, tapering of the acute ECT course or maintenance ECT, in order to reduce the risk of relapse.

BACKGROUND: Chemoradiotherapy (CRT) may induce myocardial dysfunction, congestive heart failure, and impaired physical performance in patients with esophageal cancer (EC). We aimed to investigate left ventricular (LV) function at rest and during stress, using echocardiography (echo) and a cardiopulmonary exercise (CPX) test both before and immediately after completing CRT.MATERIAL AND METHODS: Consecutive EC patients referred for curative treatment were enrolled. Patients attended either definitive CRT or neoadjuvant CRT with subsequent surgery. The evaluation included cardiac biomarkers, electrocardiogram, echo, and CPX test. The primary endpoint was changes in left ventricular (LV) global longitudinal strain (GLS) at rest. Secondary endpoints were LV ejection fraction (LVEF), LV diastolic function, LVEF and GLS at peak exercise, and maximal oxygen consumption (VO2max). The trial was registered with ClinicalTrials.gov (NCT03619317).RESULTS: Among 47 patients enrolled (94% male; median age 67 years, range 50-86 years), cardiac examinations were performed a median of three days [Interquartile range (IQR (1-5))] before CRT and one day [IQR (0-6)] after CRT. At rest, GLS and LVEF decreased, 17.6 vs. 16.4% and 56.4 vs. 55.1%, respectively (p = 0.004; p = 0.030). Furthermore, an absolute decrease of at least 5% in LVEF and 2.5% in GLS was noted in 21% of the patients. Signs of LV diastolic dysfunction increased from 13 to 21% (p = ns). VO2max significantly decreased; 21.2 ml/kg/min vs. 18.8 ml/kg/min (p CONCLUSION: LV function and physical performance decreased in EC patients after CRT, and the LV systolic reserve capacity declined. This study highlighted that EC treatment was associated with early cardiac side effects, which may have clinical and prognostic implications.

[Importance] About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts., [Objective] To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples., [Design, Setting, and Participants] Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G])., [Main Outcomes and Measures] GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition., [Results] The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04)., [Conclusions and Relevance] In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance., This work was supported by Medical Research Council Centre grant MR/L010305/1, Medical Research Council Program grant MR/P005748/1, and Medical Research Council Project grants MR/L011794/1 and MC_PC_17212 to Cardiff University and by the National Centre for Mental Health, funded by the Welsh Government through Health and Care Research Wales. This work acknowledges the support of the Supercomputing Wales project, which is partially funded by the European Regional Development Fund via the Welsh Government. Dr Pardiñas was supported by an Academy of Medical Sciences Springboard Award (SBF005\1083). Dr Andreassen was supported by the Research Council of Norway (grants 283798, 262656, 248980, 273291, 248828, 248778, and 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, and the European Union’s Horizon 2020 Research and Innovation Programme (grant 847776). Dr Ajnakina was supported by an National Institute for Health Research postdoctoral fellowship (PDF-2018-11-ST2-020). Dr Joyce was supported by the University College London Hospitals/UCL University College London Biomedical Research Centre. Dr Kowalec received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement (793530) from the government of Canada Banting postdoctoral fellowship programme and the University of Manitoba. Dr Sullivan was supported by the Swedish Research Council (Vetenskapsrådet, D0886501), the European Union’s Horizon 2020 programme (COSYN, 610307) and the US National Institute of Mental Health (U01 MH109528 and R01 MH077139). The Psychiatric Genomics Consortium was partly supported by the National Institute Of Mental Health (grants R01MH124873). The Sweden Schizophrenia Study was supported by the National Institute Of Mental Health (grant R01MH077139). The STRATA consortium was supported by a Stratified Medicine Programme grant to Dr MacCabe from the Medical Research Council (grant MR/L011794/1), which funded the research and supported Drs Pardiñas, Smart, Kassoumeri, Murray, Walters, and MacCabe. Dr Smart was supported by a Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital National Health Service Foundation Trust. The AESOP (US) cohort was funded by the UK Medical Research Council (grant G0500817). The Belfast (UK) cohort was funded by the Research and Development Office of Northern Ireland. The Bologna (Italy) cohort was funded by the European Community’s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Genetics and Psychosis project (London, UK) cohort was funded by the UK National Institute of Health Research Specialist Biomedical Research Centre for Mental Health, South London and the Maudsley National Health Service Mental Health Foundation Trust (SLAM) and the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London; Psychiatry Research Trust; Maudsley Charity Research Fund; and the European Community’s Seventh Framework program (HEALTH-F2-2009-241909, project EU-GEI). The Lausanne (Switzerland) cohort was funded by the Swiss National Science Foundation (grants 320030_135736/1, 320030-120686, 324730-144064, 320030-173211, and 171804); the National Center of Competence in Research Synaptic Bases of Mental Diseases from the Swiss National Science Foundation (grant 51AU40_125759); and Fondation Alamaya. The Oslo (Norway) cohort was funded by the Research Council of Norway (grant 223273/F50, under the Centers of Excellence funding scheme, 300309, 283798) and the South-Eastern Norway Regional Health Authority (grants 2006233, 2006258, 2011085, 2014102, 2015088, and 2017-112). The Paris (France) cohort was funded by European Community’s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Prague (Czech Republic) cohort was funded by the Ministry of Health of the Czech Republic (grant NU20-04-00393). The Santander (Spain) cohort was funded by the following grants to Dr Crespo-Facorro: Instituto de Salud Carlos III (grants FIS00/3095, PI020499, PI050427, and PI060507), Plan Nacional de Drogas Research (grant 2005-Orden sco/3246/2004), SENY Fundatio Research (grant 2005-0308007), Fundacion Marques de Valdecilla (grant A/02/07, API07/011) and Ministry of Economy and Competitiveness and the European Fund for Regional Development (grants SAF2016-76046-R and SAF2013-46292-R). The West London (UK) cohort was funded by The Wellcome Trust (grants 042025, 052247, and 064607).

Background Left atrial (LA) volumes and emptying fraction in the general population may address structural and functional aspects of atrial cardiomyopathy associated with long‐term risk of ischemic stroke in the absence of atrial fibrillation or prior stroke. We investigated the association between LA volumes and function and ischemic stroke. Methods and Results In a community‐based cohort, we measured LA minimal volume, LA maximal volume, and LA emptying fraction by transthoracic echocardiography. The primary end point was ischemic stroke. Participants with known atrial fibrillation or prior ischemic stroke were excluded, which resulted in 1866 participants. The mean age was 58±16 years, and 57% were women. During a median follow‐up of 16.5 years (interquartile range: 11.4–16.8 years), 176 (9.4%) ischemic strokes occurred. In multivariable cause‐specific regression models and competing risk models with death as a competing risk, LA emptying fraction was associated with ischemic stroke (hazard ratio [HR], 1.14 per 10% decrease [95% CI, 1.02–1.28]) and (subdistribution HR, 1.14 [95% CI, 1.01–1.29]). This association remained when adjusting for participants who developed atrial fibrillation during follow‐up (HR, 1.12 per 10% decrease [95% CI, 1.00–1.26]). Indexed LA volumes were not associated with ischemic stroke in the same models. LA emptying fraction and indexed LA volumes were not associated with all‐cause mortality. Conclusions Lower LA emptying fraction measured by transthoracic echocardiography was associated with future ischemic stroke independently of incident atrial fibrillation. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02993172.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Background Studies investigating the prevalence and risk factors for postpartum depression (PPD) have used different definitions. Some studies have used a high score on the Edinburgh Postnatal Depression Scale (EPDS) to define PPD, whereas others have used information on antidepressant medication use and/or diagnostic information on treatment for depression at a psychiatric hospital. We wanted to compare results using these two approaches to evaluate to what degree results can be compared. Moreover we wanted to evaluate, whether use of EPDS or PPAT (defined below) leads to identification of different risk factor profiles. Methods We identified women who delivered a child between 1 January 2014 and 31 December 2016 in Copenhagen or in one of the municipalities that were part of the Danish Health Visitors’ Child Health Database. The potential risk factors were demographic factors and pregnancy- and obstetrical events. Outcomes of interest were an EPDS score ≥ 13, use of antidepressants (ATC: N06A) and/or a diagnosis of depression (F32) within six months after birth. Use of antidepressants and/or diagnosis of depression will be referred to as postpartum antidepressant treatment (PPAT). Agreement between EPDS ≥ 13 and PPAT was evaluated by the kappa coefficient. Associations between risk factors and the two outcomes (EPDS ≥ 13 and PPAT) were estimated by risk ratios (RR) using log-linear binomial regression. Presence of a systematic difference between RRs based on EPDS ≥ 13 (RREPDS≥13) and PPAT (RRPPAT) was evaluated in a meta-regression approach weighted by inverse-variance and with logarithm of the RRs as outcome. Results The estimated PPD prevalence using EPDS ≥ 13 was 3.2% and of PPAT 0.4%. The agreement between the two measures was small (Kappa = 0.08), but their risk factor profile was very similar with no systematic difference between them. Conclusions Using the two different methods of case identification produced different prevalence estimates, but a similar risk factor profile. The differences in estimated prevalence and low agreement suggest that the two measures identify different potential PPD cases and using only one of the methods in defining PPD would underestimate PPD prevalence. The similar risk factor profile suggests that the considered risk factors are involved in the general development of PPD.