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Background: Understanding the risk of cancer after the diagnosis of another condition can present opportunities for earlier diagnosis. We examined the risk of cancer diagnosis conditional on prior diagnosis of atrial fibrillation (AF)., Methods: Linked electronic health records were used to identify patients aged ≥18 with new-onset AF and age-sex-matched controls. Cumulative incidence of and mortality from cancer (overall and cancer-site specific) within three months, three months to five years and beyond five years from diagnosis of AF were examined. Findings were further validated using Mendelian randomisation (MR)., Results: The cohort included 117,173 patients with new-onset AF and 117,173 matched controls (median age 78). In the first three months, 2.2% of AF patients were diagnosed with cancer vs. 0.47% in controls (relative risk: 4.7 [95%CI 4.2-5.4] in men and 4.4 [95%CI 3.8-5.0] in women). Nearly 80% of cancers related to thoracic or abdominal organs. Differences in cumulative incidence were only evident in women between three months and five years (subdistribution hazard ratio=1.1 [95%CI 1.01-1.12]) and absent in all patients beyond five years. MR analysis did not support the presence of a causal association between AF and major cancer subtypes., Conclusion: There is a large short-term increase in cancer incidence and mortality following new-onset AF. The findings may reflect incidental identification of AF or paraneoplastic manifestation. New-onset AF confers high short-term risk of cancer diagnosis, at levels comparable with symptomatic risk threshold mandating urgent assessment for suspected cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GYHL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. No fees are received personally. GYHL is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 899871., (Copyright © 2024. Published by Elsevier Inc.)

Aims: The CHA2DS2VASc score is recommended for stroke risk stratification in patients with atrial fibrillation (AF). This score assigns one extra point to female sex based on evidence from the early 2000s, suggesting higher thromboembolic risk in women. This incremental risk of thromboembolism in women has decreased over time between 2007 and 2018, becoming non-significant in recent years. The objective of this study was to assess the impact of removing the sex category (Sc) from the CHA2DS2VASc score, thus validating a non-sex CHA2DS2VASc (i.e. CHA2DS2VA) score., Methods and Results: We analysed UK primary and secondary care data comprising 195 719 patients with AF followed between 1998 and 2016 (mean age: 75.9 ± 12.3 years; 49.2% women). Among 126 428 non-anticoagulated patients, we compared the CHA2DS2VASc vs. CHA2DS2VA scores every calendar year. Throughout 413 007 patient-years, a total of 8742 events of ischaemic stroke or systemic embolism were recorded. Sex differences in thromboembolic risk were not observed in the lower-risk population, but higher stroke rates were consistently seen in female patients in the higher-risk category (i.e. CHA2DS2VA ≥2). C-statistics for both CHA2DS2VA and CHA2DS2VASc scores were similar over the years (ranging from 0.62 to 0.71). With CHA2DS2VA, no relevant differences were observed in integrated discrimination improvement, and net reclassification improvement (NRI) resulted in improved reclassification (11%) in lower thromboembolic risk groups. The NRI suggested misclassification in higher thromboembolic risk patients (-7%), but this did not affect their indication for anticoagulation (i.e. patients retained their high-risk status)., Conclusion: Removing Sc from the CHA2DS2VASc score does not affect its ability to discriminate thromboembolic events in the population with AF. The use of CHA2DS2VA may simplify initial decision-making for thromboprophylaxis., Competing Interests: Conflict of interest: G.Y.H.L. is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos. No fees were received personally. The remaining authors have no other conflicts of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Altered metabolism plays a role in the pathophysiology of cardiac diseases, such as atrial fibrillation (AF) and heart failure (HF). We aimed to identify novel plasma metabolites and proteins associating with cardiac disease., Methods: Mendelian randomisation (MR) was used to assess the association of 174 metabolites measured in up to 86,507 participants with AF, HF, dilated cardiomyopathy (DCM), and non-ischemic cardiomyopathy (NICM). Subsequently, we sourced data on 1567 plasma proteins and performed cis MR to identify proteins affecting the identified metabolites as well as the cardiac diseases. Proteins were prioritised on cardiac expression and druggability, and mapped to biological pathways., Results: We identified 35 metabolites associating with cardiac disease. AF was affected by seventeen metabolites, HF by nineteen, DCM by four, and NCIM by taurine. HF was particularly enriched for phosphatidylcholines (p = 0.029) and DCM for acylcarnitines (p = 0.001). Metabolite involvement with AF was more uniform, spanning for example phosphatidylcholines, amino acids, and acylcarnitines. We identified 38 druggable proteins expressed in cardiac tissue, with a directionally concordant effect on metabolites and cardiac disease. We recapitulated known associations, for example between the drug target of digoxin (AT1B2), taurine and NICM risk. Additionally, we identified numerous novel findings, such as higher RET values associating with phosphatidylcholines and decreasing AF and HF. RET is targeted by drugs such as regorafenib which has known cardiotoxic side-effects. Pathway analysis implicated involvement of GDF15 signalling through RET, and ghrelin regulation of energy homeostasis in cardiac pathogenesis., Conclusions: This study identified 35 plasma metabolites involved with cardiac diseases and linked these to 38 druggable proteins, providing actionable leads for drug development., (© 2024. The Author(s).)

Background: Cardiometabolic multimorbidity (CMM), defined as the co-occurrence of 2 or more cardiometabolic diseases, including myocardial infarction (MI), stroke, and type 2 diabetes (T2D), is an increasing public health challenge. Although poor diet is a known risk factor for a first cardiometabolic disease (FCMD), the relationship with subsequent occurrence of CMM is less studied., Objectives: This study aims to investigate the prospective association between baseline adherence to the Mediterranean diet and the onset of CMM across various follow-up durations., Methods: We used data from the European Prospective Investigation into Cancer-Norfolk cohort study of 21,900 adults, aged 40-79 free of prevalent MI, stroke, and T2D at baseline (1993-1997). A median-based Mediterranean diet score and a pyramid-based MDS (pyr-MDS) were used to measure baseline adherence to the Mediterranean diet. Multistate modeling was employed to investigate associations with the FCMD and the subsequent CMM event., Results: Over the entire follow-up period of 21.4 y (median), we observed 5028 FCMD and 734 CMM events. Multistate analysis indicated that the association between baseline Mediterranean diet and the risk of CMM may be stronger in shorter follow-up durations. Particularly, baseline pyr-MDS was significantly associated with the risk of subsequent CMM transitioning from FCMD when follow-up durations were limited to 10 and 15 y, with hazard ratio (95% confidence interval) being 0.67 (0.53, 0.84) and 0.80 (0.70, 0.92) per SD increase in pyr-MDS, respectively. Additionally, we observed that the risk of CMM transitioning from FCMD was modified by social class across shorter to longer follow-ups, where the impact of baseline Mediterranean diet was only significant in nonmanual workers., Conclusions: Baseline adherence to the Mediterranean diet was potentially associated with a lower risk of CMM transitioning from FCMD, particularly during shorter follow-up periods., Competing Interests: Conflict of interest The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Elevated concentrations of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia., Methods: Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson's dementia., Results: MR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson's dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4 + participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81 × 10 - 4 ., Conclusions: These results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers., (© 2024. The Author(s).)

Background: Despite the growing interest in the use of human genomic data for drug target identification and validation, the extent to which the spectrum of human disease has been addressed by genome-wide association studies (GWAS), or by drug development, and the degree to which these efforts overlap remain unclear., Methods: In this study we harmonize and integrate different data sources to create a sample space of all the human drug targets and diseases and identify points of convergence or divergence of GWAS and drug development efforts., Results: We show that only 612 of 11,158 diseases listed in Human Disease Ontology have an approved drug treatment in at least one region of the world. Of the 1414 diseases that are the subject of preclinical or clinical phase drug development, only 666 have been investigated in GWAS. Conversely, of the 1914 human diseases that have been the subject of GWAS, 1121 have yet to be investigated in drug development., Conclusions: We produce target-disease indication lists to help the pharmaceutical industry to prioritize future drug development efforts based on genetic evidence, academia to prioritize future GWAS for diseases without effective treatments, and both sectors to harness genetic evidence to expand the indications for licensed drugs or to identify repurposing opportunities for clinical candidates that failed in their originally intended indication., (© 2024. The Author(s).)

Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in interorgan communication in diverse pathological processes. ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of the alveolar macrophage (AM) markers CD11b, CD11c, and CD206 as well as ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction of inspired oxygen therapy (HO 2 ⩾30%) had increased concentrations of AM-derived EV-ASC compared with infants on lower fraction of inspired oxygen (LO 2 <30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO 2 had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood-brain barrier, and the EVs from infants on HO 2 caused inflammation, reduced cell survival, and increased cell death, with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain cross-talk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants.

Objective: Cognitive theories emphasize the central role of anger and anger suppression in obsessive-compulsive disorder (OCD). According to these theories, anger suppression is seen as a consequence of OCD, whereas cognitive beliefs, such as an inflated sense of responsibility, are seen as antecedent factors. To extend the findings from cross-sectional studies, the current study investigated the temporal associations between OCD symptoms, an inflated sense of responsibility, and anger suppression. Consistent with cognitive considerations, we hypothesized that OCD symptoms mediate the association between feelings of responsibility and anger suppression. These associations were also explored in patients presenting particularly high checking-related symptoms. Further, the stability of effects beyond controlling for depressive symptoms and medication intake was explored., Methods: A total of N = 48 patients with OCD (50% female, M = 32.46 [SD = 10.63] years of age) completed measures on obsessive beliefs, OCD symptoms, and anger suppression at three assessment points: before and after a metacognitive intervention as well as at a follow-up 6 months later. Mediation models investigating symptom associations at these three timepoints were conducted. Exploratory analyses investigating these associations in individuals presenting high checking-related symptoms (n = 20) and testing the stability of effects beyond controlling for depressive symptoms and medication intake were conducted., Results: The sense of responsibility did not significantly predict the level of anger suppression. A temporal association between OCD symptoms (as assessed with the self-report measure) and anger suppression could be evidenced, which was stable beyond controlling for depressive symptoms and medication intake. Against the expectations based on cognitive theories, the sense of responsibility did not predict OCD symptoms. No mediating effect of OCD symptoms was found., Conclusion: In line with cognitive viewpoints, the present study shows that higher OCD symptoms predict higher levels of anger suppression in a longitudinal design, thereby contributing to the suppression of anger. This effect seems to be independent from depressive symptoms and medication intake. The effect of sense of responsibility on OCD symptoms was less clear and could only be found in the subgroup of patients with OCD and checking-related symptoms, who generally presented higher levels of responsibility. Overall, this is the first study demonstrating temporal associations between OCD symptoms and anger suppression. Acknowledging that anger and anger suppression may be a consequence of OCD symptoms and may also affect aspects of psychotherapy, which can ultimately inform future adjustments to psychotherapeutic treatment., (© 2024 The Author(s). Journal of Clinical Psychology published by Wiley Periodicals LLC.)

Aims: This study aimed to validate the machine learning-based Global Registry of Acute Coronary Events (GRACE) 3.0 score and PRAISE (Prediction of Adverse Events following an Acute Coronary Syndrome) in patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI) for predicting mortality., Methods and Results: Data of consecutive patients with ACS treated with PCI in a tertiary centre in the Netherlands between 2014 and 2021 were used for external validation. The GRACE 3.0 score for predicting in-hospital mortality was evaluated in 2759 patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) treated with PCI. The PRAISE score for predicting one-year mortality was evaluated in 4347 patients with ACS treated with PCI. Both risk scores were compared with the GRACE 2.0 score. The GRACE 3.0 score showed excellent discrimination [c-statistic 0.90 (95% CI 0.84, 0.94)] for predicting in-hospital mortality, with well-calibrated predictions (calibration-in-the large [CIL] -0.19 [95% CI -0.45, 0.07]). The PRAISE score demonstrated moderate discrimination [c-statistic 0.75 (95% CI 0.70, 0.80)] and overestimated the one-year risk of mortality [CIL -0.56 (95% CI -0.73, -0.39)]. Decision curve analysis demonstrated that the GRACE 3.0 score offered improved risk prediction compared with the GRACE 2.0 score, while the PRAISE score did not., Conclusion: This study in ACS patients treated with PCI provides suggestive evidence that the GRACE 3.0 score effectively predicts in-hospital mortality beyond the GRACE 2.0 score. The PRAISE score demonstrated limited potential for predicting one-year mortality risk. Further external validation studies in larger cohorts including patients without PCI are warranted., Competing Interests: Conflict of interest: AFS has received funding from New Amsterdam Pharma for unrelated projects. FWA is supported by UCL Hospitals NIHR Biomedical Research Centre, EU Horizon (AI4HF 101080430 and DataTools4Heart 101057849), Dutch Research Council (MyDigiTwin 628.011.213)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In their influential paper Wurtele et al. (2014) investigated the degree to which individuals within the general population ( N = 435) express sexual interest in children. In the male population of their study ( n = 173), about 6% showed a propensity to engage in sexual activity with a child. Based on a German general population sample consisting of women and men ( N = 911, n = 206 males), we were able to replicate most of the results of Wurtele and colleagues (e.g., 6% of men indicated some likelihood of having sex with a child). To explain sexual offending, Seto (2019) developed the motivation-facilitation model (MFM). In our study, we were interested whether this model also translates to explaining the propensity for deviant sexual behavior in the general population. Moderated hierarchical logistic regression analyses revealed that hypersexuality and sexual fantasies had significant effects as motivating factors for deviant sexual behavior (e.g., sexually assaulting an adult), whereas we found no significant effect of psychopathy as a facilitator. For the prediction of child sexual abuse , only hypersexuality had a significant effect. Notably, after including gender in both models the effect of hypersexuality was no longer significant. Accordingly, we were able to show that the MFM is useful in explaining the propensity for deviant sexual behavior foremost in the male general population. Thus, in clinical practice an assessment of hypersexuality seems to be most relevant for the male population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

People with pedophilia (PWP) can deal with their sexual desires by relieving sexual arousal without sexually exploiting children. Study 1 investigated whether public reactions toward nonoffending pedophilic men are affected by their strategies to relieve sexual arousal (nonsexual pictures vs. child sex dolls) or to reduce their sex drive via testosterone lowering medication in legally nonproblematic ways. A sample of German-speaking participants ( N = 143) read three vignettes describing PWP using either of these strategies. Participants' (59.4% females) mean age was 39.7 ( SD  = 15.6). Although no significant difference was detected between the nonsexual pictures and sex dolls conditions on cognitive (except for dangerousness), affective, and behavioral levels, both consistently elicited more stigmatizing reactions than the testosterone-lowering medication condition. To investigate if this effect was driven by disapproving any relief of sexual arousal or the use of actual child stimuli in particular, Study 2 ( N = 151) added two conditions with PWP using adult child-like stimuli to relieve sexual arousal: adult-as-schoolgirl porn and adult partner with childlike appearance. Here, Participants' (57.6% females) mean age was 28.0 ( SD  = 13.3). Results indicate that stigmatization was driven by disapproving the use of child stimuli rather than the relief of sexual arousal in general. Individuals with a sexual interest in children face strong stigmatizing reactions, which are only alleviated when they are described as undergoing treatment lowering sex drive or - to a lesser extent - being able to mate with an adult partner or using porn with adult actors posing as schoolgirls.

Background: Retinopathy of prematurity (ROP), which often presents with bronchopulmonary dysplasia (BPD), is among the most common morbidities affecting extremely premature infants and is a leading cause of severe vision impairment in children worldwide. Activations of the inflammasome cascade and microglia have been implicated in playing a role in the development of both ROP and BPD. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly. Utilizing mouse models of both oxygen-induced retinopathy (OIR) and BPD, this study was designed to test the hypothesis that hyperoxia induces ASC speck formation, which leads to microglial activation and retinopathy, and that inhibition of ASC speck formation by a humanized monoclonal antibody, IC100, directed against ASC, will ameliorate microglial activation and abnormal retinal vascular formation., Methods: We first tested ASC speck formation in the retina of ASC-citrine reporter mice expressing ASC fusion protein with a C-terminal citrine (fluorescent GFP isoform) using a BPD model that causes both lung and eye injury by exposing newborn mice to room air (RA) or 85% O 2 from postnatal day (P) 1 to P14. The retinas were dissected on P14 and retinal flat mounts were used to detect vascular endothelium with AF-594-conjugated isolectin B4 (IB4) and citrine-tagged ASC specks. To assess the effects of IC100 on an OIR model, newborn ASC citrine reporter mice and wildtype mice (C57BL/6 J) were exposed to RA from P1 to P6, then 75% O 2 from P7 to P11, and then to RA from P12 to P18. At P12 mice were randomized to the following groups: RA with placebo PBS (RA-PBS), O 2 with PBS (O 2 -PBS), O 2  + IC100 intravitreal injection (O 2 -IC100-IVT), and O 2  + IC100 intraperitoneal injection (O 2 -IC100-IP). Retinal vascularization was evaluated by flat mount staining with IB4. Microglial activation was detected by immunofluorescence staining for allograft inflammatory factor 1 (AIF-1) and CD206. Retinal structure was analyzed on H&E-stained sections, and function was analyzed by pattern electroretinography (PERG). RNA-sequencing (RNA-seq) of the retinas was performed to determine the transcriptional effects of IC100 treatment in OIR., Results: ASC specks were significantly increased in the retinas by hyperoxia exposure and colocalized with the abnormal vasculature in both BPD and OIR models, and this was associated with increased microglial activation. Treatment with IC100-IVT or IC100-IP significantly reduced vaso-obliteration and intravitreal neovascularization. IC100-IVT treatment also reduced retinal microglial activation, restored retinal structure, and improved retinal function. RNA-seq showed that IC100 treatment corrected the induction of genes associated with angiogenesis, leukocyte migration, and VEGF signaling caused by O 2 . IC100 also corrected the suppression of genes associated with cell junction assembly, neuron projection, and neuron recognition caused by O 2 ., Conclusion: These data demonstrate the crucial role of ASC in the pathogenesis of OIR and the efficacy of a humanized therapeutic anti-ASC antibody in treating OIR mice. Thus, this anti-ASC antibody may potentially be considered in diseases associated with oxygen stresses and retinopathy, such as ROP., (© 2024. The Author(s).)

Premature infants are often exposed to hyperoxia. However, there is limited data regarding the mechanistic underpinnings linking neonatal hyperoxia exposure and its contribution to cardio-renal dysfunction in adults born preterm. Our objective was to determine whether neonatal hyperoxia induces systemic vascular stiffness and cardio-renal dysfunction in adulthood. Newborn rats were randomly assigned to room air (RA) or hyperoxia (85% O 2 ) from postnatal day 1 to 14, then recovered in RA until 1 year of life. Arterial stiffness, cardio-renal histomorphometry, and fibrosis in the aorta, heart, and kidney were assessed. RNA-sequencing (RNA-seq) of the aorta and kidney was also done. Adult rats exposed to neonatal hyperoxia had increased aortic and mesenteric artery stiffness as demonstrated by wire and pressure myography. They also had cardiomyocyte hypertrophy, glomerulomegaly, and tubular injury. Hyperoxia exposure altered the transcriptome profile associated with fibrosis and matrix remodeling in the aorta and kidney. There was also increased TGF-β1 levels and fibrosis in the aorta, left ventricle, and kidney. In conclusion, neonatal hyperoxia exposure was associated with systemic vascular and cardio-renal alterations in 1-year-old rats. Further studies to determine how targeted therapies could reprogram cardio-renal injury after neonatal hyperoxia exposure are indicated., (© 2024. The Author(s).)

Background: The darknet hosts an increasing number of hidden services dedicated to the distribution of child sexual abuse material (CSAM). Given that by contributing CSAM to the forum members subject themselves to criminal prosecution, questions regarding the motivation for members contributing to darknet CSAM forums arise., Objective: Building on insights gained from research into clearnet communities, here we examine the extent to which social incentives generated by the online CSAM community may explain members' posting behavior on darknet CSAM forums., Participants and Setting: We analyze digital forensic artifacts on the online behavior of members of a darknet CSAM forum that was shut down by law enforcement agencies in July 2015., Methods: We apply group-based trajectory modelling (GBTM), social network analysis, and mixed-effect survival models., Results: Applying GBTM three posting trajectories can be distinguished. Social network analyses finds the reply network to be more centralized than predicted by chance. Mixed-effect survival models show positive associations between the length of members' first post and the time since members' first registration on the forum and subsequent posting. Contrarily, the number of replies received appears to mitigate subsequent posting., Conclusions: Findings show posting activity on the forum to be concentrated in a minority of forum members who show posting trajectories that are both frequent and persistent. Results further suggest persistence in posting is motivated by social identity and, to a lesser extent, differential association processes., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral A β amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis -Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10 -3 ), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10 -5 ) and plasma tau concentration (0.06 log 2 (ng l -1 ) 95%CI 0.03; 0.08, p = 4.55 × 10 -6 ). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.

Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. Ninety-eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈31,000 individuals, age range 24-86 years). We used nonlinear and penalized regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N ≈102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all-cause mortality. Seven-fold cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

CETP inhibitors are a class of lipid-lowering drugs in development for treatment of coronary heart disease (CHD). Genetic studies in East Asian ancestry have interpreted the lack of CETP signal with low-density lipoprotein cholesterol (LDL-C) and lack of drug target Mendelian randomization (MR) effect on CHD as evidence that CETP inhibitors might not be effective in East Asian participants. Capitalizing on recent increases in sample size of East Asian genetic studies, we conducted a drug target MR analysis, scaled to a standard deviation increase in high-density lipoprotein cholesterol. Despite finding evidence for possible neutral effects of lower CETP levels on LDL-C, systolic blood pressure and pulse pressure in East Asians (interaction p-values < 1.6 × 10 -3 ), effects on cardiovascular outcomes were similarly protective in both ancestry groups. In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries., (© 2024. The Author(s).)

Background: Cardiometabolic diseases (CMD), including myocardial infarction, stroke, and type 2 diabetes, are leading causes of disability and mortality globally, particularly for people at an older age. The impact of adhering to the Life's Simple 7 (LS7) on the number of years an individual will live without CMD in older adults remains less studied., Methods: This study included a cohort of 2662 British men aged 60-79 years free of CMD at baseline from the British Regional Heart Study (BRHS). Each LS7 factor (BMI, blood pressure, blood glucose, total cholesterol, smoking, physical activity, and diet) was categorized as poor, intermediate, or ideal, and a composite LS7 adherence was determined by summing the number of LS7 ideal levels achieved. Flexible parametric Royston-Parmar proportional-hazards model was applied to estimate CMD-free life expectancy., Results: Here we show that compared to men with the lowest LS7 adherence [with 18.42 years (95% CI: 16.93, 19.90) of CMD-free life at age 60], men having an ideal LS7 adherence are estimated to gain an additional 4.37 years (95% CI: 2.95, 5.79) of CMD-free life. The CMD-free life gain benefits are consistent across social class groups of manual and non-manual workers. Among LS7 factors, achieving an ideal physical activity provides the largest CMD-free survival benefit: 4.84 years (95% CI: 3.37, 6.32) of additional CMD-free life compared with the physically inactive group., Conclusions: Our study quantifies and highlights the benefits of adhering to the LS7 ideal levels for living a longer life without CMD in older adults., (© 2024. The Author(s).)

Assessing another person's intention to flirt and, relatedly, their sexual interest is based on the interpretation and weighting of global (e.g., clothing style) and specific (e.g., facial expression) cues. Since cue incongruency increases the risk of erroneous judgments and thus can entail undesirable outcomes for both parties involved, detection of an individual propensity for overly relying on global (sexual) rather than specific (affective) cues is of social and clinical-forensic importance. Using a purpose-designed and pre-validated stimulus set, we developed a mouse-tracking task as an indirect behavioral measure for males' overreliance on global cues (OGC) in the context of sexual flirting. In a convenience sample of heterosexual cisgender men (N = 79), experimentally induced sexual arousal was shown to increase the probability of OGC as a function of task difficulty (i.e., congruent or incongruent combinations of global and specific cues displayed by a potential female flirting partner). While error rate and reaction time proved to be indicators of OGC, the spatial measures maximum deviation and area under the curve provided less consistent results. In addition, error rate suggested sex drive and sexual objectification to act as moderators of the relationship between sexual arousal and OGC. Exploratory analysis further revealed a theoretically meaningful pattern of correlations between mouse-tracking measures and self-report measures of problematic (e.g., disinhibited, exploitative) sexuality. Implications of the results are discussed and a framework for differentiating potential causes of OGC (i.e., misperception, lack of self-control, and egocentric hedonism) is proposed., (© 2024. The Author(s).)

Neonatal pulmonary hypertension (PH) is a devastating disorder of the pulmonary vasculature characterized by elevated pulmonary vascular resistance and mean pulmonary arterial pressure. Occurring predominantly because of maldevelopment or maladaptation of the pulmonary vasculature, PH in neonates is associated with suboptimal short-term and long-term outcomes because its pathobiology is unclear in most circumstances, and it responds poorly to conventional pulmonary vasodilators. Understanding the pathogenesis and pathophysiology of neonatal PH can lead to novel strategies and precise therapies. The review is designed to achieve this goal by summarizing pulmonary vascular development and the pathogenesis and pathophysiology of PH associated with maladaptation, bronchopulmonary dysplasia, and congenital diaphragmatic hernia based on evidence predominantly from preclinical studies. We also discuss the pros and cons of and provide future directions for preclinical studies in neonatal PH., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The decreasing costs of high-throughput genetic sequencing and increasing abundance of sequenced genome data have paved the way for the use of genetic data in identifying and validating potential drug targets. However, the number of identified potential drug targets is often prohibitively large to experimentally evaluate in wet lab experiments, highlighting the need for systematic approaches for target prioritisation. In this review, we discuss principles of genetically guided drug development, specifically addressing loss-of-function analysis, colocalization and Mendelian randomisation (MR), and the contexts in which each may be most suitable. We subsequently present a range of biomedical resources which can be used to annotate and prioritise disease-associated proteins identified by these studies including 1) ontologies to map genes, proteins, and disease, 2) resources for determining the druggability of a potential target, 3) tissue and cell expression of the gene encoding the potential target, and 4) key biological pathways involving the potential target. We illustrate these concepts through a worked example, identifying a prioritised set of plasma proteins associated with non-alcoholic fatty liver disease (NAFLD). We identified five proteins with strong genetic support for involvement with NAFLD: CYB5A, NT5C, NCAN, TGFBI and DAPK2. All of the identified proteins were expressed in both liver and adipose tissues, with TGFBI and DAPK2 being potentially druggable. In conclusion, the current review provides an overview of genetic evidence for drug target identification, and how biomedical databases can be used to provide actionable prioritisation, fully informing downstream experimental validation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AFS and CF have received funding from New Amsterdam Pharma for an unrelated project., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Intra-amniotic inflammation (IAI) is associated with increased risk of preterm birth and bronchopulmonary dysplasia (BPD), but the mechanisms by which IAI leads to preterm birth and BPD are poorly understood, and there are no effective therapies for preterm birth and BPD. The transcription factor c-Myc regulates various biological processes like cell growth, apoptosis, and inflammation. We hypothesized that c-Myc modulates inflammation at the maternal-fetal interface, and neonatal lung remodeling. The objectives of our study were 1) to determine the kinetics of c-Myc in the placenta, fetal membranes and neonatal lungs exposed to IAI, and 2) to determine the role of c-Myc in modulating inflammation at the maternal-fetal interface, and neonatal lung remodeling induced by IAI. Methods: Pregnant Sprague-Dawley rats were randomized into three groups: 1) Intra-amniotic saline injections only (control), 2) Intra-amniotic lipopolysaccharide (LPS) injections only, and 3) Intra-amniotic LPS injections with c-Myc inhibitor 10058-F4. c-Myc expression, markers of inflammation, angiogenesis, immunohistochemistry, and transcriptomic analyses were performed on placenta and fetal membranes, and neonatal lungs to determine kinetics of c-Myc expression in response to IAI, and effects of prenatal systemic c-Myc inhibition on lung remodeling at postnatal day 14. Results: c-Myc was upregulated in the placenta, fetal membranes, and neonatal lungs exposed to IAI. IAI caused neutrophil infiltration and neutrophil extracellular trap (NET) formation in the placenta and fetal membranes, and neonatal lung remodeling with pulmonary hypertension consistent with a BPD phenotype. Prenatal inhibition of c-Myc with 10058-F4 in IAI decreased neutrophil infiltration and NET formation, and improved neonatal lung remodeling induced by LPS, with improved alveolarization, increased angiogenesis, and decreased pulmonary vascular remodeling. Discussion: In a rat model of IAI, c-Myc regulates neutrophil recruitment and NET formation in the placenta and fetal membranes. c-Myc also participates in neonatal lung remodeling induced by IAI. Further studies are needed to investigate c-Myc as a potential therapeutic target for IAI and IAI-associated BPD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tan, Tong, Alvarez-Cubela, Chen, Santana, Morales, Tian, Infante, Nunes de Paiva, Kulandavelu, Benny, Dominguez-Bendala, Wu, Young, Rodrigues and Schmidt.)

Background: Preterm birth is often associated with chorioamnionitis and leads to increased risk of neurodevelopmental disorders, such as autism. Preterm birth can lead to cerebellar underdevelopment, but the mechanisms of disrupted cerebellar development in preterm infants are not well understood. The cerebellum is consistently affected in people with autism spectrum disorders, showing reduction of Purkinje cells, decreased cerebellar grey matter, and altered connectivity., Methods: Preterm rhesus macaque fetuses were exposed to intra-amniotic LPS (1 mg, E. coli O55:B5) at 127 days (80%) gestation and delivered by c-section 5 days after injections. Maternal and fetal plasma were sampled for cytokine measurements. Chorio-decidua was analyzed for immune cell populations by flow cytometry. Fetal cerebellum was sampled for histology and molecular analysis by single-nuclei RNA-sequencing (snRNA-seq) on a 10× chromium platform. snRNA-seq data were analyzed for differences in cell populations, cell-type specific gene expression, and inferred cellular communications., Results: We leveraged snRNA-seq of the cerebellum in a clinically relevant rhesus macaque model of chorioamnionitis and preterm birth, to show that chorioamnionitis leads to Purkinje cell loss and disrupted maturation of granule cells and oligodendrocytes in the fetal cerebellum at late gestation. Purkinje cell loss is accompanied by decreased sonic hedgehog signaling from Purkinje cells to granule cells, which show an accelerated maturation, and to oligodendrocytes, which show accelerated maturation from pre-oligodendrocytes into myelinating oligodendrocytes., Conclusion: These findings suggest a role of chorioamnionitis on disrupted cerebellar maturation associated with preterm birth and on the pathogenesis of neurodevelopmental disorders among preterm infants., (© 2024. The Author(s).)

Background: MYH7 variants cause hypertrophic cardiomyopathy (HCM), noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM). Screening of relatives of patients with genetic cardiomyopathy is recommended from 10 to 12 years of age onward, irrespective of the affected gene., Objectives: This study sought to study the penetrance and prognosis of MYH7 variant-associated cardiomyopathies., Methods: In this multicenter cohort study, penetrance and major cardiomyopathy-related events (MCEs) were assessed in carriers of (likely) pathogenic MYH7 variants by using Kaplan-Meier curves and log-rank tests. Prognostic factors were evaluated using Cox regression with time-dependent coefficients., Results: In total, 581 subjects (30.1% index patients, 48.4% male, median age 37.0 years [IQR: 19.5-50.2 years]) were included. HCM was diagnosed in 226 subjects, NCCM in 70, and DCM in 55. Early penetrance and MCEs (age <12 years) were common among NCCM-associated variant carriers (21.2% and 12.0%, respectively) and DCM-associated variant carriers (15.3% and 10.0%, respectively), compared with HCM-associated variant carriers (2.9% and 2.1%, respectively). Penetrance was significantly increased in carriers of converter region variants (adjusted HR: 1.87; 95% CI: 1.15-3.04; P = 0.012) and at age ≤1 year in NCCM-associated or DCM-associated variant carriers (adjusted HR: 21.17; 95% CI: 4.81-93.20; P < 0.001) and subjects with a family history of early MCEs (adjusted HR: 2.45; 95% CI: 1.09-5.50; P = 0.030). The risk of MCE was increased in subjects with a family history of early MCEs (adjusted HR: 1.82; 95% CI: 1.15-2.87; P = 0.010) and at age ≤5 years in NCCM-associated or DCM-associated variant carriers (adjusted HR: 38.82; 95% CI: 5.16-291.88; P < 0.001)., Conclusions: MYH7 variants can cause cardiomyopathies and MCEs at a young age. Screening at younger ages may be warranted, particularly in carriers of NCCM- or DCM-associated variants and/or with a family history of MCEs at <12 years., Competing Interests: Funding Support and Author Disclosures This work was supported by the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation. Dr Jansen has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA [Dutch Cardiovascular Alliance] 2020B005 DoubleDose) and from the Dutch Heart Foundation (Dekker 2015T041). Dr Christiaans has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2015-12 e-Detect). Dr de Boer has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA 2020B005 DoubleDose). Dr van Tintelen has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA 2020B005 DoubleDose and CVON2015-12 e-Detect). Dr Asselbergs has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA 2020B005 DoubleDose and CVON2015-12 e-Detect) and from the UCL Hospitals NIHR Biomedical Research Centre. Dr Baas has received support from the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, DCVA 2020B005 DoubleDose and CVON2015-12 e-Detect) and from the Dutch Heart Foundation (Dekker 2015T041). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value., (© 2023. The Author(s).)

This study combined research on human mate preferences and attraction to physical and psychological features of children. Specifically, we used the Ideals Standards Model (ISM) as a conceptual framework to investigate the sexual relevance of adult and child sex cues within the general population. A sample of 589 men (mean age 30.6 years, SD  = 16.6) answered questions about their sexual age preferences as well as different child and adult sex cues. The sample showed the full gamut of sexual age preferences (i.e. ranging from prepubescent children to adults over sixty years of age). A principal component analysis revealed five dimensions of adult and child sex cues. Sexual interest in children was positively related to the two dimensions of attraction to neotenous innocence and attraction to neotenous physical appearance while being negatively related to the factor of agency . In contrast, sexual interest in adults was indicated by the dimension of vitality . The fifth dimension of warmth-truthfulness was neither related to sexual interest in children nor sexual interest in adults. We argue that attraction to neotenous innocence and attraction to neotenous physical appearance can be used as an indicator of sexual interest in children. Moreover, we discuss how our results fit in with theoretical notions from the ISM.

Neonatal hyperoxia induces long-term systemic vascular stiffness and cardiovascular remodeling, but the mechanisms are unclear. Chemokine receptor 7 (CXCR7) represents a key regulator of vascular homeostasis and repair by modulating TGF-β1 signaling. This study investigated whether pharmacological CXCR7 agonism prevents neonatal hyperoxia-induced systemic vascular stiffness and cardiac dysfunction in juvenile rats. Newborn Sprague Dawley rat pups assigned to room air or hyperoxia (85% oxygen), received CXCR7 agonist, TC14012 or placebo for 3 weeks. These rat pups were maintained in room air until 6 weeks when aortic pulse wave velocity doppler, cardiac echocardiography, aortic and left ventricular (LV) fibrosis were assessed. Neonatal hyperoxia induced systemic vascular stiffness and cardiac dysfunction in 6-week-old rats. This was associated with decreased aortic and LV CXCR7 expression. Early treatment with TC14012, partially protected against neonatal hyperoxia-induced systemic vascular stiffness and improved LV dysfunction and fibrosis in juvenile rats by decreasing TGF-β1 expression. In vitro, hyperoxia-exposed human umbilical arterial endothelial cells and coronary artery endothelial cells had increased TGF-β1 levels. However, treatment with TC14012 significantly reduced the TGF-β1 levels. These results suggest that dysregulation of endothelial CXCR7 signaling may contribute to neonatal hyperoxia-induced systemic vascular stiffness and cardiac dysfunction., (© 2023. The Author(s).)

Despite widespread use, dosing regimens for antenatal corticosteroid (ACS) therapy are poorly unoptimized. ACS therapy exerts a programming effect on fetal development, which may be associated with an increased risk of cardiovascular disease. Having demonstrated that low-dose steroid therapy is an efficacious means of maturing the preterm lung, we hypothesized that a low-dose steroid exposure would exert fewer adverse functional and transcriptional changes on the fetal heart. We tested this hypothesis using low-dose steroid therapy (10 mg delivered to the ewe over 36 h via constant infusion) and compared cardiac effects with those of a higher dose treatment (30 mg delivered to the ewe over 24 h by intramuscular injection; simulating currently employed clinical ACS regimens). Fetal cardiac function was assessed by ultrasound on the day of ACS treatment initiation. Transcriptomic analyses were performed on fetal myocardial tissue. Relative to saline control, fetuses in the higher-dose clinical treatment group had significantly lower ratios between early diastolic ventricular filling and ventricular filling during atrial systole, and showed the differential expression of myocardial hypertrophy-associated transcripts including βMHC, GADD45γ, and PPARγ. The long-term implications of these changes remain unstudied. Irrespective, optimizing ACS dosing regimens to maximize respiratory benefit while minimizing adverse effects on key organ systems, such as the heart, offers a means of improving the acute and long-term outcomes associated with this important obstetric therapy., (© 2023. The Author(s).)

Background and Objectives: There has been considerable interest in statins because of their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to Rho small guanosine triphosphatases (Rho GTPases) proteins. We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity., Method: We used two-sample Mendelian randomization (MR) to investigate (1) the causal role of genetically mimic both cholesterol-dependent (through low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (through Rho GTPases) effects of statins on MS risk and MS severity, (2) the causal link between lipids (high-density lipoprotein cholesterol [HDL-C] and triglycerides [TG]) levels and MS risk and severity, and (3) the reverse causation between lipid fractions and MS risk. We used summary statistics from the Global Lipids Genetics Consortium (GLGC), eQTLGen Consortium, and the International MS Genetics Consortium (IMSGC) for lipids, expression quantitative trait loci, and MS, respectively (GLGC: n = 188,577; eQTLGen: n = 31,684; IMSGC (MS risk): n = 41,505; IMSGC (MS severity): n = 7,069)., Results: The results of MR using the inverse-variance weighted method show that genetically predicted RAC2 , a member of cholesterol-independent pathway (OR 0.86 [95% CI 0.78-0.95], p -value 3.80E-03), is implicated causally in reducing MS risk. We found no evidence for the causal role of LDL-C and the member of cholesterol biosynthesis pathway on MS risk. The MR results also show that lifelong higher HDL-C (OR 1.14 [95% CI 1.04-1.26], p -value 7.94E-03) increases MS risk but TG was not. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids., Discussion: Evidence from this study suggests that RAC2 is a genetic modifier of MS risk. Because RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins may reduce MS risk through a cholesterol-independent pathway (that is, RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on MS risk., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)