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Understanding the evolutionary mechanisms underlying the maintenance of individual differences in behavior and physiology is a fundamental goal in ecology and evolution. The pace-of-life syndrome hypothesis is often invoked to explain the maintenance of such within-population variation. This hypothesis predicts that behavioral traits are part of a suite of correlated traits that collectively determine an individual's propensity to prioritize reproduction or survival. A key assumption of this hypothesis is that these traits are underpinned by genetic trade-offs among life-history traits: genetic variants that increase fertility, reproduction and growth might also reduce lifespan. We performed a systematic literature review and meta-analysis to summarize the evidence for the existence of genetic trade-offs between five key life-history traits: survival, growth rate, body size, maturation rate, and fertility. Counter to our predictions, we found an overall positive genetic correlation between survival and other life-history traits and no evidence for any genetic correlations between the non-survival life-history traits. This finding was generally consistent across pairs of life-history traits, sexes, life stages, lab vs. field studies, and narrow- vs. broad-sense correlation estimates. Our study highlights that genetic trade-offs may not be as common, or at least not as easily quantifiable, in animals as often assumed.

There is growing concern that the severe respiratory disease in birds (avian influenza or ‘bird flu’) caused by the H5N1 influenza virus, might potentially spread more widely to humans and cause a pandemic. Here we discuss clinical issues related to human infections by the highly pathogenic H5N1 subtype of the avian influenza A virus and make a clinical comparison with recent information obtained from studies of SARS-CoV-2 infection. Firstly, we consider the potential increase in cardiovascular events in humans infected with the H5N1 virus. Like SARS-CoV-2 infection, H5N1 infection may result in endothelial dysfunction and the associated procoagulant and prothrombotic state, and via this mechanism, the infection can potentially increase cardiovascular morbidity, especially in vulnerable individuals with pre-existing cardiovascular disease. Secondly, we discuss the potential beneficial role of statin use, both in the prophylaxis and the treatment of individuals with influenza A(H5N1), as was found favorable for the treatment of COVID-19 caused by SARS-CoV-2 infection.

Abstract Studies linking genetics, behavior and life history in any species are rare. In Atlantic salmon (Salmo salar), age at maturity is a key life‐history trait and associates strongly with the vgll3 locus, whereby the vgll3*E allele is linked with younger age at maturity, and higher body condition than the vgll3*L allele. However, the relationship between this genetic variation and behaviors like boldness and exploration which may impact growth and reproductive strategies is poorly understood. The pace‐of‐life syndrome (POLS) framework provides predictions, whereby heightened exploratory behavior and boldness are predicted in individuals with the early maturation‐associated vgll3 genotype (EE). Here, we tested these predictions by investigating the relationship between vgll3 genotypes and exploration and boldness behaviors in 129 juveniles using the novel environment and novel object trials. Our results indicated that contrary to POLS predictions, vgll3*LL fish were bolder and more explorative, suggesting a genotype‐level syndrome including several behaviors. Interestingly, clear sex differences were observed in the latency to move in a new environment, with vgll3*EE males, but not females, taking longer to move than their vgll3*LL counterparts. Our results provide further empirical support for recent calls to consider more nuanced explanations than the pace of life theory for integrating behavior into life‐history theory.

Abstract Background Subject-level real-world data (RWD) collected during daily healthcare practices are increasingly used in medical research to assess questions that cannot be addressed in the context of a randomized controlled trial (RCT). A novel application of RWD arises from the need to create external control arms (ECAs) for single-arm RCTs. In the analysis of ECAs against RCT data, there is an evident need to manage and analyze RCT data and RWD in the same technical environment. In the Nordic countries, legal requirements may require that the original subject-level data be anonymized, i.e., modified so that the risk to identify any individual is minimal. The aim of this study was to conduct initial exploration on how well pseudonymized and anonymized RWD perform in the creation of an ECA for an RCT. Methods This was a hybrid observational cohort study using clinical data from the control arm of the completed randomized phase II clinical trial (PACIFIC-AF) and RWD cohort from Finnish healthcare data sources. The initial pseudonymized RWD were anonymized within the (k, ε)-anonymity framework (a model for protecting individuals against identification). Propensity score matching and weighting methods were applied to the anonymized and pseudonymized RWD, to balance potential confounders against the RCT data. Descriptive statistics for the potential confounders and overall survival analyses were conducted prior to and after matching and weighting, using both the pseudonymized and anonymized RWD sets. Results Anonymization affected the baseline characteristics of potential confounders only marginally. The greatest difference was in the prevalence of chronic obstructive pulmonary disease (4.6% vs. 5.4% in the pseudonymized compared to the anonymized data, respectively). Moreover, the overall survival changed in anonymization by only 8% (95% CI 4–22%). Both the pseudonymized and anonymized RWD were able to produce matched ECAs for the RCT data. Anonymization after matching impacted overall survival analysis by 22% (95% CI -21–87%). Conclusions Anonymization may be a viable technique for cases where flexible data transfer and sharing are required. As anonymization necessarily affects some aspects of the original data, further research and careful consideration of anonymization strategies are needed.

In this short narrative review, we aim at defining the pathophysiological role endothelial dysfunction in the observed COVID-19–associated rise in risk of cardiovascular disease. Variants of the SARS-CoV-2 virus have caused several epidemic waves of COVID-19, and the emergence and rapid spread of new variants and subvariants are likely. Based on a large cohort study, the incidence rate of SARS-CoV-2 reinfection is about 0.66 per 10 000 person-weeks. Both the first infection and reinfection with SARS-CoV-2 increase cardiac event risk, particularly in vulnerable patients with cardiovascular risk factors and the accompanying systemic endothelial dysfunction. By worsening pre-existing endothelial dysfunction, both the first infection and reinfection with ensuing COVID-19 may turn the endothelium procoagulative and prothrombotic, and ultimately lead to local thrombus formation. When occurring in an epicardial coronary artery, the risk of an acute coronary syndrome increases, and when occurring in intramyocardial microvessels, scattered myocardial injuries will ensue, both predisposing the COVID-19 patients to adverse cardiovascular outcomes. In conclusion, considering weakened protection against the cardiovascular risk-enhancing reinfections with emerging new subvariants of SARS-CoV-2, treatment of COVID-19 patients with statins during the illness and thereafter is recommended, partly because the statins tend to reduce endothelial dysfunction.

AbstractPatients with hypercholesterolemia often have coronary microvascular dysfunction (CMD). Viral infections, such as the SARS-CoV-2 infection, may also result in CMD. Three non-randomized studies have shown significant beneficial effects of statins on CMD in non-infected patients. Similarly, in SARS-CoV-2 - infected patients one beneficial mechanism of action of statins may be the amelioration of endothelial dysfunction, which is a major driver of CMD. Apart from statins, lipoprotein apheresis and PCSK9 inhibitors can also improve or even reverse CMD. The potential reversal of CMD by using effective cholesterol-lowering medications during and after COVID-19 infection, especially in hypercholesterolemic COVID-19 patients, is important.KEY MESSAGESCoronary microvascular dysfunction (CMD) is common in patients hospitalized with SARS-CoV-2 infectionThree nonrandomized studies in non-infected patients are showing the beneficial effects of statin treatment on CMDEffective cholesterol-lowering medication during and after SARS-CoV-2 infection, especially in hypercholesterolemic COVID-19 patients, is of great significance

Based on separate protective mechanisms related to lipid metabolism, viral cell entry and inflammation, fibrate treatment might be advantageous among patients who have been taking fibrates before SARS-CoV-2 infection and continue taking them during the infection. Based on published data on hospitalized COVID-19 patients, we recommend that the clinicians should ask their patients with metabolic syndrome who are already taking fibrates to continue fibrate treatment during the COVID-19 illness. This recommendation applies to both outpatients and hospitalized patients. However, results from the ongoing randomized controlled trials (RCTs) using fenofibrate treatment for the prevention or treatment of COVID-19 have yet to prove that fenofibrate is clinically significant for this indication.KEY MESSAGESThe role of fibrates as a repurpose to treat SARS-CoV-2 is under investigation in at least three ongoing RCTs.Obesity, diabetes, hypertension and dyslipidaemia, individually or clustered as a discrete phenotype, the metabolic syndrome, typically associate with a more severe course of COVID-19.Fibrate treatment seems to be most advantageous among patients who have been taken fibrates before SARS-CoV-2 infection and are continuing to take them during the infection.We recommend that the clinicians encourage their patients who are already taking fibrate to continue using the drug throughout the COVID-19 illness.

Research focusing on among-individual differences in behaviour ('animal personality') has been blooming for over a decade. Central theories explaining the maintenance of such behavioural variation posits that individuals expressing greater "risky" behaviours should suffer higher mortality. Here, for the first time, we synthesize the existing empirical evidence for this key prediction. Our results did not support this prediction as there was no directional relationship between riskier behaviour and greater mortality; however there was a significant absolute relationship between behaviour and survival. In total, behaviour explained a significant, but small, portion (5.8%) of the variance in survival. We also found that risky (vs. "shy") behavioural types live significantly longer in the wild, but not in the laboratory. This suggests that individuals expressing risky behaviours might be of overall higher quality but the lack of predation pressure and resource restrictions mask this effect in laboratory environments. Our work demonstrates that individual differences in behaviour explain important differences in survival but not in the direction predicted by theory. Importantly, this suggests that models predicting behaviour to be a mediator of reproduction-survival trade-offs may need revision and/or empiricists may need to reconsider their proxies of risky behaviours when testing such theory.

Abstract Saccular intracranial aneurysm (sIA) rupture leads to subarachnoid haemorrhage and is preceded by chronic inflammation and atherosclerotic changes of the sIA wall. Increased lymphangiogenesis has been detected in atherosclerotic extracranial arteries and in abdominal aortic aneurysms, but the presence of lymphatic vessels in sIAs has remained unexplored. Here we studied the presence of lymphatic vessels in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), using immunohistochemical and immunofluorescence stainings for lymphatic endothelial cell (LEC) markers. Of these LEC-markers, both extracellular and intracellular LYVE-1-, podoplanin-, VEGFR-3-, and Prox1-positive stainings were detected in 83%, 94%, 100%, and 72% of the 36 sIA walls, respectively. Lymphatic vessels were identified as ring-shaped structures positive for one or more of the LEC markers. Of the sIAs, 78% contained lymphatic vessels positive for at least one LEC marker. The presence of LECs and lymphatic vessels were associated with the number of CD68+ and CD163+ cells in the sIA walls, and with the expression of inflammation indicators such as serum amyloid A, myeloperoxidase, and cyclo-oxygenase 2, with the presence of a thrombus, and with the sIA wall rupture. Large areas of VEGFR-3 and α-smooth muscle actin (αSMA) double-positive cells were detected in medial parts of the sIA walls. Also, a few podoplanin and αSMA double-positive cells were discovered. In addition, LYVE-1 and CD68 double-positive cells were detected in the sIA walls and in the thrombus revealing that certain CD68+ macrophages are capable of expressing LEC markers. This study demonstrates for the first time the presence of lymphatic vessels in human sIA walls. Further studies are needed to understand the role of lymphatic vessels in the pathogenesis of sIA.

Since the discovery of statins and the Scandinavian Simvastatin Survival Study (4S) results three decades ago, remarkable advances have been made in the treatment of dyslipidaemia, a major risk factor for atherosclerotic cardiovascular disease. Safe and effective statins remain the cornerstone of therapeutic approach for this indication, including for children with genetic dyslipidaemia, and are one of the most widely prescribed drugs in the world. However, despite the affordability of generic statins, they remain underutilised worldwide. The use of ezetimibe to further decrease plasma LDL cholesterol and the targeting of other atherogenic lipoproteins, such as triglyceride-rich lipoproteins and lipoprotein(a), are likely to be required to further reduce atherosclerotic cardiovascular disease events. Drugs directed at these lipoproteins, including gene silencing and editing methods that durably suppress the production of proteins, such as PCSK9 and ANGPTL3, open novel therapeutic options to further reduce the development of atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

IntroductionLipoprotein(a) (Lp(a)) is an LDL-like particle with an additional apolipoprotein (apo)(a) covalently attached. Elevated levels of circulating Lp(a) are a risk factor for atherosclerosis. A proinflammatory role for Lp(a) has been proposed, but its molecular details are incompletely defined.Methods and resultsTo explore the effect of Lp(a) on human macrophages we performed RNA sequencing on THP-1 macrophages treated with Lp(a) or recombinant apo(a), which showed that especially Lp(a) induces potent inflammatory responses. Thus, we stimulated THP-1 macrophages with serum containing various Lp(a) levels to investigate their correlations with cytokines highlighted by the RNAseq, showing significant correlations with caspase-1 activity and secretion of IL-1β and IL-18. We further isolated both Lp(a) and LDL particles from three donors and then compared their atheroinflammatory potentials together with recombinant apo(a) in primary and THP-1 derived macrophages. Compared with LDL, Lp(a) induced a robust and dose-dependent caspase-1 activation and release of IL-1β and IL-18 in both macrophage types. Recombinant apo(a) strongly induced caspase-1 activation and IL-1β release in THP-1 macrophages but yielded weak responses in primary macrophages. Structural analysis of these particles revealed that the Lp(a) proteome was enriched in proteins associated with complement activation and coagulation, and its lipidome was relatively deficient in polyunsaturated fatty acids and had a high n-6/n-3 ratio promoting inflammation.DiscussionOur data show that Lp(a) particles induce the expression of inflammatory genes, and Lp(a) and to a lesser extent apo(a) induce caspase-1 activation and IL-1 signaling. Major differences in the molecular profiles between Lp(a) and LDL contribute to Lp(a) being more atheroinflammatory.

SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pace of vaccination COVID-19 will probably remain a global burden to health systems for a long time. Unfortunately, the necessary prevention and treatment strategies of COVID-19 have led to restriction measures that are hampering the routine care of common chronic metabolic conditions like hypercholesterolemia. It is of particular concern that during the acute phase of COVID-19, the control of pre-existing metabolic diseases tends to get worse which again increases the risk for complications and a poor outcome in these patients. A significant contributor to these complications is endothelial dysfunction which is associated with COVID-19. This Commentary will discuss the impact of COVID-19 on endothelial function particularly in patients with familial hypercholesterolemia (FH), a metabolic inherited disease known to in itself adversely affect endothelial function. There should be no hesitation to continue with statin therapy in severe hypercholesterolemic patients with COVID-19. We argue that in FH patients with COVID-19 the clinicians need even consider intensifying statin therapy as well as the addition of other lipid-lowering agents, such as proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors. In contrast to statins, the PCSK9 inhibitors lower lipoprotein(a) [Lp(a)] level, and, accordingly, these latter drugs need to be considered particularly in FH patients with an elevated level of Lp(a). This call applies to the in-hospital stay and also beyond. When considering that the vasculopathic effects of COVID-19 may persist, a long-term follow-up of individualized therapies in FH patients is warranted.

Abstract In atherosclerotic lesions, blood-derived monocytes differentiate into distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines, which also contains macrophage-colony stimulating factor (M-CSF) and granulocyte–macrophage-colony stimulating factor (GM-CSF). Here we generated human macrophages in the presence of either M-CSF or GM-CSF to obtain M-MØ and GM-MØ, respectively. The macrophages were converted into cholesterol-loaded foam cells by incubating them with acetyl-LDL, and their atheroinflammatory gene expression profiles were then assessed. Compared with GM-MØ, the M-MØ expressed higher levels of CD36, SRA1, and ACAT1, and also exhibited a greater ability to take up acetyl-LDL, esterify cholesterol, and become converted to foam cells. M-MØ foam cells expressed higher levels of ABCA1 and ABCG1, and, correspondingly, exhibited higher rates of cholesterol efflux to apoA-I and HDL2. Cholesterol loading of M-MØ strongly suppressed the high baseline expression of CCL2, whereas in GM-MØ the low baseline expression CCL2 remained unchanged during cholesterol loading. The expression of TNFA, IL1B, and CXCL8 were reduced in LPS-activated macrophage foam cells of either subtype. In summary, cholesterol loading converged the CSF-dependent expression of key genes related to intracellular cholesterol balance and inflammation. These findings suggest that transformation of CSF-polarized macrophages into foam cells may reduce their atheroinflammatory potential in atherogenesis.

ObjectivesImpaired protein kinase signaling is a hallmark of ischemic heart disease (IHD). Inadequate understanding of the pathological mechanisms limits the development of therapeutic approaches. We aimed to identify the key cardiac kinases and signaling pathways in patients with IHD with an effort to discover potential therapeutic strategies.MethodsCardiac kinase activity in IHD left ventricle (LV) and the related signaling pathways were investigated by kinomics, transcriptomics, proteomics, and integrated multi-omics approach.ResultsProtein kinase A (PKA) and protein kinase G (PKG) ranked on top in the activity shift among the cardiac kinases. In the IHD LVs, PKA activity decreased markedly compared with that of controls (62% reduction, p = 0.0034), whereas PKG activity remained stable, although the amount of PKG protein increased remarkably (65%, p = 0.003). mRNA levels of adenylate cyclases (ADCY 1, 3, 5, 9) and cAMP-hydrolysing phosphodiesterases (PDE4A, PDE4D) decreased significantly, although no statistically significant alterations were observed in that of PKGs (PRKG1 and PRKG2) and guanylate cyclases (GUCYs). The gene expression of natriuretic peptide CNP decreased remarkably, whereas those of BNP, ANP, and neprilysin increased significantly in the IHD LVs. Proteomics analysis revealed a significant reduction in protein levels of “Energy metabolism” and “Muscle contraction” in the patients. Multi-omics integration highlighted intracellular signaling by second messengers as the top enriched Reactome pathway.ConclusionThe deficiency in cAMP/PKA signaling pathway is strongly implicated in the pathogenesis of IHD. Natriuretic peptide CNP could be a potential therapeutic target for the modulation of cGMP/PKG signaling.