Experimental infection of pigs and ferrets with "pre-pandemic," human-adapted, and swine-adapted variants of the H1N1pdm09 influenza A virus reveals significant differences in viral dynamics and pathological manifestations.

Influenza A viruses are RNA viruses that cause epidemics in humans and are enzootic in the pig population globally. In 2009, pig-to-human transmission of a reassortant H1N1 virus (H1N1pdm09) caused the first influenza pandemic of the 21st century. This study investigated the infection dynamics, pathogenesis, and lesions in pigs and ferrets inoculated with natural isolates of swine-adapted, human-adapted, and "pre-pandemic" H1N1pdm09 viruses. Additionally, the direct-contact and aerosol transmission properties of the three H1N1pdm09 isolates were assessed in ferrets. In pigs, inoculated ferrets, and ferrets infected by direct contact with inoculated ferrets, the pre-pandemic H1N1pdm09 virus induced an intermediary viral load, caused the most severe lesions, and had the highest clinical impact. The swine-adapted H1N1pdm09 virus induced the highest viral load, caused intermediary lesions, and had the least clinical impact in pigs. The human-adapted H1N1pdm09 virus induced the highest viral load, caused the mildest lesions, and had the least clinical impact in ferrets infected by direct contact. The discrepancy between viral load and clinical impact presumably reflects the importance of viral host adaptation. Interestingly, the swine-adapted H1N1pdm09 virus was transmitted by aerosols to two-thirds of the ferrets. Further work is needed to assess the risk of human-to-human aerosol transmission of swine-adapted H1N1pdm09 viruses.

Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Multigenerational Fitness Effects of Natural Immigration Indicate Strong Heterosis and Epistatic Breakdown in a Wild Bird Population.

AbstractThe fitness of immigrants and their descendants produced within recipient populations fundamentally underpins the genetic and population dynamic consequences of immigration. Immigrants can in principle induce contrasting genetic effects on fitness across generations, reflecting multifaceted additive, dominance, and epistatic effects. Yet full multigenerational and sex-specific fitness effects of regular immigration have not been quantified within naturally structured systems, precluding inference on underlying genetic architectures and population outcomes. We used four decades of song sparrow (Melospiza melodia) life history and pedigree data to quantify fitness of natural immigrants, natives, and their F1, F2, and backcross descendants and test for evidence of nonadditive genetic effects. Values of key fitness components (including adult lifetime reproductive success and zygote survival) of F1 offspring of immigrant-native matings substantially exceeded their parent mean, indicating strong heterosis. Meanwhile, F2 offspring of F1-F1 matings had notably low values, indicating surprisingly strong epistatic breakdown. Furthermore, magnitudes of effects varied among fitness components and differed between female and male descendants. These results demonstrate that strong nonadditive genetic effects on fitness can arise within weakly structured and fragmented populations experiencing frequent natural immigration. Such effects will substantially affect the net degree of effective gene flow and resulting local genetic introgression and adaptation.

The genetic basis of dispersal in a vertebrate metapopulation.

Dispersal affects evolutionary processes by changing population size and genetic composition, influencing the viability and persistence of populations. Investigating which mechanisms underlie variation in dispersal phenotypes and whether populations harbour adaptive potential for dispersal is crucial to understanding the eco-evolutionary dynamics of this important trait. Here, we investigate the genetic architecture of dispersal among successfully recruited individuals in an insular metapopulation of house sparrows. We use an extensive long-term individual-based ecological data set and high-density single-nucleotide polymorphism (SNP) genotypes for over 2500 individuals. We conducted a genome-wide association study (GWAS), and found a relationship between dispersal probability and a SNP located near genes known to regulate circadian rhythm, glycogenesis and exercise performance, among other functions. However, this SNP only explained 3.8% of variance, suggesting that dispersal is a polygenic trait. We then used an animal model to estimate heritable genetic variation (σA 2 ), which composes 10% of the total variation in dispersal probability. Finally, we investigated differences in σA 2 across populations occupying ecologically relevant habitat types (farm vs. non-farm) using a genetic groups animal model. We found different adaptive potentials across habitats, with higher mean breeding value, σA 2 , and heritability for the habitat presenting lower dispersal rates, suggesting also different roles of environmental variation. Our results suggest a complex genetic architecture of dispersal and demonstrate that adaptive potential may be environment dependent in key eco-evolutionary traits. The eco-evolutionary implications of such environment dependence and consequent spatial variation are likely to become ever more important with the increased fragmentation and loss of suitable habitats for many natural populations.

The effect of robot-assisted versus standard training on motor function following subacute rehabilitation after ischemic stroke - protocol for a randomised controlled trial nested in a prospective cohort (RoboRehab).

BACKGROUND: Body weight unloaded treadmill training has shown limited efficacy in further improving functional capacity after subacute rehabilitation of ischemic stroke patients. Dynamic robot assisted bodyweight unloading is a novel technology that may provide superior training stimuli and continued functional improvements in individuals with residual impairments in the chronic phase after the ischemic insult. The aim of the present study is to investigate the effect of dynamic robot-assisted versus standard training, initiated 6 months post-stroke, on motor function, physical function, fatigue, and quality of life in stroke-affected individuals still suffering from moderate-to-severe disabilities after subacute rehabilitation. METHODS: Stroke-affected individuals with moderate to severe disabilities will be recruited into a prospective cohort with measurements at 3-, 6-, 12- and 18-months post-stroke. A randomised controlled trial (RCT) will be nested in the prospective cohort with measurements pre-intervention (Pre), post-intervention (Post) and at follow-up 6 months following post-intervention testing. The present RCT will be conducted as a multicentre parallel-group superiority of intervention study with assessor-blinding and a stratified block randomisation design. Following pre-intervention testing, participants in the RCT study will be randomised into robot-assisted training (intervention) or standard training (active control). Participants in both groups will train 1:1 with a physiotherapist two times a week for 6 months (groups are matched for time allocated to training). The primary outcome is the between-group difference in change score of Fugl-Meyer Lower Extremity Assessment from pre-post intervention on the intention-to-treat population. A per-protocol analysis will be conducted analysing the differences in change scores of the participants demonstrating acceptable adherence. A priori sample size calculation allowing the detection of the minimally clinically important between-group difference of 6 points in the primary outcome (standard deviation 6 point, α = 5% and ß = 80%) resulted in 34 study participants. Allowing for dropout the study will include 40 participants in total. DISCUSSION: For stroke-affected individuals still suffering from moderate to severe disabilities following subacute standard rehabilitation, training interventions based on dynamic robot-assisted body weight unloading may facilitate an appropriate intensity, volume and task-specificity in training leading to superior functional recovery compared to training without the use of body weight unloading. TRIAL REGISTRATION: ClinicalTrials.gov. NCT06273475. TRIAL STATUS: Recruiting. Trial identifier: NCT06273475. Registry name: ClinicalTrials.gov. Date of registration on ClinicalTrials.gov: 22/02/2024.

Pathological Diagnosis of Pulmonary Aspergillosis.

Pulmonary aspergillosis constitutes an increasingly prevalent and potentially fatal complex of mycotic diseases, caused by different species of Aspergillus. The broad spectrum of pathological manifestations associated with pulmonary aspergillosis necessitates a differentiation of commensalism from saprophytic colonization, hypersensitivity reactions, and true invasive infections, which highlights the importance of histopathology as a gold standard in a diagnostic setting. For the past decades, changes in terminology and contradicting contributions from different diagnostic disciplines have made the classification of pulmonary aspergillosis rather confusing. This review offers a categorization of aspergillosis lesions based on what can be histopathologically identified and distinguished, differentiating between acute invasive infection and forms of subacute, chronic, and allergic diseases and coinfections, and summarizes important manifestations of lesions associated with the different forms of pulmonary aspergillosis.

Patient Preferences in the Treatment of Moderate-to-severe Atopic Dermatitis.

Atopic dermatitis is a chronic, inflammatory skin disease. A variety of systemic treatments are available for patients with moderate-to-severe atopic dermatitis. The efficacy, safety and administration profile of these treatments vary, and determining the optimal treatment strategy may require weighing the benefits and drawbacks of therapies with diverse characteristics. This study used an online discrete choice experiment survey to investigate treatment preferences among adults with atopic dermatitis from Denmark, France, the UK, or Canada. Participants were identified through existing online panels. The survey included questions regarding different treatment attributes, defined based on currently approved treatments for moderate to severe atopic dermatitis. Treatment preferences were measured as the relative importance of different treatment attributes. A total of 713 respondents met the inclusion criteria and completed the survey. The discrete choice experiment identified a significant preference for avoiding the risk of severe adverse events, and for oral pill every day compared with biweekly injections. The time to full effect was not rated as being important. These findings suggest that patients with moderate-to-severe atopic dermatitis prioritize safety as most important, followed by ease of administration in their treatment preferences, while time to full effect and monitoring requirements were the least important attributes.

Characterization of DNA-protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus.

Nanotechnology enables investigations of single biomacromolecules, but technical challenges have limited the application in liquid biopsies, for example, blood plasma. Nonetheless, tools to characterize single molecular species in such samples represent a significant unmet need with the increasing appreciation of the physiological importance of protein structural changes at nanometer scale. Mannose-binding lectin (MBL) is an oligomeric plasma protein and part of the innate immune system through its ability to activate complement. MBL also serves a role as a scavenger for cellular debris, especially DNA. This may link functions of MBL with several inflammatory diseases in which cell-free DNA now appears to play a role, but mechanistic insight has been lacking. By making nanoparticle tracking analysis possible in human plasma, we now show that superoligomeric structures of MBL form nanoparticles with DNA. These oligomers correlate with disease activity in systemic lupus erythematosus patients. With the direct quantification of the hydrodynamic radius, calculations following the principles of Taylor dispersion in the blood stream connect the size of these complexes to endothelial inflammation, which is among the most important morbidities in lupus. Mechanistic insight from an animal model of lupus supported that DNA-stabilized superoligomers stimulate the formation of germinal center B cells and drive loss of immunological tolerance. The formation involves an inverse relationship between the concentration of MBL superoligomers and antibodies to double-stranded DNA. Our approach implicates the structure of DNA-protein nanoparticulates in the pathobiology of autoimmune diseases.

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.

A Clinical Diagnostic Test for Calcium Release Deficiency Syndrome.

Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Performance Measures and Plasma Biomarker Levels in Patients with Multiple Sclerosis after 14 Days of Fampridine Treatment: An Explorative Study.

Peripheral cytokine levels may serve as biomarkers for treatment response and disease monitoring in patients with multiple sclerosis (pwMS). The objectives were to assess changes in plasma biomarkers in PwMS after 14 days of fampridine treatment and to explore correlations between changes in performance measures and plasma biomarkers. We included 27 PwMS, 14 women and 13 men, aged 52.0 ± 11.6 years, with a disease duration of 17 ± 8.5 years, and an Expanded Disability Status Scale of 6 [IQR 5.0/6.5]. Gait and hand function were assessed using performance tests completed prior to fampridine and after 14 days of treatment. Venous blood was obtained, and chemiluminescence analysis conducted to assess plasma cytokines and neurodegenerative markers. All performance measures demonstrated improvements. Biomarkers showed decreased tumor necrosis factor (TNF) receptor-2 levels. Associations were found between change scores in (i) Six Spot Step Test and Interleukin (IL)-2, IL-8, and IL-17 levels; (ii) timed 25-foot walk and interferon-γ, IL-2, IL-8, TNF-α, and neurofilament light levels, and (iii) 12-Item Multiple Sclerosis Walking Scale and IL-17 levels. The associations may reflect increased MS-related inflammatory activity rather than a fampridine-induced response or that a higher level of inflammation induces a better response to fampridine.

Group Structure as a Foundation for Entropies.

Entropy can signify different things. For instance, heat transfer in thermodynamics or a measure of information in data analysis. Many entropies have been introduced, and it can be difficult to ascertain their respective importance and merits. Here, we consider entropy in an abstract sense, as a functional on a probability space, and we review how being able to handle the trivial case of non-interacting systems, together with the subtle requirement of extensivity, allows for a systematic classification of the functional form.

Taylor Dispersion-Induced Phase Separation for the Efficient Characterisation of Protein Condensate Formation.

Biomolecular condensates have emerged as important structures in cellular function and disease, and are thought to form through liquid-liquid phase separation (LLPS). Thorough and efficient in vitro experiments are therefore needed to elucidate the driving forces of protein LLPS and the possibility to modulate it with drugs. Here we present Taylor dispersion-induced phase separation (TDIPS), a method to robustly measure condensation phenomena using a commercially available microfluidic platform. It uses only nanoliters of sample, does not require extrinsic fluorescent labels, and is straightforward to implement. We demonstrate TDIPS by screening the phase behaviour of two proteins that form biomolecular condensates in vivo, PGL-3 and Ddx4. Uniquely accessible to this method, we find an unexpected re-entrant behaviour at very low ionic strength, where LLPS is inhibited for both proteins. TDIPS can also probe the reversibility of assemblies, which was shown for both α-synuclein and for lysozyme, relevant for health and biotechnology, respectively. Finally, we highlight how effective inhibition concentrations and partitioning of LLPS-modifying compounds can be screened highly efficiently.

Clinical Characteristics, Incidences, and Mortality Rates for Type A and B Aortic Dissections: A Nationwide Danish Population-Based Cohort Study From 1996 to 2016.

BACKGROUND: Population-based epidemiologic studies of aortic dissections (ADs) are needed. This study aimed to report clinical characteristics, incidences, and mortality rates for adult patients admitted to Danish hospitals with type A AD (TAAD) or type B AD (TBAD) from 1996 through 2016. METHODS: We conducted a nationwide, population-based register study. All cases of AD registered with International Classification of Diseases, Tenth Revision codes in the Danish National Patient Registry at time of admission to a hospital with available medical records underwent validation. Data were merged between nationwide health registries including the cause of death registry. Patients with validated AD were matched 1:10 on sex and age with patients with hypertension from the general Danish population. RESULTS: Of 5018 registered cases of AD, 4183 cases underwent review and 3023 (60.2%) were validated as AD. After exclusions, the distribution of validated TAAD and TBAD was 1620 (60.5%) and 1059 (39.5%; P<0.001), 67.5% and 67.0% of patients were men, and mean ages at dissection were 63.5±12.9 and 67.5±12.2 years (P<0.001), respectively. The most prevalent comorbidities for TAAD were hypertension (55.2%), thoracic aortic aneurysms (14.6%), and chronic obstructive pulmonary disease (13.1%); for TBAD, the most prevalent comorbidities were hypertension (64.1%), aortic aneurysms at any location (7.5% to 12.0%), and chronic obstructive pulmonary disease (15.7%). The overall mean annual incidence rate was 4.2/100 000 patient-years. Incidence was significantly higher for TAAD (2.2/100 000) compared with TBAD (1.5/100 000; P<0.001). The 30-day mortality rates for validated TAAD and TBAD were 22.0% and 13.9% (P<0.001), respectively, with no significant changes over time or between sexes. Adjusted 5-year overall mortality rates for TAAD and TBAD were hazard ratio 3.2 (2.9 to 3.5; P<0.001; aortic-related cause of death, 57.0%) and hazard ratio 2.1 (1.9 to 2.4; P<0.001; aortic-related cause of death, 42.8%), respectively, compared with the general hypertensive population. Among patients who survived 30 days from dissection, the adjusted 5-year overall mortality rates were hazard ratio 1.1 (1.0 to 1.3; P=0.12; aortic-related cause of death, 23.2%) and hazard ratio 1.4 (1.2 to 1.6; P<0.001; aortic-related cause of death, 25.6%) for TAAD and TBAD, respectively. CONCLUSIONS: Hypertension, aortic aneurysms, and chronic obstructive pulmonary disease were the most prevalent comorbidities. The 30-day mortality frequencies were consistent over time with no significant differences between sexes. The 5-year mortality rate was higher for TAAD than TBAD. If the patient survived 30 days from dissection, the mortality rate for patients with TAAD was comparable with that of the general hypertensive population, but the mortality rate was significantly higher in patients with TBAD.

Composition of mucus- and digesta-associated bacteria in growing pigs with and without diarrhea differed according to the presence of colonic inflammation.

BACKGROUND: In the pig production, diarrhea can occur during different growth stages including the period 4-16 weeks post weaning, during which a diarrheal outbreak also termed as colitis-complex diarrhea (CCD) can occur and it is distinct from post-weaning diarrhea (1-2 weeks post weaning). We hypothesized that CCD in growing pigs is associated with changes in colonic microbiota composition and fermentation patterns, and the aim of the present observational study was to identify changes in digesta-associated bacteria (DAB) and mucus-associated bacteria (MAB) in the colon of growing pigs with and without diarrhea. A total number of 30 pigs (8, 11, and 12 weeks of age) were selected; 20 showed clinical signs of diarrhea and 10 appeared healthy. Based on histopathological examination of colonic tissues, 21 pigs were selected for further studies and classified as follows: without diarrhea, no colon inflammation (NoDiar; n = 5), with diarrhea, without colonic inflammation (DiarNoInfl; n = 4), and with diarrhea, with colonic inflammation (DiarInfl; n = 12). Composition (based on 16S rRNA gene amplicon sequencing) and fermentation pattern (short-chain fatty acids; SCFA profile) of the DAB and MAB communities were characterized. RESULTS: The DAB showed higher alpha diversity compared to MAB in all pigs, and both DAB and MAB showed lowest alpha diversity in the DiarNoInfl group. Beta diversity was significantly different between DAB and MAB as well as between diarrheal groups in both DAB and MAB. Compared to NoDiar, DiarInfl showed increased abundance of various taxa, incl. certain pathogens, in both digesta and mucus, as well as decreased digesta butyrate concentration. However, DiarNoInfl showed reduced abundance of different genera (mainly Firmicutes) compared to NoDiar, but still lower butyrate concentration. CONCLUSION: Diversity and composition of MAB and DAB changed in diarrheal groups depending on presence/absence of colonic inflammation. We also suggest that DiarNoInfl group was at the earlier stage of diarrhea compared with DiarInfl, with a link to dysbiosis of colonic bacterial composition as well as reduced butyrate concentration, which plays a pivotal role in gut health. This could have led to diarrhea with inflammation due to a dysbiosis, associated with an increase in e.g., Escherichia-Shigella (Proteobacteria), Helicobacter (Campylobacterota), and Bifidobacterium (Actinobacteriota), which may tolerate or utilize oxygen and cause epithelial hypoxia and inflammation. The increased consumption of oxygen in epithelial mucosal layer by infiltrated neutrophils may also have added up to this hypoxia. Overall, the results confirmed that changes in DAB and MAB were associated with CCD and reduced butyrate concentration in digesta. Moreover, DAB might suffice for future community-based studies of CCD.

Polygenic risk scores in coronary artery disease.

PURPOSE OF REVIEW: Recent advances in genetics have facilitated the calculation of polygenic risk scores (PRSs) based on common genetic risk variants of coronary artery disease (CAD). Here, we provide an explanation of the genetic basis for PRSs and review recent literature investigating PRSs and the clinical utility for different aspects of CAD. RECENT FINDINGS: CAD-based PRSs are strongly associated with atherosclerosis burden in the coronary arteries and other vascular beds. In multiple studies, PRSs have proven to be a measure of CAD risk, more powerful than most established risk factors alone, that can be used from early life to stratify individuals into varying trajectories of lifetime risk. When implemented in risk stratification models for primary prevention of cardiovascular disease, PRSs provide modest improvements in discrimination (C-index generally increasing 0-4% points) and reclassification, but yield significant clinical benefit as a risk enhancer. Additionally, data suggest possible value of PRSs for aiding decisions in other aspects of diagnostics and treatment in CAD. SUMMARY: Once genotyped, the genetic information may be used to calculate an infinite number of PRSs and contribute to personalize medicine providing clinical value for risk stratification, diagnostics and treatment in CAD as well as in other diseases.

Spatial variation in the evolutionary potential and constraints of basal metabolic rate and body mass in a wild bird.

An organism's energy budget is strongly related to resource consumption, performance, and fitness. Hence, understanding the evolution of key energetic traits, such as basal metabolic rate (BMR), in natural populations is central for understanding life-history evolution and ecological processes. Here we used quantitative genetic analyses to study evolutionary potential of BMR in two insular populations of the house sparrow (Passer domesticus). We obtained measurements of BMR and body mass (Mb ) from 911 house sparrows on the islands of Leka and Vega along the coast of Norway. These two populations were the source populations for translocations to create an additional third, admixed 'common garden' population in 2012. With the use of a novel genetic group animal model concomitant with a genetically determined pedigree, we differentiate genetic and environmental sources of variation, thereby providing insight into the effects of spatial population structure on evolutionary potential. We found that the evolutionary potential of BMR was similar in the two source populations, whereas the Vega population had a somewhat higher evolutionary potential of Mb than the Leka population. BMR was genetically correlated with Mb in both populations, and the conditional evolutionary potential of BMR (independent of body mass) was 41% (Leka) and 53% (Vega) lower than unconditional estimates. Overall, our results show that there is potential for BMR to evolve independently of Mb , but that selection on BMR and/or Mb may have different evolutionary consequences in different populations of the same species.

Formation of ß-Configured Thioglycosides of d-Glucosamine and d-Galactosamine and Synthesis of Protected Human Milk Oligosaccharides.

We report on the stereoselective multigram scale preparation of cyclohexyl- and phenyl thioglycosides of 2-azido-2-deoxy-ß-d-gluco- and galactopyranosides from d-N-acetylglucosamine using a catalytic and solvent-free method. Two of the prepared building blocks were used as key intermediates for the synthesis of human milk oligosaccharides LNT and LNnT in their protected form.

Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course. METHODS: The Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed. RESULTS: We evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 ARVC (27% vs 4%, p<0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among PKP2 than DSC2/DSG2/DSP carriers: HR 0.25 (0.10-0.68, p<0.01) for atrial fibrillation/flutter, HR 0.67 (0.44-1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42-0.95, p<0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with DSC2/DSG2/DSP carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01). CONCLUSION: In this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.

Low potential for evolutionary rescue from climate change in a tropical fish.

Climate change is increasing global temperatures and intensifying the frequency and severity of extreme heat waves. How organisms will cope with these changes depends on their inherent thermal tolerance, acclimation capacity, and ability for evolutionary adaptation. Yet, the potential for adaptation of upper thermal tolerance in vertebrates is largely unknown. We artificially selected offspring from wild-caught zebrafish (Danio rerio) to increase (Up-selected) or decrease (Down-selected) upper thermal tolerance over six generations. Selection to increase upper thermal tolerance was also performed on warm-acclimated fish to test whether plasticity in the form of inducible warm tolerance also evolved. Upper thermal tolerance responded to selection in the predicted directions. However, compared to the control lines, the response was stronger in the Down-selected than in the Up-selected lines in which evolution toward higher upper thermal tolerance was slow (0.04 ± 0.008 °C per generation). Furthermore, the scope for plasticity resulting from warm acclimation decreased in the Up-selected lines. These results suggest the existence of a hard limit in upper thermal tolerance. Considering the rate at which global temperatures are increasing, the observed rates of adaptation and the possible hard limit in upper thermal tolerance suggest a low potential for evolutionary rescue in tropical fish living at the edge of their thermal limits.