Aortic valve disease: multimodality imaging for risk stratification and evaluation of therapy

With the rising global health burden of aortic valve diseas and growing awareness of the consequences of severe AS, more patients are expected to be referred for aortic valve replacement. Multimodality imaging remains of paramount importance for proper patient selection, determining optimal timing of intervention and in the evaluation of therapy. For risk stratification and defining optimal timing of intervention, conventional and advanced echocardiography and computed tomography are crucial. Conventional echocardiography can be used to assess extra-aortic valvular cardiac damage in patients with severe AS. On top of conventional echocardiography, advanced echocardiography can provide additional insights. Left ventricular GLS by speckle tracking echocardiography has been suggested as a more sensitive marker of LV systolic dysfunction. LV GLS may be of help to define more optimal timing of intervention in asymptomatic patients with severe AS. Also, LV GLS may be of incremental value on top of conventional echocardiographic parameters for the assessment of cardiac injury. For the evaluation of prothesis function and durability after aortic valve implantation and detection of possible (late) complications, echocardiography is the mainstay imaging modality. Also, both conventional and advanced echocardiography can provide additional information on the effects of therapy on LV function and remodelling. ChipSoft Canon Medical Systems Nederland HartstichtingLUMC / Geneeskund

Selection for longevity in dairy cattle

This thesis deals with several aspects of longevity of dairy cattle. When breeding organizations want to implement longevity in their breeding programs they have to make several decisions. This thesis aims to give tools to make those decisions.Chapter 2 gives an overview of the literature containing estimates of heritabilities of longevity traits and correlations between longevity and conformation traits. The results of Chapters 3 and 4 of this thesis are included as well. There are many different definitions of longevity. In this thesis, two distinctions are made: 1. between lifetime and stayability traits, and 2. between uncorrected and functional longevity traits. Lifetime traits measure the period a cow is alive or producing, and are usually expressed in days. Stayability traits measure whether or not a cow is alive at a certain point in time. Functional longevity traits are corrected for milk production, thus aiming to be a better measure for involuntary culling. In Chapters 1 and 7 of this thesis, residual longevity is introduced, which is longevity corrected not only for milk production but also for all other traits that are already in the breeding goal. So far, this trait has not been used in practice. From the literature it is concluded that, in general, heritability of longevity traits is below 0.10. The heritability of stayability traits is lower (around 0.04) than that of lifetime traits (around 0.09), and the heritability of functional longevity traits is lower (around 0.07 for lifetime traits and around 0.03 for stayability traits) than that of uncorrected longevity traits. Genetic correlations among different longevity traits are generally strong. Genetic correlations between longevity and conformation traits are strongest for conformation traits describing the mammary system and, to a lesser extent, feet and legs. The reliability of a breeding value prediction of a sire based solely on the conformation information of his daughters is approximately 55% at maximum.In Chapter 3, the longevity realized of cows born in different years (1978 through 1985) has been calculated. Longevity of cows born in 1978 through 1984 decreases, and longevity of cows born in 1985 is at the same level as the longevity of cows born in 1978. In 1984, the quota system was implemented in the Netherlands and farmers culled 20% more cows than their normal annual culling percentage. These cows, of course, were born before 1984. Besides this process, during the eighties large-scale crossing with Holstein-Friesian bulls took place. The original Dutch-Friesian cow population was replaced by Holstein-Friesians, and this process was accelerated by imlementation of the quota system. Both processes not only affected longevity of dairy cows realized in the Netherlands, but also the estimates of heritabilities. Data on cows born in 1978, 1982, or 1985 were used to estimate heritabilities, and the estimates were highest for the 1978 dataset, lower for the 1982 dataset, and lowest for the 1985 dataset. Possible explanations are that the population was under strong selection during the period considered, that the genetic background of the population changed, and that under the quota system, farmers base their culling decisions on a shorter planning horizon, thus increasing the environmental variation of longevity traits.In Chapter 4, data on cows born in different years (1978, 1982, and 1989/1990) were used to estimate genetic correlations between longevity and conformation traits. These parameters were also affected by the changing population structure during the eighties. In the 1978 data file, the correlation between functional herdlife and type was rather weak (0.16) while in the 1982 data file, this correlation was very strong (0.46). For the 1989/1990 data file, only stayability traits could be analysed because cows had not had enough time to be culled. The correlation between functional stayability until 48 months of age and type was 0.21. The strongest correlation was between functional stayability and the subjective score for udder (0.93), followed by the subjective score for feet and legs (0.43). The estimate of 0.93 is probably too high but also from other studies it was concluded that, apart from production, the udder is the most important factor determining longevity of a dairy cow. From Chapters 3 and 4 it was concluded that especially in an upgrading population estimates of genetic parameters should be based on the most recent data possible, and that estimation of these parameters should be repeated regularly.In Chapter 5 the value of a relatively new method in animal breeding was investigated: survival analysis. Survival analysis differs in two aspects from traditional methods of analysis: 1. it correctly utilizes information from censored records, i.e., records of cows that are still alive at the moment of data collection; and 2. effects can be modelled in a time-dependent way, yielding a more realistic model. Breeding values of sires for longevity were estimated in three different ways: as the average realized longevity of the sire's daughters, with a best linear unbiased prediction, and with survival analysis. This was done using data from small and from large farms to identify a possible genotype by environment interaction. The phenotypic average of the sire's daughters had weak rank correlations with the other two methods of breeding value prediction (ranging from -0.32 to 0.46). The correlation between the best linear unbiased prediction and the survival analysis prediction was strong (-0.91 and -0.94 on small and large farms, respectively) if only uncensored records were used in the survival analysis, and weaker (-0.71 on both small and large farms) if censored records were included as well. Correlations were negative due to the definition of the traits: in the best linear unbiased prediction the length of productive life was analysed, and in the survival analysis the risk of being culled. A long length of productive life is associated with a small risk of being culled. Thus it was concluded that best linear unbiased prediction and survival analysis mainly differ by the data that can be included in the analysis. No different rankings of sires on small or large farms were found with any of the three methods. From the survival analysis, it appeared that cows with a high percentage of Holstein-Friesian genes had a lower chance of being culled than cows with a low percentage, confirming the hypothesis in Chapters 3 and 4.Even though censored records can be analysed as well in survival analysis, a certain number of uncensored data is needed for a reliable breeding value prediction. Young bulls will probably not have a sufficient large number of daughters that have already been culled. Thus, conformation traits might be used for an early breeding value prediction, because they have reasonably strong correlations with longevity and can be measured early in a cow's life. In practice, a breeding value prediction will contain parental information on longevity, direct information on longevity of a sire's daughters, and indirect information on conformation of a sire's daughters. In Chapter 6 survival analysis was used to investigate the importance of conformation traits for the risk of a cow to be culled. This risk was corrected for milk production. Both the phenotypes of the cows themselves and their sires' breeding values for conformation were included in a model. The cows' phenotypes explained more variation in the risk of being culled than their sires' breeding values. In general, smaller cows with a steep rump angle, shallow udder, high score for udder and for feet and legs had the lowest chance of being culled. Survival analysis was also used to predict breeding values of sires for longevity based solely on the longevity of their daughters. These breeding values were correlated with the sires' national proofs for conformation traits, to obtain approximations of genetic correlations. The correlations were strong for nearly all conformation traits except height, rear legs set, and size. In the national proofs the conformation traits were not corrected for each other, while in the survival analysis they were.In Chapter 7 it was argued that survival analysis should be used whenever possible to predict breeding values for longevity, even though with current computer capacities only a sire model can be used. Choosing this method implies that a lifetime trait has to be analysed. If length of productive life is analysed, a Weibull model can be assumed, which simplifies the calculations. In practice, this breeding value prediction will have to be combined with information on conformation to obtain a reliable breeding value for longevity early in a bull's life. Because most breeding programs of dairy cows pay already much attention to milk production, functional longevity will be more informative for breeding decisions than uncorrected longevity.</p

Neural processing of social rejection: the role of schizotypal personality traits

A fear of being rejected can cause perceptions of more insecurity and stress in close relationships. Healthy individuals activate the dorsal anterior cingulate cortex (dACC) when experiencing social rejection, while those who are vulnerable to depression deactivate the dACC presumably to downregulate salience of rejection cues and minimize distress. Schizotypal individuals, characterized by unusual perceptual experiences and/or odd beliefs, are more rejection sensitive than normal. We tested the hypothesis, for the first time, that individuals with high schizotypy also have an altered dACC response to rejection stimuli. Twenty-six healthy individuals, 14 with low schizotypy (LS) and 12 with high schizotypy (HS), viewed depictions of rejection and acceptance and neutral scenes while undergoing functional MRI. Activation maps in LS and HS groups during each image type were compared using SPM5, and their relation to participant mood and subjective ratings of the images was examined. During rejection relative to neutral scenes, LS activated and HS deactivated the bilateral dACC, right superior frontal gyrus, and left ventral prefrontal cortex. Across both groups, a temporo-occipito-parieto-cerebellar network was active during rejection, and a left fronto-parietal network during acceptance, relative to neutral scenes, and the bilateral lingual gyrus during rejection relative to acceptance scenes. Our finding of dACC-dorso-ventral PFC activation in LS, but deactivation in HS individuals when perceiving social rejection scenes suggests that HS individuals attach less salience to and distance themselves from such stimuli. This may enable them to cope with their higher-than-normal sensitivity to rejection

Prevalence and Prognostic Relevance of Ventricular Conduction Disturbances in Patients With Aortic Stenosis

Cardiolog

Prognostic implications of renal dysfunction in patients with aortic stenosis

Aortic stenosis (AS) and renal dysfunction share risk factors and often occur simultaneously. The influence of renal dysfunction on the prognosis of patients with various grades of AS has not been extensively described. The present study aimed to assess the prognostic implications of renal dysfunction in a large cohort of patients with aortic sclerosis and patients with various grades of AS. Patients diagnosed with various grades of AS by transthoracic echocardiography were assessed and divided according to renal function by estimated glomerular filtration rate (eGFR). The occurrence of all-cause mortality (primary end point) and aortic valve replacement (AVR) was noted. Of 1,178 patients (mean age 70 +/- 13 years, 60% male), 327 (28%) had aortic sclerosis, 86 (7%) had mild AS, 285 (24%) had moderate AS, and 480 (41%) had severe AS. Renal dysfunction (eGFR <60 ml/min/1.73 m(2)) was present in 440 (37%) patients, and moderate to severe AS was observed more often in these patients compared to patients without (70 vs 62%, respectively; p = 0.008). After a median follow-up of 95 [31 to 149] months, 626 (53%) patients underwent AVR and 549 (47%) patients died. Severely impaired renal function (eGFR <30 ml/min/1.73 m(2)) and AVR were independently associated with all-cause mortality after correcting for AS severity. In conclusion, renal dysfunction is highly prevalent in patients with various grades of AS. After correcting for AS severity and AVR, severely impaired renal function (eGFR <30 ml/min/1.73 m(2)) was independently associated with all-cause mortality. Independent of renal function, AVR was associated with improved survival. (C) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license.Cardiolog

Are genetic risk factors for psychosis also associated with dimension-specific psychotic experiences in adolescence?

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value=2.57x10-4) and rs9960767 (p-value=6.23x10-4). Replication in an independent sample of 16-year-olds (N=3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed

Prevalence of aortic valve stenosis in patients with ST-segment elevation myocardial infarction and effect on long-term outcome

Several studies have shown an association between aortic valve stenosis (AS), atherosclerosis and cardiovascular risk factors. These risk factors are frequently encountered in patients with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to evaluate the prevalence and the prognostic implications of AS in patients presenting with STEMI. A total of 2041 patients (61 +/- 12 years old, 76% male) admitted with STEMI and treated with primary percutaneous coronary intervention were included. Patients with previous myocardial infarction and previous aortic valve replacement were excluded. Echocardiography was performed at index admission. Patients were divided in 3 groups: 1) any grade of AS, 2) aortic valve sclerosis and 3) normal aortic valve. Any grade of AS was defined as an aortic valve area = 85 years, respectively). Patients with AS showed a significantly higher mortality rate when compared to the other two groups (p < 0.001) and AS was independently associated with all-cause mortality, with a HR of 1.81 (CI 95%: 1.02 to 3.22; p = 0.04). In conclusion, AS is not uncommon in patients with STEMI, and concomitant AS in patients with first STEMI is independently associated with all-cause mortality at long-term follow up. (C) 2021 The Author(s). Published by Elsevier Inc.Cardiolog