Acute kidney injury and outcome following aortic valve replacement for aortic stenosis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Most studies on acute kidney injury (AKI) following open-heart surgery have focused on short-term outcome following coronary artery bypass grafting. We reviewed the incidence, risk factors and outcome, including long-term survival, of AKI after aortic valve replacement (AVR) in a population-based cohort.A retrospective review of 365 patients who underwent AVR for aortic stenosis during 2002-2011 was made. AKI was defined according to the RIFLE criteria. All patients requiring dialysis were followed up in a centralized registry. Risk factors for AKI were analysed with univariable and multivariable analysis, and survival was graphically presented with the Kaplan-Meier method.The rate of AKI was 82/365 (22.5%); 40, 28 and 14 patients belonging to the Risk, Injury and Failure groups, respectively. Preoperatively, 37 (45.1%) AKI patients had reduced kidney function. Transfusion of red blood cells, obesity and prolonged cardiopulmonary bypass time were independent risk factors for AKI. Acute postoperative dialysis was required in 15 patients (4.1%), and 1 patient developed dialysis-dependent end-stage renal disease. Major postoperative complications were more common in the AKI group (65 vs 22%, P < 0.001). The 30-day mortality rate in the AKI group was 18%, as opposed to 2% in the non-AKI group (P < 0.001), with a 5-year survival rate of 66 vs 87%, respectively (P < 0.001). In multivariable analysis AKI was an independent predictor of operative mortality [odds ratio = 5.89, 95% confidence interval (CI) = 1.99-18.91] but not of long-term survival (hazard ratio = 1.44, 95% CI = 0.86-2.42).More than 1 in 5 patients (22.5%) who underwent AVR developed AKI postoperatively. AKI was associated with higher morbidity and was an independent predictor of operative mortality. However, AKI was not a determinant of long-term survival.Landspitali University Research Fund, University of Iceland Research Fund, Helga Gudmundsdottir and Sigurlidi Kristjansson Memorial Fund

A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease

The genetic history of Scandinavia from the Roman Iron Age to the present

The authors acknowledge support from the National Genomics Infrastructure in Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation and the Swedish Research Council, and SNIC/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. We used resources from projects SNIC 2022/23-132, SNIC 2022/22-117, SNIC 2022/23-163, SNIC 2022/22-299, and SNIC 2021-2-17. This research was supported by the Swedish Research Council project ID 2019-00849_VR and ATLAS (Riksbankens Jubileumsfond). Part of the modern dataset was supported by a research grant from Science Foundation Ireland (SFI), grant number 16/RC/3948, and co-funded under the European Regional Development Fund and by FutureNeuro industry partners.Peer reviewedPublisher PD

The population genomic legacy of the second plague pandemic

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%-40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th-19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.publishedVersio

The population genomic legacy of the second plague pandemic

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.publishedVersio

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Epidemiology of psychiatric disorders in Iceland

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldEpidemiological psychiatric research in Iceland illustrating the uses of epidemiology is reviewed briefly. The incidence and disease expectancy have not changed during the twentieth century except for alcoholism, which has increased during the latter half of the century. The prevalence of mental disorders in the population aged 5-59 years is about 20% but increases after the age of 70 due to organic mental disorders. The incidence rate for psychiatric consultations has been slightly less than 1% per year. Disease expectancy until the age of 61 years has been estimated to be 34%, and until the age of 87 years 85%. The prevalence of inpatients in psychiatric wards decreased from 1.87 per 1000 inhabitants in 1953 to 0.6 in 1989, while the number of admissions, day patients, and outpatient visits increased markedly. Approximately 19,400 psychiatric outpatient visits per 100,000 inhabitants were registered in 1992 in outpatient clinics and in private practice. The number of inpatient beds for short-term treatment of alcoholics increased sixfold during 1975-85, and first admission rates for alcoholism increased by 200%; at the same time the average alcohol consumption increased very little. During 1 month in 1984 the prescriptions for psychotropic medications in Reykjavik amounted to 92.7 DDD per 1000 adult men and 146.7 for women. This decreased slightly in 1989 due to a decrease in the use of tranquillizers and hypnotics, which was partly balanced by an increase in prescriptions for antidepressants. Psychiatrists issued only 17% of the prescriptions. Studies relating to course, disability and mortality are mentioned briefly, as is identification of risk groups

Antidepressants and public health in Iceland. Time series analysis of national data

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: Major depressive disorder is the second leading cause of disability-adjusted life-years in developed regions of the world and antidepressants are the third-ranking therapy class worldwide. AIMS: To test the public health impact of the escalating sales of antidepressants. METHOD: Nationwide data from Iceland are used as an example to study the effect of sales of antidepressants on suicide, disability, hospital admissions and out-patient visits. RESULTS: Sales of antidepressants increased from 8.4 daily defined doses per 1000 inhabitants per day in 1975 to 72.7 in 2000, which is a user prevalence of 8.7% for the adult population. Suicide rates fluctuated during 1950-2000 but did not show any definite trend. Rates for out-patient visits increased slightly over the period 1989-2000 and admission rates increased even more. The prevalence of disability due to depressive and anxiety disorders has not decreased over the past 25 years. CONCLUSIONS: The dramatic increase in the sales of antidepressants has not had any marked impact on the selected public health measures. Obviously, better treatment for depressive disorders is still needed in order to reduce the burden caused by them