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Since their first appearance in the context of schizophrenia and bipolar disorder in 2009, polygenic risk scores (PRSs) have been described for a large number of common complex diseases. However, the clinical utility of PRSs in disease risk assessment or therapeutic decision making is likely limited because PRSs usually only account for the heritable component of a trait and ignore the etiological role of environment and lifestyle. We surveyed the current state of PRSs for various diseases, including breast cancer, diabetes, prostate cancer, coronary artery disease, and Parkinson disease, with an extra focus upon the potential improvement of clinical scores by their combination with PRSs. We observed that the diagnostic and prognostic performance of PRSs alone is consistently low, as expected. Moreover, combining a PRS with a clinical score at best led to moderate improvement of the power of either risk marker. Despite the large number of PRSs reported in the scientific literature, prospective studies of their clinical utility, particularly of the PRS-associated improvement of standard screening or therapeutic procedures, are still rare. In conclusion, the benefit to individual patients or the health care system in general of PRS-based extensions of existing diagnostic or treatment regimens is still difficult to judge. [ABSTRACT FROM AUTHOR]

Purpose: Reported antibiotic use in coronavirus disease 2019 (COVID-19) is far higher than the actual rate of reported bacterial co- and superinfection. A better understanding of antibiotic therapy in COVID-19 is necessary. Methods: 6457 SARS-CoV-2-infected cases, documented from March 18, 2020, until February 16, 2021, in the LEOSS cohort were analyzed. As primary endpoint, the correlation between any antibiotic treatment and all-cause mortality/progression to the next more advanced phase of disease was calculated for adult patients in the complicated phase of disease and procalcitonin (PCT) ≤ 0.5 ng/ml. The analysis took the confounders gender, age, and comorbidities into account. Results: Three thousand, six hundred twenty-seven cases matched all inclusion criteria for analyses. For the primary endpoint, antibiotic treatment was not correlated with lower all-cause mortality or progression to the next more advanced (critical) phase (n = 996) (both p > 0.05). For the secondary endpoints, patients in the uncomplicated phase (n = 1195), regardless of PCT level, had no lower all-cause mortality and did not progress less to the next more advanced (complicated) phase when treated with antibiotics (p > 0.05). Patients in the complicated phase with PCT > 0.5 ng/ml and antibiotic treatment (n = 286) had a significantly increased all-cause mortality (p = 0.029) but no significantly different probability of progression to the critical phase (p > 0.05). Conclusion: In this cohort, antibiotics in SARS-CoV-2-infected patients were not associated with positive effects on all-cause mortality or disease progression. Additional studies are needed. Advice of local antibiotic stewardship- (ABS-) teams and local educational campaigns should be sought to improve rational antibiotic use in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Many crime cases require clarification whether or not a trace was left by a suspect. This is achieved by comparing their DNA profiles, a match indicating identity of suspect and donor. In sexual crimes, the trace is often a mixture of male and female material. This renders the analysis of the Y chromosome useful, but the interpretation of the genetic results is complicated by the specific mode of inheritance. We review some of the arising challenges as well as recently suggested solutions. [ABSTRACT FROM AUTHOR]

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Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of 'transcriptomic' MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10− 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis. [ABSTRACT FROM AUTHOR]

The conduct of genetic epidemiological research on complex diseases has massively changed during the past decades, shifting from candidate-gene studies via array-based genome-wide association studies (GWAS) to sequencing approaches. Liu and Montgomery ([6]) in their review give an overview on the timely topic of using cell type information as a follow-up to GWAS studies. She concludes that missing heritability is an ill-posed problem, because heritability is defined through an oversimplified model that does not fit the underlying complex biological structure. Evolutionary perspectives on polygenic selection, missing heritability, and GWAS. [Extracted from the article]

Leprosy, a chronic infectious disease caused by Mycobacterium leprae (M. leprae), was very common in Europe till the 16th century. Here, we perform an ancient DNA study on medieval skeletons from Denmark that show lesions specific for lepromatous leprosy (LL). First, we test the remains for M. leprae DNA to confirm the infection status of the individuals and to assess the bacterial diversity. We assemble 10 complete M. leprae genomes that all differ from each other. Second, we evaluate whether the human leukocyte antigen allele DRB1*15:01, a strong LL susceptibility factor in modern populations, also predisposed medieval Europeans to the disease. The comparison of genotype data from 69 M. leprae DNApositive LL cases with those from contemporary and medieval controls reveals a statistically significant association in both instances. In addition, we observe that DRB1*15:01 co-occurs with DQB1*06:02 on a haplotype that is a strong risk factor for inflammatory diseases today. [ABSTRACT FROM AUTHOR]

Background: Photocoagulation lesion intensity relies on the judgement of retinal blanching. Lesions turn out variable due to observer-dependent judgement and time dependency of blanching. We investigated lesion variability per patient and per physician in clinical routine treatments. Methods: In this observational clinical trial, different physicians performed panretinal photocoagulation for diabetic retinopathy. Study eyes received 20-30 study lesions at 20 ms (three physicians, nine eyes) and 200 ms (four physicians, 12 eyes) irradiation time (532 nm continuous wave photocoagulator, 300 μm spot size). Lesions were imaged after 1 hour with photography and optical coherence tomography (OCT). We measured lesion diameters in fundus and OCT images, and graded intensities according to a previously published six-step classifier. Results: 200-ms lesions were larger and more severe (568, 474-625 μm [median, IQR], predominantly class 6) than 20-ms lesions (397, 347-459 μm, predominantly classes 3-4). The impact of laser power was small compared to other factors. Lesion intensities and diameters in fundus and OCT images varied significantly between patients and between physicians. Median photographic lesion diameters varied by up to a factor of 1.61 ( 20 ms) or 1.5 ( 200 ms) respectively. Conclusions: In this study, the treated area of retina varied by up to a factor of 1.61 = 2.59 for a given spot number. As clinical efficacy depends on the treated area, which is a function of lesion number by area per lesion, our results implicate poor control of the overall treatment effect if treatments are administered according to lesion number or spacing alone. Better ways of laser effect control should be sought. [ABSTRACT FROM AUTHOR]

A correction to the article "All-cause Mortality and Disease Progression in SARS-CoV-2-infecte Patients With or Without Antibiotic Therapy: An Analysis of the LEOSS Cohort" that was published online on December 15, 2021, is presented.

Human longevity is a multifactorial phenotype influenced by both genetic and environmental factors. Despite its heritability of 25-32 %, the genetic background of longevity is as yet largely unexplained. Apart from APOE status, variation in the FOXO3A gene is the only confirmed genetic contributor to survival into old age. On the other hand, FOXO3A activity is known to be downregulated in various cancers, and the gene was recently identified as a novel deletion hotspot in human lung adenocarcinoma. In view of the strong association between smoking and lung cancer, we set out to explore whether smoking modifies the known association between FOXO3A variation and longevity. To this end, we conducted a case-control study in two different populations, drawing upon extensive collections of old-aged individuals and younger controls available to us (1,613 German centenarians/nonagenarians and 1,104 controls; 1,088 Danish nonagenarians and 736 controls). In the German sample, 21 single nucleotide polymorphisms (SNPs) from the FOXO3A gene region were genotyped, whereas 15 FOXO3A SNPs were analyzed in the Danish sample. Eight SNPs were typed in both populations. Logistic regression analysis revealed that adjustment for smoking does not systematically alter the association between FOXO3A variation and longevity in neither population. Our analysis therefore suggests that the said association is not largely due to the confounding effects of lung cancer. [ABSTRACT FROM AUTHOR]

Background: The extent of retinal tissue deformation by histological processing needs to be separately measured for every workup protocol. This work presents a simple approach for its quantitative assessment, and shows lateral and axial scaling factors for a common protocol. We calibrated histological measurements by in-vivo photographic and optical coherence tomographic (OCT) measurements, using retinal photocoagulation lesions as calibration markers. Methods: We evaluated four rabbit eyes that were examined histologically after fixation in Margo's solution (1 % paraformaldehyde:1.25 % glutaraldehyde), isopropanol dehydration, paraffin embedding and hematoxylin and eosin staining. Distances between 51 pairs of laser lesions were compared in photographs and on histological slides. Retinal thickness measurements were performed at 15 anatomically defined sites in these eyes, and related to anatomically matched OCT thickness measurements of six different rabbit eyes. Results: We found that the ratio of histological over photographic lesion distances was 1.17 (95 % CI 1.13-1.22), indicating 17 % lateral retinal stretching or expansion by the processing. Thickness measurements in histology were 65.6 % of the in-vivo thickness as measured in OCT, indicating 1/3 axial tissue compression or shrinkage. Conclusions: We provide an analysis of retinal tissue deformation after fixation in Margo's solution and paraffin embedding. In spite of protocol optimization for reduced tissue deformation, the workup caused 1/3 axial compression/shrinkage and 17 % lateral elongation, which was unexpected. We show a simple way how to calibrate retina specimens by fundus photography and OCT, two methods that are readily available to most ophthalmologists. Our findings underline the necessity to calibrate specimens prior to morphometry. [ABSTRACT FROM AUTHOR]

Purpose: The treatment of ovarian tumors is carried out with platinum medicine which can lead to incompatibilities or resistances. Thus, it is of great interest to check new medicine suitability for its application. AZD1152 is an Aurora kinase inhibitor predominantly works against Aurora kinase B involved in the chromosome segregation. Cells become polyploidy and reduce the proliferation by this impairment. To investigate whether AZD1152, may play a role in the treatment of ovarian carcinoma we serving it to the cisplatinum-resistant cell line SKOV3 alone and in combination with platinum. Methods: We look at the proliferation, the ploidy, the phases of cell cycle and the apoptosis activity of the cells. Results and conclusion: We could show that the combination of both medicines in the preclinical experiment produces a working advantage. [ABSTRACT FROM AUTHOR]

The gene tyrosine hydroxylase 1 (TH01) has been suggested as a candidate for human longevity. A previous study has shown an association between longevity and specific alleles of the TH01 short tandem repeat (STR) polymorphism in an Italian population. This STR locus is also widely used in forensic genetics. If the TH01-longevity association could be confirmed in independent samples, this finding would have important ramifications for the use of this polymorphism in a forensic context. In the present study, we sought to replicate the previous association result by investigating 471 long-lived individuals (96-110 years) and 462 younger controls (19-75 years) from Germany. In the analyzed samples, the association between TH01 and longevity was not replicated. However, the obtained TH01 allele frequencies were consistent with published data. We observed considerable differences in the allele distribution between Germans and Italians, in particular with regard to allele 9.3, which displayed a previously undetected decreasing West-East and North-South cline across Europe. The discrepant TH01-longevity association results in Germans and Italians could therefore be due to population-specific effects. This finding highlights the need to take into consideration population genetic data when dealing with association studies. [ABSTRACT FROM AUTHOR]

Background: In spite of the widespread use of laparoscopic appendectomy, there is an ongoing debate on the advantages of this method when compared to open appendectomy. In the evaluation of a postoperative procedure, long-term quality of life is essential. Patients and methods: From 1999 to 2001, 493 patients diagnosed with acute appendicitis were operated in a German general district hospital and included in an observational study. In a median postoperative interval of 7 years, these patients were re-evaluated regarding their quality of life after surgery. A Short-Form 36 Health Survey (SF-36) questionnaire was applied to evaluate the general parameters of quality of life after surgery. This questionnaire was supplemented by an additional self-developed module referring to the appendectomy. The primary outcome was the recommendation of the experienced operating procedure to relatives and friends. Results: A total of 243 patients underwent a laparoscopic procedure: 132 patients were re-evaluated (recovery rate 54%). In the open group, 250 patients were operated: 121 patients were re-evaluated (recovery rate 48%). The median interval from operation to evaluation was 7 years in the laparoscopic group and 7.7 years in the open group. For the primary outcome, patients with laparoscopic appendectomy would significantly more often recommend the procedure than patients with the open operation method. For secondary outcomes, the cosmetic results were judged significantly more favourably in the laparoscopic group. The eight scaled scores of the SF-36 questionnaire did not differ significantly between the two groups. Four patients of the open group and nine patients of the laparoscopic group (including one converted procedure) needed a reoperation because of incisional hernia, adhesions and late infections. Conclusion: Patients after laparoscopic appendectomy show a higher degree of satisfaction with their body and their scar than patients after open appendectomy. [ABSTRACT FROM AUTHOR]

Secure fixation of the mesh in groin hernia repair is essential to avoid mesh dislocation. The fixation, however, is also thought to be a source of chronic postoperative pain. We tested the new self-fixating mesh Parietene progrip© vs. traditional suture fixating Lichtenstein repair in a double-blinded randomized study evaluating postoperative pain and the use of analgesics. Fifty patients were randomized into two groups: Patients of group A (24 patients) were operated with the new self-fixating Parietene progrip© mesh without fixation sutures and patients of group B (26 patients) were operated with the traditional Lichtenstein repair. Postoperative course including pain and the use of analgesics were monitored. Patients were reinvestigated after 6 months regarding pain score and the amount of analgesics used during this interval. Primary end point was pain on the first operative day. The visual analog scale pain score showed at the first postoperative day a significantly lower level in group A than in group B (mean 17.9 vs. 32.3 mm, p = 0.03). Additionally, the cumulative dose of postoperatively required analgesics was lower in group A than in group B. The operative time in group A was significantly shorter than in group B. Six months after the operation, a trend toward a lower pain score was observed in group A, but this did not reach statistical significance. This is the first randomized study to show a beneficial effect of the new self-fixating mesh on pain score. According to our investigations, operative time is reduced, which is a considerable fact with regard to economic aspects as well as the beneficial aspects for the patients. A study with a larger cohort of patients should be conducted to confirm the promising results of this exploratory study. [ABSTRACT FROM AUTHOR]

Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene–disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309 790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.European Journal of Human Genetics (2009) 17, 967–975; doi:10.1038/ejhg.2008.266; published online 21 January 2009 [ABSTRACT FROM AUTHOR]

Incisional hernias after laparotomy are a large financial burden for society as well as for the patients suffering from pain and limitations of activity over time. The introduction of alloplastic materials such as polypropylene seems to improve the results. The question of whether to apply open or laparoscopic implantation of the mesh is of ongoing interest. We compare the available alloplastic materials and try to clarify the question of whether the laparoscopic procedure is superior to the conventional (open) technique based on the available randomized studies. All available meshes for intraperitoneal and extraperitoneal implantation were described regarding their handling and their pros and cons. A database search (PubMed, Medline, Ovid, and in the secondary literature) was carried out to retrieve all randomized studies comparing laparoscopic and open hernia repair. Data were reviewed by two independent scientists for surgical and statistical design. The ideal mesh for a laparoscopic maintenance of abdominal wall hernias as well as the optimal fixation of the mesh has not been found yet. Recent available literature shows no evidence demonstrating the superiority of one of these meshes. The available studies found a lower infection rate, but higher occurrence of seroma for the laparoscopic procedure. The value of the different studies is reduced due to deficiency in study design and power. Guidelines for further studies are discussed to avoid surgical and statistical pitfalls. Laparoscopic incisional hernia repair shows, in some (randomized) studies as well as a large number of retrospective analyses and in case control studies, superiority compared to conventional hernia repair. Long-term results with a high level of evidence are not available. Additional well-designed randomized trials including long-term observation of patients are required in order to clarify a number of interesting questions. [ABSTRACT FROM AUTHOR]

Our study demonstrates that the genetic investigation of forkhead box O3A gene (FOXO3A), a validated human longevity gene, is greatly hampered by the fact that its exonic regions have 99% sequence homology with the FOXO3B pseudogene. If unaccounted for, this high degree of homology can cause serious genotyping or sequencing errors. Here, we present an experimental set-up that allows reliable data generation for the highly homologous regions and that can be used for the evaluation of assay specificity. Using this design, we exemplarily showed FOXO3A-specific results for two single-nucleotide polymorphisms (SNPs) (rs4945816 and rs4946936) that are significantly associated with longevity in our centenarian-control sample (Peach=0.0008). Because both SNPs are located in the 3′ untranslated region of FOXO3A, they could be of functional relevance for the longevity phenotype. Our experimental set-up can be used for reliable and reproducible data generation for further sequencing and genotyping studies of FOXO3A with the aim of discovering new SNPs of functional relevance. [ABSTRACT FROM AUTHOR]

Risk alleles for age-related diseases are expected to decrease in frequency in the population strata of increasing age. Consistent with this hypothesis, earlier studies showed a depletion of the Alzheimer's disease risk factor APOE*ɛ4 in long-lived individuals (LLIs). To evaluate whether this observation also holds for a previously suggested Alzheimer's disease risk haplotype in the A2M gene, we analyzed this particular haplotype in 1042 German LLIs (aged 95–100 years) and 1040 younger individuals (aged 60–75 years). Our results show a significant depletion of this haplotype in LLIs, thus confirming it as a mortality factor in the elderly. Consequently, our data support an involvement of the suggested A2M risk haplotype in the pathogenesis of Alzheimer's disease and adds new evidence to the risk-allele depletion hypothesis. [ABSTRACT FROM AUTHOR]

The original version of this Article contained an error in the spelling of the author Jule Müller, which was incorrectly given as Julia Müller. Additionally, in Fig. 4a, the blue-red colour scale for fold change in ageing/disease regulation included a blue stripe in place of a red stripe at the right-hand end of the scale. These errors have been corrected in both the PDF and HTML versions of the Article. [ABSTRACT FROM AUTHOR]

Disease epidemiology during ageing shows a transition from cancer to degenerative chronic disorders as dominant contributors to mortality in the old. Nevertheless, it has remained unclear to what extent molecular signatures of ageing reflect this phenomenon. Here we report on the identification of a conserved transcriptomic signature of ageing based on gene expression data from four vertebrate species across four tissues. We find that ageing-associated transcriptomic changes follow trajectories similar to the transcriptional alterations observed in degenerative ageing diseases but are in opposite direction to the transcriptomic alterations observed in cancer. We confirm the existence of a similar antagonism on the genomic level, where a majority of shared risk alleles which increase the risk of cancer decrease the risk of chronic degenerative disorders and vice versa. These results reveal a fundamental trade-off between cancer and degenerative ageing diseases that sheds light on the pronounced shift in their epidemiology during ageing. Ageing is associated with a pronounced shift in mortality from cancer to degenerative diseases. Here, the authors show that in concordance with this shift, conserved transcriptional alterations during ageing across four vertebrates align with degenerative diseases but are opposite to those in cancer. [ABSTRACT FROM AUTHOR]

Pigs (Sus scrofa) were first domesticated between 8,500 and 8,000 cal BC in the Near East, from where they were subsequently brought into Europe by agriculturalists. Soon after the arrival of the first domestic pigs in northern Europe (~4500 BC), farmers are thought to have started to incorporate local wild boars into their swine herds. This husbandry strategy ultimately resulted in the domestication of European wild boars. Here, we set out to provide a more precise geographic and temporal framework of the early management of suid populations in northern Europe, drawing upon mitochondrial DNA haplotype data from 116 Neolithic Sus specimens. We developed a quantitative mathematical model tracing the haplotypes of the domestic pigs back to their most likely geographic origin. Our modelling results suggest that, between 5000 and 4000 BC, almost all matrilines in the north originated from domesticated animals from the south of central Europe. In the following period (4000-3000 BC), an estimated 78-100% of domesticates in the north were of northern matrilineal origin, largely from local wild boars. These findings point towards a dramatic change in suid management strategies taking place throughout south-central and northern Europe after 4000 BC. [ABSTRACT FROM AUTHOR]