Publications by authors named "Stefan Weiss"

190 Publications

Ozone as oxidizing agent for the total oxidizable precursor (TOP) assay and as a preceding step for activated carbon treatments concerning per- and polyfluoroalkyl substance removal.

J Environ Manage 2021 Sep 9;300:113692. Epub 2021 Sep 9.

Environment Agency Austria, Spittelauer Lände 5, A-1090, Vienna, Austria.

Several thousands of highly persistent per- and polyfluoroalkyl substances (PFAS) exist and it is therefore challenging to analytically determine a larger spectrum of these compounds simultaneously in one sample. It is even more difficult to efficiently remove mobile PFAS in wastewater treatment plants (WWTPs) to protect the receiving waters. The total oxidizable precursor (TOP) assay is an approach that enables the detection of the total PFAS content in a sample via oxidation of precursors, followed by subsequent analysis of the perfluoroalkyl acid (PFAA) concentration before and after oxidative processes. Activated carbon combined with a preceding ozonation step is considered a promising tool for the removal of micropollutants but considering PFAS removal efficiencies in effluents for this process combination more information is required. The focus of the study was to implement and assess the TOP assay with ozone as oxidizing agent to estimate the total PFAS content in a WWTP effluent. Additionally, granular activated carbon (GAC) and powdered activated carbon (PAC) with a preceding ozonation step was tested for the removal efficiencies for 22 PFAS. For the TOP assay the obtained accordance in molarity using spiked tap water as quality control was 95.2% (15 mg O/L) and 99.1% (6 mg O/L). Applying the TOP assay, an estimated total PFAS content of 840 ng/L was determined in the respective effluent, which was 91.1% higher than obtained by target PFAS analysis, implying the presence of unknown precursors not included in common monitoring. While all treatment techniques that included ozone or a preceding ozonation step solely transformed precursors and long-chain perfluoroalkyl acids (PFAA, i.e., >C9) to shorter congeners, PAC was the only tested water treatment application that was able to remove 19.3% of the total PFAS molarity.
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http://dx.doi.org/10.1016/j.jenvman.2021.113692DOI Listing
September 2021

Corrigendum: Genes Involved in Stress Response and Especially in Phytoalexin Biosynthesis Are Upregulated in Four Genotypes in Response to Apple Replant Disease.

Front Plant Sci 2021 28;12:723957. Epub 2021 Jul 28.

Institute for Breeding Research on Fruit Crops, Julius Kühn-Institut, Federal Research Centre for Cultivated Plants, Dresden, Germany.

[This corrects the article DOI: 10.3389/fpls.2019.01724.].
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http://dx.doi.org/10.3389/fpls.2021.723957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358931PMC
July 2021

Salivary metabolites associated with a 5-year tooth loss identified in a population-based setting.

BMC Med 2021 07 14;19(1):161. Epub 2021 Jul 14.

Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University Medicine Greifswald, Fleischmannstr. 42, 17475, Greifswald, Germany.

Background: Periodontitis is among the most common chronic diseases worldwide, and it is one of the main reasons for tooth loss. Comprehensive profiling of the metabolite content of the saliva can enable the identification of novel pathways associated with periodontitis and highlight non-invasive markers to facilitate time and cost-effective screening efforts for the presence of periodontitis and the prediction of tooth loss.

Methods: We first investigated cross-sectional associations of 13 oral health variables with saliva levels of 562 metabolites, measured by untargeted mass spectrometry among a sub-sample (n = 938) of the Study of Health in Pomerania (SHIP-2) using linear regression models adjusting for common confounders. We took forward any candidate metabolite associated with at least two oral variables, to test for an association with a 5-year tooth loss over and above baseline oral health status using negative binomial regression models.

Results: We identified 84 saliva metabolites that were associated with at least one oral variable cross-sectionally, for a subset of which we observed robust replication in an independent study. Out of 34 metabolites associated with more than two oral variables, baseline saliva levels of nine metabolites were positively associated with a 5-year tooth loss. Across all analyses, the metabolites 2-pyrrolidineacetic acid and butyrylputrescine were the most consistent candidate metabolites, likely reflecting oral dysbiosis. Other candidate metabolites likely reflected tissue destruction and cell proliferation.

Conclusions: Untargeted metabolic profiling of saliva replicated metabolic signatures of periodontal status and revealed novel metabolites associated with periodontitis and future tooth loss.
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http://dx.doi.org/10.1186/s12916-021-02035-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278731PMC
July 2021

Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.

Circ Genom Precis Med 2021 Aug 9;14(4):e003258. Epub 2021 Jul 9.

Department of Epidemiology (N.F., G.H.), University of North Carolina, Chapel Hill.

Background: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.

Methods: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.

Results: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).

Conclusions: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.
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http://dx.doi.org/10.1161/CIRCGEN.120.003258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435075PMC
August 2021

Gene Variants Determine Placental Transfer of Perfluoroalkyl Substances (PFAS), Mercury (Hg) and Lead (Pb), and Birth Outcome: Findings From the UmMuKi Bratislava-Vienna Study.

Front Genet 2021 16;12:664946. Epub 2021 Jun 16.

Environment Agency Austria, Vienna, Austria.

Prenatal exposure to perfluoroalkyl substances (PFAS), bisphenol A (BPA), lead (Pb), total mercury (THg), and methylmercury (MeHg) can affect fetal development. Factors influencing placental transfer rate of these toxins are poorly investigated. Whether prenatal exposure to pollutants has an effect on birth weight is incompletely understood. We therefore aimed (1) to determine placental transfer rates of PFAS, BPA, Pb, THg, and MeHg, (2) to analyze relationships between fetal exposure and birth outcome and (3) to analyze gene variants as mediators of placental transfer rates and birth outcome. Two hundred healthy pregnant women and their newborns participated in the study. BPA, 16 PFAS, THg, MeHg, and Pb were determined using HPLCMS/MS (BPA, PFAS), HPLC-CV-ICPMS (MeHg), CV-AFS (THg), and GF-AAS (Pb). Questionnaires and medical records were used to survey exposure sources and birth outcome. 20 single nucleotide polymorphisms and two deletion polymorphisms were determined by real-time PCR from both maternal and newborn blood. Genotype-phenotype associations were analyzed by categorical regression and logistic regression analysis. Specific gene variants were associated with altered placental transfer of PFAS ( Lys59Asn, Gln141Lys), THg ( Tyr85Asp, del, rs246221) and Pb ( Ala114Val). A certain combination of three gene polymorphisms ( rs246221, rs4130 His63Asp) was over-represented in newborns small for gestational age. 36% of Austrian and 75% of Slovakian mothers had levels exceeding the HBM guidance value I (2 μg/L) of the German HBM Commission for PFOA. 13% of newborns and 39% of women had Ery-Pb levels above 24 μg/kg, an approximation for the BMDL of 12 μg/L set by the European Food Safety Authority (EFSA). Our findings point to the need to minimize perinatal exposures to protect fetal health, especially those genetically predisposed to increased transplacental exposure.
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http://dx.doi.org/10.3389/fgene.2021.664946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242356PMC
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

The C-Mannosylome of Human Induced Pluripotent Stem Cells Implies a Role for ADAMTS16 C-Mannosylation in Eye Development.

Mol Cell Proteomics 2021 May 8;20:100092. Epub 2021 May 8.

Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany. Electronic address:

C-mannosylation is a modification of tryptophan residues with a single mannose and can affect protein folding, secretion, and/or function. To date, only a few proteins have been demonstrated to be C-mannosylated, and studies that globally assess protein C-mannosylation are scarce. To interrogate the C-mannosylome of human induced pluripotent stem cells, we compared the secretomes of CRISPR-Cas9 mutants lacking either the C-mannosyltransferase DPY19L1 or DPY19L3 to WT human induced pluripotent stem cells using MS-based quantitative proteomics. The secretion of numerous proteins was reduced in these mutants, including that of A Disintegrin And Metalloproteinase with ThromboSpondin Motifs 16 (ADAMTS16), an extracellular protease that was previously reported to be essential for optic fissure fusion in zebrafish eye development. To test the functional relevance of this observation, we targeted dpy19l1 or dpy19l3 in embryos of the Japanese rice fish medaka (Oryzias latipes) by CRISPR-Cas9. We observed that targeting of dpy19l3 partially caused defects in optic fissure fusion, called coloboma. We further showed in a cellular model that DPY19L1 and DPY19L3 mediate C-mannosylation of a recombinantly expressed thrombospondin type 1 repeat of ADAMTS16 and thereby support its secretion. Taken together, our findings imply that DPY19L3-mediated C-mannosylation is involved in eye development by assisting secretion of the extracellular protease ADAMTS16.
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http://dx.doi.org/10.1016/j.mcpro.2021.100092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256286PMC
May 2021

Recreational activity after cementless total hip arthroplasty in patients older than 75 years.

Arch Orthop Trauma Surg 2021 May 3. Epub 2021 May 3.

ARCUS Sportklinik, Rastatterstr. 17-19, 75179, Pforzheim, Germany.

Introduction: This retrospective study aimed to compare activity levels before and at mid-term follow-up after primary cementless total hip arthroplasty (THA) in patients older than 75 years.

Materials And Methods: A cohort of 79 patients with a mean age at surgery of 78 years (range 76-84 years) was evaluated 6.3 years (range 4-8 years) after cementless THA due to osteoarthritis and was followed up with a questionnaire to determine their activity level. Pre- and post-operative recreational activities were assessed at routine follow-up using the University of California, Los Angeles activity score, and the Schulthess Clinic sports and activity questionnaire. Post-operative health-related quality of life was measured using Veterans Rand 12-item survey (VR-12).

Results: Six years after THA, 72% of preoperatively active patients had returned to activity. Comparing activity preoperatively (before the onset of symptoms) and 6 years after THA, the number of disciplines and session length has decreased significantly. A significant decline in high-impact activities was observed, while participation in low-impact activities significantly increased.

Conclusion: The majority of patients maintained a recreational activity level in the mid-term after primary cementless THA. However, a change in disciplines toward low-impact activities was observed.
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http://dx.doi.org/10.1007/s00402-021-03896-yDOI Listing
May 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
April 2021

Knock-down of LRP/LR influences signalling pathways in late-stage colorectal carcinoma cells.

BMC Cancer 2021 Apr 9;21(1):392. Epub 2021 Apr 9.

School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa.

Background: The 37 kDa/67 kDa laminin receptor (LRP/LR) is involved in several tumourigenic-promoting processes including cellular viability maintenance and apoptotic evasion. Thus, the aim of this study was to assess the molecular mechanism of LRP/LR on apoptotic pathways in late stage (DLD-1) colorectal cancer cells upon siRNA-mediated down-regulation of LRP/LR.

Methods: siRNAs were used to down-regulate the expression of LRP/LR in DLD-1 cells which was assessed using western blotting and qPCR. To evaluate the mechanistic role of LRP/LR, proteomic analysis of pathways involved in proliferation and apoptosis were investigated. The data from the study was analysed using a one-way ANOVA, followed by a two-tailed student's t-test with a confidence interval of 95%.

Results: Here we show that knock-down of LRP/LR led to significant changes in the proteome of DLD-1 cells, exposing new roles of the protein. Moreover, analysis showed that LRP/LR may alter components of the MAPK, p53-apoptotic and autophagic signalling pathways to aid colorectal cancer cells in continuous growth and survival. Knock-down of LRP/LR also resulted in significant decreases in telomerase activity and telomerase-related proteins in the DLD-1 cells.

Conclusions: These findings show that LRP/LR is critically implicated in apoptosis and cell viability maintenance and suggest that siRNA-mediated knock-down of LRP/LR may be a possible therapeutic strategy for the treatment of colorectal cancer.
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http://dx.doi.org/10.1186/s12885-021-08081-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035741PMC
April 2021

Midterm Survivorship of an Uncemented Hydroxyapatite-Coated Titanium Femoral Component and Clinically Meaningful Outcomes in Patients Older Than 75 Years.

J Clin Med 2021 Mar 2;10(5). Epub 2021 Mar 2.

ARCUS Sportklinik, Rastatterstr. 17-19, 75179 Pforzheim, Germany.

Purpose: It remains controversial whether cementless femoral components are safe in elderly patients. The aim of this study was (1) to determine the stem survival rate in patients >75 years of age who were treated with an uncemented femoral component and (2) to report clinically significant results on a mid-term follow-up.

Methods: 107 total hip arthroplasties (THA) were retrospectively evaluated in 97 patients over 75 years of age (mean age 78 years, range 75-87) treated with an uncemented femoral stem. The minimum follow-up was five years (mean 6.4 years, range 5-8). Stem survival rates, clinically meaningful outcomes, and incidence of complications were evaluated.

Results: Kaplan-Meier survival analysis, with the endpoint revision for any reason, showed a 6.4-year survival rate of 98% (95% CI, 95-99%; 63 hips at risk). The survival rates were comparable for male and female patients (log-rank test, = 0.58). The modified Harris Hip Score (mHHS) improved from 42.2 (12 to 85) points to 81.1 (22 to 97) points ( < 0.0001). Mid-term minimal clinically important difference (MCID), substantial clinical benefit (SCB), and patient acceptable symptomatic state (PASS) were 25, 84, and 70, respectively.

Conclusion: An uncemented stem is a viable option in patients over 75 years with good clinical outcomes and survivorship. Periprosthetic fractures were not a relevant failure mechanism with the stem used.
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http://dx.doi.org/10.3390/jcm10051019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958839PMC
March 2021

A Comprehensive View on the Human Antibody Repertoire Against Antigens in the General Population.

Front Immunol 2021 10;12:651619. Epub 2021 Mar 10.

Department Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.

Our goal was to provide a comprehensive overview of the antibody response to antigens in the general population as a basis for defining disease-specific profiles and diagnostic signatures. We tested the specific IgG and IgA responses to 79 staphylococcal antigens in 996 individuals from the population-based Study of Health in Pomerania. Using a dilution-based multiplex suspension array, we extended the dynamic range of specific antibody detection to seven orders of magnitude, allowing the precise quantification of high and low abundant antibody specificities in the same sample. The observed IgG and IgA antibody responses were highly heterogeneous with differences between individuals as well as between bacterial antigens that spanned several orders of magnitude. Some antigens elicited significantly more IgG than IgA and vice versa. We confirmed a strong influence of colonization on the antibody response and quantified the influence of sex, smoking, age, body mass index, and serum glucose on anti-staphylococcal IgG and IgA. However, all host parameters tested explain only a small part of the extensive variability in individual response to the different antigens of .
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http://dx.doi.org/10.3389/fimmu.2021.651619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987813PMC
September 2021

Carrying asymptomatic gallstones is not associated with changes in intestinal microbiota composition and diversity but cholecystectomy with significant dysbiosis.

Sci Rep 2021 03 23;11(1):6677. Epub 2021 Mar 23.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

Gallstone disease affects up to twenty percent of the population in western countries and is a significant contributor to morbidity and health care expenditure. Intestinal microbiota have variously been implicated as either contributing to gallstone formation or to be affected by cholecystectomy. We conducted a large-scale investigation on 404 gallstone carriers, 580 individuals post-cholecystectomy and 984 healthy controls with similar distributions of age, sex, body mass index, smoking habits, and food-frequency-score. All 1968 subjects were recruited from the population-based Study-of-Health-in-Pomerania (SHIP), which includes transabdominal gallbladder ultrasound. Fecal microbiota profiles were determined by 16S rRNA gene sequencing. No significant differences in microbiota composition were detected between gallstone carriers and controls. Individuals post-cholecystectomy exhibited reduced microbiota diversity, a decrease in the potentially beneficial genus Faecalibacterium and an increase in the opportunistic pathogen Escherichia/Shigella. The absence of an association between the gut microbiota and the presence of gallbladder stones suggests that there is no intestinal microbial risk profile increasing the likelihood of gallstone formation. Cholecystectomy, on the other hand, is associated with distinct microbiota changes that have previously been implicated in unfavorable health effects and may not only contribute to gastrointestinal infection but also to the increased colon cancer risk of cholecystectomized patients.
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http://dx.doi.org/10.1038/s41598-021-86247-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988160PMC
March 2021

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Eur Heart J 2021 05;42(20):2000-2011

Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France.

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.

Methods And Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.

Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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http://dx.doi.org/10.1093/eurheartj/ehab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139853PMC
May 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome.

Nat Genet 2021 02 18;53(2):147-155. Epub 2021 Jan 18.

Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.

The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory, neurologic and neoplastic diseases. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain. Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition. In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a 'metaorganism' broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management.
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http://dx.doi.org/10.1038/s41588-020-00747-1DOI Listing
February 2021

Sports activity and patient-related outcomes after fixed-bearing lateral unicompartmental knee arthroplasty.

Knee 2021 Jan 10;28:64-71. Epub 2020 Dec 10.

ARCUS Sportklinik Pforzheim, Germany.

Background: Unicompartmental osteoarthrosis increasingly affects younger patients who have high expectations concerning their postoperative level of activity. However, there is no available data on the activity level after fixed-bearing lateral unicompartmentalkneearthroplasty (UKA). The aim of this study was to report sports activity after fixed-bearing lateral UKA with a minimum two-year follow up.

Methods: Nineteen patients were surveyed to determine their sporting activities at a mean follow up of 4.6 years (range 2.0-9.7 years) after fixed-bearing lateral UKA. We also assessed the Knee Injury and Osteoarthritis Outcome Score Joint Replacement (KOOS JR) Score and the University of California, Los Angeles activity scale (UCLA scale) at baseline and latest follow up.

Results: Before the onset of the first symptoms, 15 of 19 patients were active in at least one sport compared with 13 of 19 patients after surgery. Eighty-six per cent of the patients returned to activity. Within 6 months, 68% returned to their activities after surgery. The mean postoperative UCLA score was 6.4 (±1.3). Half of the patients reached a high activity level (UCLA ≥ 7). Most common activities after surgery were long walks, biking and hiking. High-impact activities showed a significant decrease.

Conclusion: Eighty-six per cent of the patients were able to return to regular recreational and sporting activities. In general, a shift from high-impact to low-impact activities was observed. There was no difference in the number of disciplines performed. Overall, the session length and frequency remained unchanged. However, male patients and younger patients participated in sports less frequently compared with preoperative levels.
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http://dx.doi.org/10.1016/j.knee.2020.11.011DOI Listing
January 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Comparison of extraction methods for per- and polyfluoroalkyl substances (PFAS) in human serum and placenta samples-insights into extractable organic fluorine (EOF).

Anal Bioanal Chem 2021 Jan 19;413(3):865-876. Epub 2020 Nov 19.

Man-Technology-Environment Research Centre (MTM), Örebro University, 701 82, Örebro, Sweden.

Since the detection of per- and polyfluoroalkyl substances (PFAS) in humans and different environmental media in the last two decades, this substance group has attracted a lot of attention as well as increasing concerns. The fluorine mass balance approach, by comparing the levels of targeted PFAS after conversion to fluorine equivalents with those of extractable organic fluorine (EOF), showed the presence of unidentified organofluorine in different environmental samples. Out of the thousands of PFAS in existence, only a very small fraction is included in routine analysis. In recent years, liquid chromatography coupled with tandem-mass spectrometry (LC-MS/MS) has demonstrated the ability to analytically cover a wide spectrum of PFAS. In contrast, conventional extraction methods developed 10 to 15 years ago were only evaluated for a limited number of PFAS. The aim of the present study was to evaluate the advantages and disadvantages of three different extraction methods, adapted from the literatures without further optimization (ion-pair liquid-liquid extraction, solid-phase extraction (SPE), using hydrophilic-lipophilic (HLB) or weak anion exchange (WAX) sorbents), for human biomonitoring of 61 PFAS in serum and placental tissue samples. In addition, levels of EOF were compared among these extraction methods via spiked samples. Results showed that performance, in terms of recovery, differed between the extraction methods for different PFAS; different extraction methods resulted in different EOF concentrations indicating that the choice of extraction method is important for target PFAS and EOF analysis. Results of maternal serum samples, analyzed in two different laboratories using two different extraction methods, showed an accordance of 107.6% (± 21.3); the detected perfluoroalkyl acids (PFAAs) in maternal and cord serum samples were in the range of 0.076 to 2.9 ng/mL.Graphical abstract.
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http://dx.doi.org/10.1007/s00216-020-03041-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809006PMC
January 2021

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

PLoS One 2020 13;15(11):e0230035. Epub 2020 Nov 13.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, United States of America.

Background: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

Methods And Results: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

Conclusion: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230035PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665790PMC
December 2020

Associations of plasma YKL-40 concentrations with heel ultrasound parameters and bone turnover markers in the general adult population.

Bone 2020 12 6;141:115675. Epub 2020 Oct 6.

Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, Greifswald, Germany. Electronic address:

Objective: YKL-40, also known as chitinase-3-like protein 1, is a new proinflammatory biomarker, that might play a role in tissue remodeling and bone resorption. Here we evaluated the associations of the YKL-40 plasma concentration with heel ultrasound parameters and bone turnover markers (BTMs) in adult men and women from the general population. We tested for a causal role of YKL-40 on bone metabolism using published single nucleotide polymorphisms (SNPs) with consequences for YKL-40 expression and function.

Methods: Data were obtained from two population-based cohorts: the Study of Health in Pomerania (SHIP) and SHIP-Trend. Quantitative ultrasound (QUS) measurements at the heel were performed and bone turnover was assessed by measurement of intact amino-terminal propeptide of type I procollagen (PINP) and carboxy-terminal telopeptide of type I collagen (CTX). Associations between the YKL-40 plasma concentration and the QUS-based parameters, bone turnover marker (BTM) concentrations and 44 SNPs, including the lead SNP rs4950928, were evaluated in 382 subjects. Furthermore, we assessed the associations between the same SNPs and the QUS-based parameters (n = 5777) or the BTM concentrations (n = 7190).

Results: Sex-specific linear regression models adjusted for a comprehensive panel of interfering covariantes revealed statistically significant inverse associations between YKL-40 and all QUS-based parameters as well as positive associations with CTX in women. The rs4950928 polymorphism was associated with YKL-40 in men and women but none of the tested SNPs was associated with the QUS-based parameters or the BTMs after correction for multiple testing.

Conclusions: Plasma YKL-40 concentrations are associated with QUS-based parameters as well as CTX concentrations in women but these associations are probably not causal.
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http://dx.doi.org/10.1016/j.bone.2020.115675DOI Listing
December 2020

The Membrane Transporter OAT7 (SLC22A9) Is Not a Susceptibility Factor for Osteoporosis in Europeans.

Front Endocrinol (Lausanne) 2020 18;11:532. Epub 2020 Aug 18.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

Bone production, maintenance, and modeling are a well-balanced process involving mineralization by osteoblasts and resorption by osteoclasts. Sex steroid hormones, including their conjugated forms, contribute majorly to maintaining this balance. Recently, variants in the gene have been associated with osteoporosis in Korean females. We had recently shown that , encoding organic anion transporter 7 (OAT7), is an uptake transporter of estrone sulfate and identified several genetic variants in Europeans leading to functional consequences . We therefore hypothesized that genetic variants may contribute to the pathophysiology of osteoporosis in Europeans. To test this hypothesis, we examined the associations of variants with bone quality, fractures, and bone turnover markers. We genotyped variants in 5,701 (2,930 female) subjects (age range, 20-93 years) extracted from the population-based Study of Health in Pomerania (SHIP and SHIP-TREND) covered by the Illumina Infinium HumanExome BeadChip version v1.0 (Exome Chip). Descriptive data (e.g., history of fractures), ultrasonography of the calcaneus, as well as serum concentrations of carboxy-terminal telopeptide of type I collagen, amino-terminal propeptide of type I procollagen, and vitamin D were determined. Comprehensive statistical analyses revealed no association between low-frequency and rare variants and bone quality, fractures, and bone turnover markers. Our results indicate that single genetic variants do not have a major impact on osteoporosis risk prediction in Europeans, yet findings need to be replicated in larger-scale studies.
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http://dx.doi.org/10.3389/fendo.2020.00532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461822PMC
June 2021

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Cell 2020 09;182(5):1214-1231.e11

Laboratory of Epidemiology and Population Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
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http://dx.doi.org/10.1016/j.cell.2020.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482360PMC
September 2020

Genome-Wide DNA Alterations in X-Irradiated Human Gingiva Fibroblasts.

Int J Mol Sci 2020 Aug 12;21(16). Epub 2020 Aug 12.

Human Molecular Genetics Group, Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany.

While ionizing radiation (IR) is a powerful tool in medical diagnostics, nuclear medicine, and radiology, it also is a serious threat to the integrity of genetic material. Mutagenic effects of IR to the human genome have long been the subject of research, yet still comparatively little is known about the genome-wide effects of IR exposure on the DNA-sequence level. In this study, we employed high throughput sequencing technologies to investigate IR-induced DNA alterations in human gingiva fibroblasts (HGF) that were acutely exposed to 0.5, 2, and 10 Gy of 240 kV X-radiation followed by repair times of 16 h or 7 days before whole-genome sequencing (WGS). Our analysis of the obtained WGS datasets revealed patterns of IR-induced variant (SNV and InDel) accumulation across the genome, within chromosomes as well as around the borders of topologically associating domains (TADs). Chromosome 19 consistently accumulated the highest SNVs and InDels events. Translocations showed variable patterns but with recurrent chromosomes of origin (e.g., Chr7 and Chr16). IR-induced InDels showed a relative increase in number relative to SNVs and a characteristic signature with respect to the frequency of triplet deletions in areas without repetitive or microhomology features. Overall experimental conditions and datasets the majority of SNVs per genome had no or little predicted functional impact with a maximum of 62, showing damaging potential. A dose-dependent effect of IR was surprisingly not apparent. We also observed a significant reduction in transition/transversion (Ti/Tv) ratios for IR-dependent SNVs, which could point to a contribution of the mismatch repair (MMR) system that strongly favors the repair of transitions over transversions, to the IR-induced DNA-damage response in human cells. Taken together, our results show the presence of distinguishable characteristic patterns of IR-induced DNA-alterations on a genome-wide level and implicate DNA-repair mechanisms in the formation of these signatures.
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http://dx.doi.org/10.3390/ijms21165778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460866PMC
August 2020

miRNA Mechanisms Underlying the Association of Beta Blocker Use and Bone Mineral Density.

J Bone Miner Res 2021 01 22;36(1):110-122. Epub 2020 Sep 22.

Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, Portland, ME, USA.

Osteoporosis is a debilitating and costly disease that causes fractures in 33% of women and 20% of men over the age of 50 years. Recent studies have shown that beta blocker (BB) users have higher bone mineral density (BMD) and decreased risk of fracture compared with non-users. The mechanism underlying this association is thought to be due to suppression of adrenergic signaling in osteoblasts, which leads to increased BMD in rodent models; however, the mechanism in humans is unknown. Also, several miRNAs are associated with adrenergic signaling and BMD in separate studies. To investigate potential miRNA mechanisms, we performed a cross-sectional analysis using clinical data, dual-energy X-ray absorptiometry (DXA) scans, and miRNA and mRNA profiling of whole blood from the Framingham Study's Offspring Cohort. We found nine miRNAs associated with BB use and increased BMD. In parallel network analyses, we discovered a subnetwork associated with BMD and BB use containing two of these nine miRNAs, miR-19a-3p and miR-186-5p. To strengthen this finding, we showed that these two miRNAs had significantly higher expression in individuals without incident fracture compared with those with fracture in an external data set. We also noted a similar trend in association between these miRNA and Z-score as calculated from heel ultrasound measures in two external cohorts (SOS-Hip and SHIP-TREND). Because miR-19a directly targets the ADRB1 mRNA transcript, we propose BB use may downregulate ADRB1 expression in osteoblasts through increased miR-19a-3p expression. We used enrichment analysis of miRNA targets to find potential indirect effects through insulin and parathyroid hormone signaling. This analysis provides a starting point for delineating the role of miRNA on the association between BB use and BMD. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140522PMC
January 2021

The Migration Pattern of a Cementless Hydroxyapatite-Coated Titanium Stem under Immediate Full Weight-Bearing-A Randomized Controlled Trial Using Model-Based RSA.

J Clin Med 2020 Jul 2;9(7). Epub 2020 Jul 2.

Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.

(1) Background: High primary stability is important for the long-term survival of cementless femoral stems in total hip arthroplasty (THA). The objective of this study was to investigate the migration pattern of a hydroxyapatite-coated cementless hip stem developed for minimally invasive surgery using model-based radiostereometric analysis (RSA). (2) Methods: In this randomized controlled trial, 44 patients with an indication for cementless primary THA were randomly allocated to receive either the SL-PLUS MIA stem, developed for minimally invasive surgery, or the SL-PLUS stem (Smith & Nephew Orthopaedics, Baar, Switzerland) which served as a control group. Unlimited weight-bearing was permitted postoperatively in both groups. Model-based RSA was performed after six weeks and after 3, 6, 12 and 24 months postoperatively. (3) Results: Mean total stem subsidence at two-year follow-up was 0.40 mm (SD 0.66 mm) in the SL-PLUS group and 1.08 mm (SD 0.93 mm) in the SL-PLUS MIA group ( = 0.030). Stem subsidence occurred during the first six weeks after surgery, indicating initial settling of the stem under full weight-bearing. Both stem designs showed good osseointegration and high secondary stability with no further migration after initial settling. (4) Conclusions: Settling of a cementless straight femoral stem occurs during the first six weeks after surgery under full weight-bearing. Although initial stem migration was higher in the SL-PLUS MIA group, it had no influence on secondary stability. All implants showed good osseointegration and high secondary stability with no signs of implant loosening during this two-year follow-up period.
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http://dx.doi.org/10.3390/jcm9072077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408977PMC
July 2020

Comparison of short-stem with conventional-stem prostheses in total hip arthroplasty: an 8-year follow-up study.

Arch Orthop Trauma Surg 2020 Sep 22;140(9):1285-1291. Epub 2020 Jun 22.

ARCUS Sportklinik Pforzheim, Rastatterstr. 17-19, 75179, Pforzheim, Germany.

Purpose: Coxarthrosis is a common disease of the adult hip joint. Elderly patients have mainly been treated with total hip arthroplasty (THA); however, younger patients are increasingly affected. Short-stem prostheses were developed for this special patient group. There have been few studies on the clinical outcomes of this type of prosthesis. This study compared the mid-term results of a short-stem prosthesis and a standard-stem prosthesis 8 years after implantation.

Methods: According to our clinical registry, patients who received a short-stem prosthesis before 2011 were identified. Patients in the standard-stem prosthesis group were matched based on the sex, age, height, weight, and degree of arthrosis. At the follow-up time, the modified Harris Hip Score (mHHS), University of California Los Angeles (UCLA) activity score and visual analog scale (VAS) pain score were collected and compared with the preoperative values.

Results: Fifty-five patients could be matched and analyzed for both groups. No patients needed revision surgery. In both groups, there were significant improvements at the follow-up time. The pre- and postoperative mHHSs, UCLA scores, and VAS scores were 41.9 and 95 (p < 0.0001), 3.75 and 7.9 (p < 0.0001), and 7.6 and 0.9 (p < 0.0001), respectively, in the short-stem group and 44.8 and 96.25 (p < 0.0001), 3.6 and 7.7 (p < 0.0001), and 7.7 and 0.9 (p < 0.0001), respectively, in the control group, with no significant differences between the groups at the follow-up time.

Conclusion: The short-stem prosthesis provides mid-term results comparable to those of a standard-stem prosthesis. In both groups, excellent patient-reported outcomes were achieved after an average of 8 years.

Level Of Evidence: IV.
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http://dx.doi.org/10.1007/s00402-020-03519-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211593PMC
September 2020

LRP::FLAG Reduces Phosphorylated Tau Levels in Alzheimer's Disease Cell Culture Models.

J Alzheimers Dis 2020 ;76(2):753-768

School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, Republic of South Africa.

Background: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently, it has been demonstrated that the 37 kDa/67 kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aβ pathology. Since both LRP/LR and telomerase are known to play a role in the Aβ facet of AD, we hypothesized that they might also play a role in tauopathy.

Objective: This study aimed to determine if LRP/LR has a relationship with tau and whether overexpression of LRP::FLAG has an effect on tauopathy-related proteins.

Methods: We employed confocal microscopy and FRET to determine whether LRP/LR and tau co-localize and interact. LRP::FLAG overexpression in HEK-293 and SH-SY5Y cells as well as analysis of tauopathy-related proteins was assessed by western blotting.

Results: We demonstrate that LRP/LR co-localizes with tau in the perinuclear cell compartment and confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Overexpression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrPc levels, a tauopathy-related protein. LRP::FLAG overexpression also resulted in increased hTERT levels.

Conclusion: This data suggest that LRP/LR extends its role in AD through a direct interaction with tau, and recommend LRP::FLAG as a possible alternative AD therapeutic via decreasing phosphorylated tau levels.
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http://dx.doi.org/10.3233/JAD-200244DOI Listing
May 2021
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