Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to ...allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.
Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major ...effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.
Purpose
Due to the lack of evidence, it was the aim of the study to investigate current possible cutbacks in orthopaedic healthcare due to the coronavirus disease 2019 pandemic (COVID-19).
Methods
An ...online survey was performed of orthopaedic surgeons in the German-speaking Arthroscopy Society (Gesellschaft für Arthroskopie und Gelenkchirurgie, AGA). The survey consisted of 20 questions concerning four topics: four questions addressed the origin and surgical experience of the participant, 12 questions dealt with potential cutbacks in orthopaedic healthcare and 4 questions addressed the influence of the pandemic on the particular surgeon.
Results
Of 4234 contacted orthopaedic surgeons, 1399 responded. Regarding arthroscopic procedures between 10 and 30% of the participants stated that these were still being performed—with actual percentages depending on the specific joint and procedure. Only 6.2% of the participants stated that elective total joint arthroplasty was still being performed at their centre. In addition, physical rehabilitation and surgeons’ postoperative follow-ups were severely affected.
Conclusion
Orthopaedic healthcare services in Austria, Germany, and Switzerland are suffering a drastic cutback due to COVID-19. A drastic reduction in arthroscopic procedures like rotator cuff repair and cruciate ligament reconstruction and an almost total shutdown of elective total joint arthroplasty were reported. Long-term consequences cannot be predicted yet. The described disruption in orthopaedic healthcare services has to be viewed as historic.
Level of evidence
V.
In this work, a new surface pre-treatment based on a modified hexafluorozirconic acid solution with addition of copper was studied as a replacement of the phosphating process. The main purpose of ...this study is to compare the formation mechanism and kinetics of Zr-based conversion coatings on three different base substrates: Aluminium alloy (AA) 6014, cold rolled steel and hot dip galvanized steel. For that purpose, open circuit potential (OCP) measurements during the deposition of the conversion coatings are performed in combination with different ex-situ surface characterization techniques. The elemental distribution was analyzed by means of (Field Emission) Auger Electron Spectroscopy (FE-AES) depth profiles and mappings. Furthermore, the surface chemistry of the conversion layer was evaluated by X-ray Photoelectron Spectroscopy (XPS). The results showed that while the mechanism of formation is similar for the different substrates, the rate of formation strongly depends on the substrate type. Additionally, the thickness and lateral and in-depth elemental distribution of the Zr-based conversion layers also largely depend on the underlying metal.
•A modified Zr-based conversion pre-treatment was studied on different metals.•Electrochemical analysis was used to study the deposition mechanism in-situ.•Surface analytical techniques were implemented to study the coating chemistry.•The thickness of Zr-based conversion layers depends on the underlying metal.•The elemental distribution of the Zr-based coatings depends on the substrate.
Cognitive performance is both heritable and sensitive to environmental inputs and sustained practice over time. However, it is currently unclear how genetic effects on cognitive performance change ...over the course of learning. We examine how polygenic scores (PGS) created from genome-wide association studies of educational attainment and cognitive performance are related to improvements in performance across nine cognitive tests (measuring perceptual speed, working memory, and episodic memory) administered to 131 adults (N = 51, ages = 20-31, and N = 80, ages = 65-80 years) repeatedly across 100 days. We observe that PGS associations with performance on a given task can change over the course of learning, with the specific pattern of change in associations differing across tasks. PGS correlations with pre-test to post-test scores may mask variability in how soon learning occurs over the course of practice. The associations between PGS and learning do not appear to simply reconstitute patterns of association between baseline performance and subsequent learning. Associations involving PGSs, however, were small with large confidence intervals. Intensive longitudinal research such as that described here may be of substantial value for clarifying the genetics of learning when implemented as far larger scale.
Dopamine (DA) integrity is suggested as a potential cause of individual differences in working memory (WM) performance among older adults. Still, the principal dopaminergic mechanisms giving rise to ...WM differences remain unspecified. Here, 61 single-nucleotide polymorphisms, located in or adjacent to various dopamine-related genes, were assessed for their links to WM performance in a sample of 1313 adults aged 61–80 years from the Berlin Aging Study II. Least Absolute Shrinkage and Selection Operator (LASSO) regression was conducted to estimate associations between polymorphisms and WM. Rs40184 in the DA transporter gene, SLC6A3, showed allelic group differences in WM, with T-carriers performing better than C homozygotes (p<0.01). This finding was replicated in an independent sample from the Cognition, Brain, and Aging study (COBRA; baseline: n = 181, ages: 64–68 years; 5-year follow up: n = 129). In COBRA, in vivo DA integrity was measured with 11C-raclopride and positron emission tomography. Notably, WM as well as in vivo DA integrity was higher for rs40184 T-carriers at baseline (p<0.05 for WM and caudate and hippocampal D2-receptor availability) and at the 5-year follow-up (p<0.05 for WM and hippocampal D2 availability). Our findings indicate that individual differences in DA transporter function contribute to differences in WM performance in old age, presumably by regulating DA availability.
Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), ...leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.
This study investigates the influence of surface conditioning on the deposition of Zr-based conversion films on AA6014. For that purpose, different treatments were used to control the formation of ...well-defined oxides layers with different hydroxyl fractions and similar thicknesses prior to the conversion layer formation process. The elemental distribution and surface chemistry of the treated samples before and after the formation of the Zr-based conversion layer were evaluated by Auger Electron Spectroscopy (AES) depth profiling and X-ray Photoelectron Spectroscopy (XPS). Moreover, the Open Circuit Potential (OCP) evolution as a function of time was recorded during the formation of the Zr-based conversion layers in order to evaluate the electrochemical surface activity and formation mechanism in-situ. The results have shown that a higher initial hydroxyl fraction encourages the formation of a thicker Zr-based layer.
•A Cu-containing hexafluorozirconic acid pre-treatment was studied on AA6014.•The film chemistry and thickness were evaluated with surface analytical techniques.•The formation mechanism was studied in-situ using electrochemical analysis.•High OH− fractions on AA6014 are beneficial for the formation of Zr-based films.
Purpose
To document the status-quo of orthopaedic health-care services as the COVID-19 pandemic recedes, and to determine the rate of resumption of orthopaedic surgery in the German-speaking ...countries in May 2020.
Methods
A prospective online survey was sent out to 4234 surgeons of the AGA - Society of Arthroscopy and Joint-Surgery (Gesellschaft für Arthroskopie und Gelenkchirurgie, AGA). The survey was created using SurveyMonkey software and consisted of 23 questions relating to the reduction of orthopaedic services at the participating centres and the impact that the pandemic is having on each surgeon.
Results
A total of 890 orthopaedic surgeons responded to the online survey. Approximately 90% of them experienced a reduction in their surgical caseload and patient contact. 38.7% stated that their institutions returned to providing diagnostic arthroscopies. 54.5% reported that they went back to performing anterior cruciate ligament reconstructions (ACLR), 62.6% were performing arthroscopic meniscus procedures, and 55.8% had resumed performing shoulder arthroscopy. Only 31.9% of the surgeons were able to perform elective total joint arthroplasty. 60% of the participants stated that they had suffered substantial financial loss due to the pandemic.
Conclusion
A gradual resumption of orthopaedic health-care services was observed in May 2020. Typical orthopaedic surgical procedures like ACLR, shoulder arthroscopy and elective total joint arthroplasty were reported to be currently performed by 54%, 56% and 32% of surgeons, respectively. Despite signs of improvement, it appears that there is a prolonged curtailment of orthopaedic health-care at present in the middle of Europe.
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