Impaired response to COVID-19 vaccination is of particular concern in immunosuppressed patients. To determine the best vaccination strategy for this vulnerable group we performed a single center, 1:1 ...randomized blinded clinical trial. Patients who failed to seroconvert upon two mRNA vaccinations (BNT162b2 or mRNA-1273) are randomized to receive either a third dose of the same mRNA or the vector vaccine ChAdOx1 nCoV-19. Primary endpoint is the difference in SARS-CoV-2 spike antibody seroconversion rate between vector and mRNA vaccinated patients four weeks after the third dose. Secondary outcomes include cellular immune responses. Seroconversion rates at week four are significantly higher in the mRNA (homologous vaccination, 15/24, 63%) as compared to the vector vaccine group (heterologous vaccination, 4/22, 18%). SARS-CoV-2-specific T-cell responses are reduced but could be increased after a third dose of either vector or mRNA vaccine. In a multivariable logistic regression analysis, patient age and vaccine type are associated with seroconversion. No serious adverse event is attributed to COVID-19 booster vaccination. Efficacy and safety data underline the importance of a booster vaccination and support the use of a homologous mRNA booster vaccination in immunosuppressed patients.Trial registration: EudraCT No.: 2021-002693-10.
The scarf osteotomy is a well-established surgical method for correcting a hallux valgus deformity. It is often combined with an Akin osteotomy. However, clear guidelines defining indication criteria ...are missing. The purpose of this study was to analyze the radiological outcome after scarf osteotomy in dependence of additional Akin osteotomy.
This study included 184 patients in whom a hallux valgus deformity was corrected with a scarf osteotomy (group S), and 63 patients in whom an additional Akin osteotomy was performed (group SA). Weight-bearing radiographs were evaluated preoperatively, postoperatively, after 6 weeks, after 3 months and at a follow-up with a mean of 45.4 months. Analysis was made for the following radiological parameters: the intermetatarsal angle (IMA), the hallux valgus angle (HVA), the distal metatarsal articular angle (DMAA), the proximal to distal phalangeal articular angle (PDPAA), and the position of the sesamoids as well as the joint congruity.
Radiographic recurrence (HVA > 20°) was detected in 1 patient (1.6% of recurrence) in the SA group, and in 27 patients in the S group (14.7% of recurrence) at follow-up. Outcome between the two groups differed significantly showing reduced loss of HVA correction in the SA group (p < 0.001). The subgroup with a preoperative PDPAA above eight degrees showed significant inferiority of outcome for the S group compared to the SA group.
Radiological outcome after scarf osteotomy is superior with concomitant Akin osteotomy. A preoperative PDPAA above eight degrees makes additional Akin osteotomy recommendable.
Therapeutic, Level III, retrospective comparative series.
The colorectal cancer (CRC) screening program B-PREDICT is a population based invited two stage screening project using a faecal immunochemical test (FIT) for initial screening followed by a ...colonoscopy for those with a positive FIT. B-PREDICT was compared with the opportunistic screening colonoscopy (OPP-COL), performed in course of the nationwide screening program.
Within B-PREDICT all residents of the Austrian federal state Burgenland, aged between 40 and 80 are annually invited to FIT testing. All individuals who underwent initial colonoscopy in Burgenland between 01/2003 and 12/2014, were included in this study. Individuals from the FIT-triggered invited screening program B-PREDICT were compared with those from the non-FIT triggered OPP-COL.
15 133 individuals from B-PREDICT were compared to 10 045 individuals with OPP-COL. CRC detection rates were 1.34% (CI-95%, 1.15; 1.52) in B-PREDICT compared to 0.54% in OPP-COL (95%-CI, 0.39; 0.68 p < 0.001). The decrease in the age standardized incidence rates of CRC was more pronounced in the population screened with FIT than in the general population screened with colonoscopy. Changes in incidence rates per year were -4.4% (95%-CI, -5.1; -3.7) vs. -1.8% (95%-CI, -1.9; -1.6 p < 0.001).
B-PREDICT shows a two-fold higher detection rate of CRC as well as HRA compared to OPP-COL.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of ...associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA. For different case-control comparisons, we report models including between 1-14 candidate SNPs. A genome-wide significant association of rs17659990 (P=5.43×10
,
, chromosome 3p21.2) with colorectal cancer risk was observed. Furthermore, 56 SNPs known to influence susceptibility to colorectal cancer and advanced adenoma were tested in a hypothesis-driven approach and several of them were found to be relevant in our Austrian cohort. After correction for multiple testing (α=8.9×10
), the most significant associations were observed for SNPs rs10505477 (P=6.08×10
) and rs6983267 (P=7.35×10
) of
, rs3802842 (P=8.98×10
,
), and rs12953717 (P=4.64×10
,
). All previously unreported SNPs demand replication in additional samples. Reanalysis of existing GWAS datasets using model selection as tool to detect SNPs associated with a complex trait may present a promising resource to identify further genetic risk variants not only for colorectal cancer.
In this article, we review and analyze different modes of exposure to ultrafine particles in order to assess particle-induced inflammatory responses and the underlying mechanisms in vitro and in ...vivo. Based on results from monocytic cells cultured under submerged conditions, we discuss (1) the impact of particle properties such as surface area and oxidative potential on lipid metabolism as a highly sensitive regulatory pathway and (2) the interference of diesel exhaust particles with toll-like receptor-mediated inflammatory responses. Furthermore, new developments of air-liquid interface exposure used as an alternative approach to simulate cell particle interactions are presented. In addition to the in vitro approaches, animal exposure studies are described that apply selected mouse models to elucidate potential allergic and inflammatory pulmonary responses and mast-cell-related mechanisms after particle exposure. Long-term inhalation of ultrafine particles might lead to irreversible changes in lung structure and function. Clinical studies addressing the characteristics of inflammatory airway cells are a promising approach to understand underlying pathophysiological mechanisms in chronic obstructive pulmonary disease. Finally, a potential outcome of human particle exposure is chronic cough in children. Here, discrimination between asthmatic and nonasthmatic cough by means of immunological parameters appears to be an important step toward improving diagnosis and therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Characterization of the colon cancer immunome and its autoantibody signature from differentially-reactive antigens (DIRAGs) could provide insights into aberrant cellular mechanisms or enriched ...networks associated with diseases. The purpose of this study was to characterize the antibody profile of plasma samples from 32 colorectal cancer (CRC) patients and 32 controls using proteins isolated from 15,417 human cDNA expression clones on microarrays. 671 unique DIRAGs were identified and 632 were more highly reactive in CRC samples. Bioinformatics analyses reveal that compared to control samples, the immunoproteomic IgG profiling of CRC samples is mainly associated with cell death, survival, and proliferation pathways, especially proteins involved in EIF2 and mTOR signaling. Ribosomal proteins (e.g., RPL7, RPL22, and RPL27A) and CRC-related genes such as APC, AXIN1, E2F4, MSH2, PMS2, and TP53 were highly enriched. In addition, differential pathways were observed between the CRC and control samples. Furthermore, 103 DIRAGs were reported in the SEREX antigen database, demonstrating our ability to identify known and new reactive antigens. We also found an overlap of 7 antigens with 48 “CRC genes.” These data indicate that immunomics profiling on protein microarrays is able to reveal the complexity of immune responses in cancerous diseases and faithfully reflects the underlying pathology.
The design of structures using topology optimization can improve the structural performance and save material, in turn reducing costs. Using a framework of large-scale, three-dimensional topology ...optimization implemented by the authors in an open-source multiphysical software, we investigate the influence of uncertain loading on the optimized design. Direct differentiation is used to reveal the relationship between displacements and applied force, giving an efficient and effective tool to postprocess optimized topologies. The developed methodology for the assessment of the sensitivity with respect to applied forces is explored using two three-dimensional examples: the classic MBB cantilever and a cableway pylon. The advantages and limitations of this method are discussed.
Large-Scale Material Extrusion (LS-MEX) is increasingly being used in small-scale production and prototyping due to its ability to create components in new temporal and spatial dimensions. However, ...the use of this manufacturing process poses microscopic and macroscopic challenges not encountered in previous small-scale production systems. These challenges arise primarily from the prolonged retention of heat in the material, which leads to insufficient strength in the extruded strands at the macrostructural level. As a result, the component can collapse, a phenomenon known as 'slumping'. Thermal energy also influences microstructural changes, such as crystallisation kinetics, which affect properties such as the strength and stiffness of the final product. The duration and dynamics of thermal energy are influenced by manufacturing parameters and the possible use of additional peripheral equipment, which affects component quality. In this study, the influence of thermal energy on structural processes through simulations of polyamide 6 with 40% carbon fibres (PA6 wt.%40 CF) is investigated. The results show that by adjusting the process parameters and using modification units, the thermal profile of the material can be accurately controlled, which allows the microstructural processes to be precisely controlled. This leads to the targeted modification of the macroscopic material properties. The focus of this work is on the combination of numerical simulations of the LS-MEX process with semi-empirical methods for the analysis of crystallisation processes. The application of the Nakamura model, which is used throughout similar investigations, allows a detailed description and prediction of the crystallisation kinetics during the manufacturing process. The study shows that the absolute degree of crystallisation can be determined with simplified assumptions using a combination of thermal simulations and semi-empirical approaches. It was found that the absolute degree of crystallisation increases from the outer interface of the strand to the print bed across the cross-section. This can be attributed to the specific thermal boundary conditions and the resulting temperature profiles at different points.
Background:
Recurrence after hallux valgus correction is a relatively frequent occurrence. Little is known about the importance of initial correction on radiologic outcome. The objective of our study ...was to determine postoperative radiologic parameters correlating with loss of correction after scarf osteotomy and the combined scarf/akin osteotomy, respectively.
Methods:
Loss of correction was evaluated based on a group of 53 feet with isolated scarf osteotomy (S group) and a group of 17 feet with combined scarf and akin osteotomy (SA group) in a retrospective analysis. The intermetatarsal angle (IMA), the hallux valgus angle (HVA), the distal metatarsal articular angle (DMAA), the proximal to distal phalangeal articular angle (PDPAA), the position of the sesamoids, and joint congruity were measured in weight-bearing radiographs preoperatively and postoperatively throughout a mean follow-up of 44.8 ± 23.6 months.
Results:
Loss of correction was comparable between the S and the SA group (P > .05). In contrast, we found higher loss of HVA correction in the S subgroup with a preoperative PDPAA above 8 degrees (P = .011), whereas loss of correction in the S subgroup below 8 degrees of PDPAA was comparable to the SA group. In the S group, loss of correction showed significant correlation with postoperative IMA (P = .015) and PDPAA (P = .008), whereas in the SA group a correlation could be detected for IMA only (P = .045).
Conclusion:
In cases with a PDPAA above 8 degrees, we recommend a combined scarf/akin osteotomy to diminish the potential for loss of correction.
Level of Evidence:
Level III, therapeutic, retrospective comparative series.
SARS-CoV-2-induced COVID-19 has led to exponentially rising mortality, particularly in immunosuppressed patients, who inadequately respond to conventional COVID-19 vaccination.
In this blinded ...randomised clinical trial, we compare the efficacy and safety of an additional booster vaccination with a vector versus mRNA vaccine in non-seroconverted patients. We assigned 60 patients under rituximab treatment, who did not seroconvert after their primary mRNA vaccination with either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), to receive a third dose, either using the same mRNA or the vector vaccine ChAdOx1 nCoV-19 (Oxford-AstraZeneca). Patients were stratified according to the presence of peripheral B cells. The primary efficacy endpoint was the difference in the SARS-CoV-2 antibody seroconversion rate between vector (heterologous) and mRNA (homologous) vaccinated patients by week 4. Key secondary endpoints included the overall seroconversion and cellular immune response; safety was assessed at week 1 and week 4.
Seroconversion rates at week 4 were comparable between vector (6/27 patients, 22%) and mRNA (9/28, 32%) vaccines (p=0.6). Overall, 27% of patients seroconverted; specific T cell responses were observed in 20/20 (100%) vector versus 13/16 (81%) mRNA vaccinated patients. Newly induced humoral and/or cellular responses occurred in 9/11 (82%) patients. 3/37 (8%) of patients without and 12/18 (67%) of the patients with detectable peripheral B cells seroconverted. No serious adverse events, related to immunisation, were observed.
This enhanced humoral and/or cellular immune response supports an additional booster vaccination in non-seroconverted patients irrespective of a heterologous or homologous vaccination regimen.
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