<i>TP53</i> hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy

Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5–8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 %) patients that were treated with combination chemotherapy +/− rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P < 0.0001. TP53 mutations were identified in 32/86 (37.2 %), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This study suggests that disruption of the p53-pathway by MUT-TP53in hotspot/direct DNA contact codons is predictive of outcome in CCT-treated PCNSL patients, and concomitant MUT-TP53 and MIR34A methylation are associated with poor PFS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-016-0307-6) contains supplementary material, which is available to authorized users

Effectiveness of accelerated perioperative care and rehabilitation intervention compared to current intervention after hip and knee arthroplasty. A before-after trial of 247 patients with a 3-month follow-up

<p>Abstract</p> <p>Background</p> <p>In Denmark, approximately 12,000 hip and knee arthroplasties were performed in 2006, and the hospital costs were close to US$ 110,000,000. In a randomized clinical trial, we have recently demonstrated the efficacy of accelerated perioperative care and rehabilitation intervention after hip and knee arthroplasty compared to current intervention under ideal circumstances. We do not, however, know whether these results could be reached under usual circumstances of healthcare practice. We therefore investigated whether length of stay after implementation of accelerated perioperative care and rehabilitation after hip and knee arthroplasty could be reduced in a normal healthcare setting, and how the achieved results matched those observed during the randomized clinical trial.</p> <p>Methods</p> <p>An effectiveness study as a before-after trial was undertaken in which all elective primary total hip and total knee arthroplasty patients were divided into a before-implementation group receiving the current perioperative procedure, and an after-implementation group receiving the new accelerated perioperative care and rehabilitation procedures as provided by a new multi-disciplinary organization. We used the Breakthrough Series Collaborative Model for implementation. The primary outcome measure was in hospital length of stay (LOS), and the secondary outcome measure was adverse effects within 3 months postoperatively.</p> <p>Results</p> <p>We included a total of 247 patients. Mean LOS was significantly (<it>P </it>< 0.001) reduced by 4.4 (95% CI 3.8–5.0) days after implementation of the accelerated intervention, from 8.8 (SD 3.0) days before implementation to 4.3 (SD 1.8) days after implementation. No significant differences in adverse effects were observed. LOS in this effectiveness study was significantly lower than LOS reported in the efficacy study.</p> <p>Conclusion</p> <p>Accelerated perioperative care and rehabilitation intervention after hip and knee arthroplasty was successfully and effectively implemented. Results obtained during usual hospital circumstances matched the results achieved under ideal circumstances in this group of patients.</p

Vaccines against toxoplasma gondii : challenges and opportunities

Development of vaccines against Toxoplasma gondii infection in humans is of high priority, given the high burden of disease in some areas of the world like South America, and the lack of effective drugs with few adverse effects. Rodent models have been used in research on vaccines against T. gondii over the past decades. However, regardless of the vaccine construct, the vaccines have not been able to induce protective immunity when the organism is challenged with T. gondii, either directly or via a vector. Only a few live, attenuated T. gondii strains used for immunization have been able to confer protective immunity, which is measured by a lack of tissue cysts after challenge. Furthermore, challenge with low virulence strains, especially strains with genotype II, will probably be insufficient to provide protection against the more virulent T. gondii strains, such as those with genotypes I or II, or those genotypes from South America not belonging to genotype I, II or III. Future studies should use animal models besides rodents, and challenges should be performed with at least one genotype II T. gondii and one of the more virulent genotypes. Endpoints like maternal-foetal transmission and prevention of eye disease are important in addition to the traditional endpoint of survival or reduction in numbers of brain cysts after challenge

Gender Differences and the Impact of Partnership and Children on Quality of Life During the COVID-19 Pandemic

Objectives: The COVID-19 pandemic and its protective measures have changed the daily lives of families and may have affected quality of life (QoL). The aim of this study was to analyze gender differences in QoL and to examine individuals living in different partnership and family constellations.Methods: Data from the Gutenberg COVID-19 cohort study (N = 10,250) with two measurement time points during the pandemic (2020 and 2021) were used. QoL was assessed using the EUROHIS-QOL questionnaire. Descriptive analyses and autoregressive regressions were performed.Results: Women reported lower QoL than men, and QoL was significantly lower at the second measurement time point in both men and women. Older age, male gender, no migration background, and higher socioeconomic status, as well as partnership and children (especially in men), were protective factors for QoL. Women living with children under 14 and single mothers reported significantly lower QoL.Conclusion: Partnership and family were protective factors for QoL. However, women with young children and single mothers are vulnerable groups for lower QoL. Support is especially needed for women with young children

Pig α₁-Acid Glycoprotein: Characterization and First Description in Any Species as a Negative Acute Phase Protein.

The serum protein α1-acid glycoprotein (AGP), also known as orosomucoid, is generally described as an archetypical positive acute phase protein. Here, porcine AGP was identified, purified and characterized from pooled pig serum. It was found to circulate as a single chain glycoprotein having an apparent molecular weight of 43 kDa by SDS-PAGE under reducing conditions, of which approximately 17 kDa were accounted for by N-bound oligosaccharides. Those data correspond well with the properties of the protein predicted from the single porcine AGP gene (ORM1, Q29014 (UniProt)), containing 5 putative glycosylation sites. A monoclonal antibody (MAb) was produced and shown to quantitatively and specifically react with all microheterogenous forms of pig AGP as analyzed by 2-D electrophoresis. This MAb was used to develop an immunoassay (ELISA) for quantification of AGP in pig serum samples. The adult serum concentrations of pig AGP were in the range of 1-3 mg/ml in a number of conventional pig breeds while it was lower in Göttingen and Ossabaw minipigs (in the 0.3 to 0.6 mg/ml range) and higher in young (2-5 days old) conventional pigs (mean: 6.6 mg/ml). Surprisingly, pig AGP was found to behave as a negative acute phase protein during a range of experimental infections and aseptic inflammation with significant decreases in serum concentration and in hepatic ORM1 expression during the acute phase response. To our knowledge this is the first description in any species of AGP being a negative acute phase protein

Toxicity Associated with Stavudine Dose Reduction from 40 to 30 mg in First-Line Antiretroviral Therapy

To compare the incidence and timing of toxicity associated with the use of a reduced dose of stavudine from 40 to 30 mg in first-line antiretroviral therapy (ART) for HIV treatment and to investigate associated risk factors