Fast recognition of alternating groups of unknown degree

We present a constructive recognition algorithm to decide whether a given black-box group is isomorphic to an alternating or a symmetric group without prior knowledge of the degree. This eliminates the major gap in known algorithms, as they require the degree as additional input. Our methods are probabilistic and rely on results about proportions of elements with certain properties in alternating and symmetric groups. These results are of independent interest; for instance, we establish a lower bound for the proportion of involutions with small support.Comment: 31 pages, submitted to Journal of Algebr

Perturbations of mesenchymal stromal cells after allogeneic hematopoietic cell transplantation predispose for bone marrow graft- versus-host-disease

Functional impairment of the bone marrow (BM) niche has been suggested as a major reason for prolonged cytopenia and secondary graft failure after allogeneic hematopoietic cell transplantation (alloHCT). Because mesenchymal stromal cells (MSCs) serve as multipotent progenitors for several niche components in the BM, they might play a key role in this process. We used collagenase digested trephine biopsies to directly quantify MSCs in 73 patients before (n = 18) and/or after alloHCT (n = 65). For the first time, we demonstrate that acute graft-versus-host disease (aGvHD, n = 39) is associated with a significant decrease in MSC numbers. MSC reduction can be observed even before the clinical onset of aGvHD (n = 10). Assessing MSCs instantly after biopsy collection revealed phenotypic and functional differences depending on the occurrence of aGvHD. These differences vanished during ex vivo expansion. The MSC endotypes observed revealed an enhanced population of donor-derived classical dendritic cells type 1 and alloreactive T cells as the causing agent for compartmental inflammation and MSC damage before clinical onset of aGvHD was ascertained. In conclusion, MSCs endotypes may constitute a predisposing conductor of alloreactivity after alloHCT preceding the clinical diagnosis of aGvHD

Health related Quality of Life over time in German sarcoma patients. An analysis of associated factors - results of the PROSa study

Introduction Sarcomas are rare cancers and very heterogeneous in their location, histological subtype, and treatment. Health-Related Quality of Life (HRQoL) of sarcoma patients has rarely been investigated in longitudinal studies. Methods Here, we assessed adult sarcoma patients and survivors between September 2017 and February 2020, and followed-up for one year in 39 study centers in Germany. Follow-up time points were 6 (t1) and 12 months (t2) after inclusion. We used a standardized, validated questionnaire (the European Organisation for Research and Treatment of Cancer Quality of Life Core Instrument (EORTC QLQ-C30) and explored predictors of HRQoL in two populations (all patients (Analysis 1), patients in ongoing complete remission (Analysis 2)) using generalized linear mixed models. Results In total we included up to 1111 patients at baseline (915 at t1, and 847 at t2), thereof 387 participants were in complete remission at baseline (334 at t1, and 200 at t2). When analyzing all patients, HRQoL differed with regard to tumor locations: patients with sarcoma in lower extremities reported lower HRQoL values than patients with sarcomas in the upper extremities. Treatment which included radiotherapy and/or systemic therapy was associated with lower HRQoL. For patients in complete remission, smoking was associated with worse HRQoL-outcomes. In both analyses, bone sarcomas were associated with the worst HRQoL values. Being female, in the age group 55-&lt;65 years, having lower socioeconomic status, and comorbidities were all associated with a lower HRQoL, in both analyses. Discussion HRQoL increased partially over time since treatment and with sporting activities. HRQoL improved with time since treatment, although not in all domains, and was associated with lifestyle and socioeconomic factors. Bone sarcomas were the most affected subgroup. Methods to preserve and improve HRQoL should be developed for sarcoma patients. </sec

Community-developed checklists for publishing images and image analysis

Images document scientific discoveries and are prevalent in modern biomedical research. Microscopy imaging in particular is currently undergoing rapid technological advancements. However for scientists wishing to publish the obtained images and image analyses results, there are to date no unified guidelines. Consequently, microscopy images and image data in publications may be unclear or difficult to interpret. Here we present community-developed checklists for preparing light microscopy images and image analysis for publications. These checklists offer authors, readers, and publishers key recommendations for image formatting and annotation, color selection, data availability, and for reporting image analysis workflows. The goal of our guidelines is to increase the clarity and reproducibility of image figures and thereby heighten the quality of microscopy data is in publications.Comment: 28 pages, 8 Figures, 3 Supplmentary Figures, Manuscript, Essential recommendations for publication of microscopy image dat

Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection

Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes (gag-pol-vif-vpr-tat-rev-vpu-env-nef) and replicated efficiently in primary human CD4+ T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12–20 mo, viruses exhibited concentrated mutations at 17–34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses

Predicting the Need for Biopsy to Detect Clinically Significant Prostate Cancer in Patients with a Magnetic Resonance Imaging-detected Prostate Imaging Reporting and Data System/Likert ≥3 Lesion: Development and Multinational External Validation of the Imperial Rapid Access to Prostate Imaging and Diagnosis Risk Score

BACKGROUND: Although multiparametric magnetic resonance imaging (MRI) has high sensitivity, its lower specificity leads to a high prevalence of false-positive lesions requiring biopsy. OBJECTIVE: To develop and externally validate a scoring system for MRI-detected Prostate Imaging Reporting and Data System (PIRADS)/Likert ≥3 lesions containing clinically significant prostate cancer (csPCa). DESIGN, SETTING, AND PARTICIPANTS: The multicentre Rapid Access to Prostate Imaging and Diagnosis (RAPID) pathway included 1189 patients referred to urology due to elevated age-specific prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE); April 27, 2017 to October 25, 2019. INTERVENTION: Visual-registration or image-fusion targeted and systematic transperineal biopsies for an MRI score of ≥4 or 3 + PSA density ≥0.12 ng/ml/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Fourteen variables were used in multivariable logistic regression for Gleason ≥3 + 4 (primary) and Gleason ≥4 + 3, and PROMIS definition 1 (any ≥4 + 3 or ≥6 mm any grade; secondary). Nomograms were created and a decision curve analysis (DCA) was performed. Models with varying complexity were externally validated in 2374 patients from six international cohorts. RESULTS AND LIMITATIONS: The five-item Imperial RAPID risk score used age, PSA density, prior negative biopsy, prostate volume, and highest MRI score (corrected c-index for Gleason ≥3 + 4 of 0.82 and 0.80-0.86 externally). Incorporating family history, DRE, and Black ethnicity within the eight-item Imperial RAPID risk score provided similar outcomes. The DCA showed similar superiority of all models, with net benefit differences increasing in higher threshold probabilities. At 20%, 30%, and 40% of predicted Gleason ≥3 + 4 prostate cancer, the RAPID risk score was able to reduce, respectively, 11%, 21%, and 31% of biopsies against 1.8%, 6.2%, and 14% of missed csPCa (or 9.6%, 17%, and 26% of foregone biopsies, respectively). CONCLUSIONS: The Imperial RAPID risk score provides a standardised tool for the prediction of csPCa in patients with an MRI-detected PIRADS/Likert ≥3 lesion and can support the decision for prostate biopsy. PATIENT SUMMARY: In this multinational study, we developed a scoring system incorporating clinical and magnetic resonance imaging characteristics to predict which patients have prostate cancer requiring treatment and which patients can safely forego an invasive prostate biopsy. This model was validated in several other countries

Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection

Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes (gag-pol-vif-vpr-tat-rev-vpu-env-nef) and replicated efficiently in primary human CD4+ T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12–20 mo, viruses exhibited concentrated mutations at 17–34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses