Simplified modeling of EM field coupling to complex cable bundles

In this contribution, the procedure "Equivalent Cable Bundle Method" is used for the simplification of large cable bundles, and it is extended to the application on differential signal lines. The main focus is on the reduction of twisted-pair cables. Furthermore, the process presented here allows to take into account cables with wires that are situated quite close to each other. The procedure is based on a new approach to calculate the geometry of the simplified cable and uses the fact that the line parameters do not uniquely correspond to a certain geometry. For this reason, an optimization algorithm is applied

Multiple imputation for cause-specific Cox models: assessing methods for estimation and prediction

In studies analyzing competing time-to-event outcomes, interest often lies in both estimating the effects of baseline covariates on the cause-specific hazards and predicting cumulative incidence functions. When missing values occur in these baseline covariates, they may be discarded as part of a complete-case analysis or multiply imputed. In the latter case, the imputations may be performed either compatibly with a substantive model pre-specified as a cause-specific Cox model [substantive model compatible fully conditional specification (SMC-FCS)], or approximately so [multivariate imputation by chained equations (MICE)]. In a large simulation study, we assessed the performance of these three different methods in terms of estimating cause-specific regression coefficients and predicting cumulative incidence functions. Concerning regression coefficients, results provide further support for use of SMC-FCS over MICE, particularly when covariate effects are large and the baseline hazards of the competing events are substantially different. Complete-case analysis also shows adequate performance in settings where missingness is not outcome dependent. With regard to cumulative incidence prediction, SMC-FCS and MICE are performed more similarly, as also evidenced in the illustrative analysis of competing outcomes following a hematopoietic stem cell transplantation. The findings are discussed alongside recommendations for practising statisticians.Development and application of statistical models for medical scientific researc

Conditional embryonic lethality to improve the sterile insect technique in Ceratitis capitata (Diptera: Tephritidae)

<p>Abstract</p> <p>Background</p> <p>The sterile insect technique (SIT) is an environment-friendly method used in area-wide pest management of the Mediterranean fruit fly <it>Ceratitis capitata </it>(Wiedemann; Diptera: Tephritidae). Ionizing radiation used to generate reproductive sterility in the mass-reared populations before release leads to reduction of competitiveness.</p> <p>Results</p> <p>Here, we present a first alternative reproductive sterility system for medfly based on transgenic embryonic lethality. This system is dependent on newly isolated medfly promoter/enhancer elements of cellularization-specifically-expressed genes. These elements act differently in expression strength and their ability to drive lethal effector gene activation. Moreover, position effects strongly influence the efficiency of the system. Out of 60 combinations of driver and effector construct integrations, several lines resulted in larval and pupal lethality with one line showing complete embryonic lethality. This line was highly competitive to wildtype medfly in laboratory and field cage tests.</p> <p>Conclusion</p> <p>The high competitiveness of the transgenic lines and the achieved 100% embryonic lethality causing reproductive sterility without the need of irradiation can improve the efficacy of operational medfly SIT programs.</p

Specific Class I HLA Supertypes but Not HLA Zygosity or Expression Are Associated with Outcomes following HLA-Matched Allogeneic Hematopoietic Cell Transplant: HLA Supertypes Impact Allogeneic HCT Outcomes

Maximizing the probability of antigen presentation to T cells through diversity in HLAs can enhance immune responsiveness and translate into improved clinical outcomes, as evidenced by the association of heterozygosity and supertypes at HLA class I loci with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors. We investigated the impact of HLA heterozygosity, supertypes, and surface expression on outcomes in adult and pediatric patients with acute myeloid leukemia (AML), myelodysplastic syndrome, acute lymphoblastic leukemia, and non-Hodgkin lymphoma who underwent 8/8 HLA-matched, T cell replete, unrelated, allogeneic hematopoietic cell transplant (HCT) from 2000 to 2015 using patient data reported to the Center for International Blood and Marrow Transplant Research. HLA class I heterozygosity and HLA expression were not associated with overall survival, relapse, transplant-related mortality (TRM), disease-free survival (DFS), and acute graft-versus-host disease following HCT. The HLA-B62 supertype was associated with decreased TRM in the entire patient cohort (hazard ratio [HR], 0.79; 95% CI, 0.69 to 0.90; P = .00053). The HLA-B27 supertype was associated with worse DFS in patients with AML (HR = 1.21; 95% CI, 1.10 to 1.32; P = .00005). These findings suggest that the survival benefit of HLA heterozygosity seen in solid tumor patients receiving immune checkpoint inhibitors does not extend to patients undergoing allogeneic HCT. Certain HLA supertypes, however, are associated with TRM and DFS, suggesting that similarities in peptide presentation between supertype members play a role in these outcomes. Beyond implications for prognosis following HCT, these findings support the further investigation of these HLA supertypes and the specific immune peptides important for transplant outcomes

EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL)

Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.Peer reviewe

Allele-Level KIR Genotyping of More Than a Million Samples: Workflow, Algorithm, and Observations

The killer-cell immunoglobulin-like receptor (KIR) genes regulate natural killer cell activity, influencing predisposition to immune mediated disease, and affecting hematopoietic stem cell transplantation (HSCT) outcome. Owing to the complexity of the KIR locus, with extensive gene copy number variation (CNV) and allelic diversity, high-resolution characterization of KIR has so far been applied only to relatively small cohorts. Here, we present a comprehensive high-throughput KIR genotyping approach based on next generation sequencing. Through PCR amplification of specific exons, our approach delivers both copy numbers of the individual genes and allelic information for every KIR gene. Ten-fold replicate analysis of a set of 190 samples revealed a precision of 99.9%. Genotyping of an independent set of 360 samples resulted in an accuracy of more than 99% taking into account consistent copy number prediction. We applied the workflow to genotype 1.8 million stem cell donor registry samples. We report on the observed KIR allele diversity and relative abundance of alleles based on a subset of more than 300,000 samples. Furthermore, we identified more than 2,000 previously unreported KIR variants repeatedly in independent samples, underscoring the large diversity of the KIR region that awaits discovery. This cost-efficient high-resolution KIR genotyping approach is now applied to samples of volunteers registering as potential donors for HSCT. This will facilitate the utilization of KIR as additional selection criterion to improve unrelated donor stem cell transplantation outcome. In addition, the approach may serve studies requiring high-resolution KIR genotyping, like population genetics and disease association studies

Breast cancer mortality of older patients with and without recurrence analysed by novel multi-state models

Introduction: In older patients with breast cancer, the risk of dying from other causes than breast cancer strongly increases after the age of 70. The aim of this study was to assess contributions of breast cancer mortality versus other-cause mortality after locoregio-nal or distant recurrence in a population-based cohort of older patients analysed by multi-state models. Methods: Surgically treated patients >70 years diagnosed with stage I-III breast cancer in 2003-2009 were selected from the Netherlands Cancer Registry. A novel multi-state model with locoregional and distant recurrence that incorporates relative survival was fitted. Other-cause and breast cancer mortality were indicated as population and excess mortality. Results: Overall, 18,419 patients were included. Ten-year cumulative incidences of locoregio-nal and distant recurrence were 2.8% (95%CI 2.6-3.1%) and 12.5% (95%CI 11.9-13.1%). Other-cause mortality increased from 23.9% (95%CI 23.7-24.2%) in patients 70-74 years to 73.8% (95%CI 72.2-75.4%) in those >80 years. Ten-year probabilities of locoregional or distant recurrence with subsequent breast cancer death were 0.4-1.3% and 10.2-14.6%, respectively. For patients with a distant recurrence in the first two years after diagnosis, breast cancer death probabilities were 95.3% (95%CI 94.2-96.4%), 93.1% (95%CI 91.6-94.6%), and 88.6% (95%CI 86.5-90.8%) in patients 70-74, 75-79, and >80 years. Conclusion: In older patients without recurrence, prognosis is driven by other-cause mortality. Although locoregional recurrence is a predictor for worse outcome, given its low incidence it contributes little to breast cancer mortality after diagnosis. For patients who develop a distant recurrence, breast cancer remains the dominant cause of death, even at old age.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Experimentele farmacotherapi

Allogeneic hematopoietic cell transplantation for patients with TP53 mutant or deleted chronic lymphocytic leukemia: results of a prospective observational study

Development and application of statistical models for medical scientific researc

De Novo assembly and transcriptome analysis of the mediterranean fruit fly ceratitis capitata early embryos

The agricultural pest Ceratitis capitata, also known as the Mediterranean fruit fly or Medfly, belongs to the Tephritidae family, which includes a large number of other damaging pest species. The Medfly has been the first non-drosophilid fly species which has been genetically transformed paving the way for designing geneticbased pest control strategies. Furthermore, it is an experimentally tractable model, in which transient and transgene-mediated RNAi have been successfully used. We applied Illumina sequencing to total RNA preparations of 8-10 hours old embryos of C. capitata, This developmental window corresponds to the blastoderm cellularization stage. In summary, we assembled 42,614 transcripts which cluster in 26,319 unique transcripts of which 11,045 correspond to protein coding genes; we identified several hundreds of long ncRNAs; we found an enrichment of transcripts encoding RNA binding proteins among the highly expressed transcripts, such as CcTRA-2, known to be necessary to establish and, most likely, to maintain female sex of C. capitata. Our study is the first de novo assembly performed for Ceratitis capitata based on Illumina NGS technology during embryogenesis and it adds novel data to the previously published C. capitata EST databases. We expect that it will be useful for a variety of applications such as gene cloning and phylogenetic analyses, as well as to advance genetic research and biotechnological applications in the Medfly and other related Tephritidae

Idelalisib treatment prior to allogeneic stem cell transplantation for patients with chronic lymphocytic leukemia: a report from the EBMT chronic malignancies working party

No studies have been reported so far on bridging treatment with idelalisib for patients with chronic lymphocytic leukemia (CLL) prior to allogeneic hematopoietic cell transplantation (alloHCT). To study potential carry-over effects of idelalisib and to assess the impact of pathway-inhibitor (PI) failure we performed a retrospective EBMT registry-based study. Patients with CLL who had a history of idelalisib treatment and received a first alloHCT between 2015 and 2017 were eligible. Data on 72 patients (median age 58 years) were analyzed. Forty percent of patients hadTP53(mut/del)CLL and 64% had failed on at least one PI. No primary graft failure occurred. Cumulative incidences of acute GVHD degrees II-IV and chronic GVHD were 51% and 39%, respectively. Estimates for 2-year overall survival (OS), progression-free survival (PFS), and cumulative incidences of relapse/progression (CIR) and non-relapse mortality NRM were 59%, 44%, 25%, and 31%. In univariate analysis, drug sensitivity was a strong risk factor. For patients who had failed neither PI treatment nor chemoimmunotherapy (CIT) the corresponding 2-year estimates were 73%, 65%, 15%, and 20%, respectively. In conclusion, idelalisib may be considered as an option for bridging therapy prior to alloHCT. Owing to the high risk for acute GVHD intensified clinical monitoring is warranted.Development and application of statistical models for medical scientific researc