European Classification Research Articles

Phase II Trial of Venetoclax (Ven) in Combination with Azacitidine (AZA) As Maintenance Therapy for High-Risk Acute Leukemia Following Allogeneic Stem Cell Transplantation (SCT)

Introduction: Allogeneic SCT remains the only potentially curative therapy for acute leukemia patients but with inferior outcomes for high-risk patients. Prior data on maintenance therapies, including AZA, have yielded conflicting results on its efficacy to improve outcomes. Considering the clinical efficacy of VEN in acute myeloid and lymphoid leukemia (AML/ALL) with its known tolerability when used with AZA, we thought VEN and AZA might be an attractive maintenance strategy to improve outcomes after SCT. Methods: This is a single center, open label, Phase II clinical trial to assess the safety and efficacy of VEN with AZA as maintenance therapy after SCT. Inclusion criteria was 1) high risk AML or B cell and T cell ALL or mixed phenotype leukemia, 2) absolute neutrophil count >/= 1.0 x 109/L and platelet >/= 30 x 109/L without any support, 3) absence of active graft versus host disease (GvHD) and infection, 4) absence of minimal residual disease at enrollment. Treatment consisted of up to 12 cycles of VEN 100 mg on Days 1-7 with AZA 32 mg/m 2/day IV/SC on Days 1-5 every 28 days. VEN dosing was adjusted for patients on concomitant CYP3A inhibitors or those with severe cytopenias. After the first 11 patients enrolled, due to myelosuppression observed, VEN dose was changed to 50 mg on days 1-7 if patients were on posaconazole. Treatment delays, up to 70 days, were allowed by toxicity. The primary objectives are relapse-free survival (RFS) after initiation of VEN and AZA and the safety and tolerability of the combination. The study has been ongoing. Results: The study enrolled a total of 30 patients (27 AML, 3 ALL). Demographics across all AML patients included mean age 52 years (range: 40-74), 67% males, 15% second SCT, 48% in first complete remission (CR1) at SCT, 41% adverse risk by European Leukemia Net classification. The majority (63%) received a myeloablative intensity conditioning regimen using intravenous busulfan. The three ALL patients were younger with mean age of 35 and all were in CR1 at SCT. The median time to start the maintenance treatment was 70.5 days (range, 42-103). As of the data cutoff date of 13 July 2022, patients completed a median of 4 cycles (range, 1-12) of study treatment with 9 patients (30%) remaining on study treatment. The primary reasons for study treatment discontinuation among 21 patients were complications like myelosuppresssion, infections and GvHD in 11, relapse in 6 and completion of 12 cycles of treatment in 4. The median follow-up time was 8.67 months (95% CI, 7.23 to 13.6).The median RFS and OS were not reached. The estimates of RFS and OS at 1-year were 69.2% (95% CI, 52.1% to 91.8%) and 90.2% (95%CI, 78% to 100%), respectively, after the initiation of VEN and AZA maintenance (Figure 1&2). Assuming a Bayesian Poisson-Gamma Model with a Gamma (1,1) prior; the mean number of grade≥3 treatment related adverse events (AEs) per patient was estimated. The mean number of AEs were 1.87 (range, 0-8) for decreased white blood cell count; 1.68 (range, 0-7) for decreased absolute neutrophil count; 1.06 (range, 0-6) for decreased platelet count; 0.55 (range, 0-6) for anemia; 0.13 (range, 0-1) for pneumonia and 0.06 (range 0-1) for each event of febrile neutropenia, maculopapular rash, respiratory failure and secondary graft failure (GF). The secondary GF was observed in one patient after the 4th cycle of treatment leading to discontinuation of study treatment. No patient died to due to treatment related AEs. Due to frequent and prolonged myelosuppression observed, 9 patients (30%) required dose reduction of VEN; mostly right after the first cycle of treatment (6 of 9 patients). After the protocol amendment for VEN to be given as 50 mg on days 1-7 on posaconazole, the requirement for dose changes decreased though still some patients required lower doses of VEN (as 30 mg on days 1-5) on subsequent cycles. Conclusion: Post-SCT maintenance therapy with VEN/AZA was safe and tolerable with favorable results in patients with high-risk AML and ALL. The majority of reported AEs was related to myelosuppression which is a known complication of VEN. Many patients required dose modification of VEN and treatment delays between cycles, highlighting the importance of monitoring these patients very closely. On the other hand, the observed RFS and OS data were highly encouraging compared to the historical outcomes for this high-risk group of patients although longer follow-up is needed. The study has been ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostication of the 2016-Who AML with Myelodysplasia-Related Changes Subclass and Mutations in MDS-Related Genes Using the 2022 European Leukemianet Risk Classification: A Retrospective Study

Introduction The European LeukemiaNet (ELN) 2022 Recommendations adopted the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemia, which has recently revised the 2016 World Health Organization (WHO) classification of acute myeloid leukemia (AML). In the recent ICC classification, two new categories were added: AML with myelodysplasia (MDS)-related cytogenetic abnormalities category and AML with MDS-related gene mutations category, defined by mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2. The 2016 WHO AML with myelodysplasia-related changes (AML-MRC) subtype was no longer an AML category, given that dysplastic morphology, currently used as a criterion for AML-MRC, lacked independent prognostic significance. In this context, we aimed to explore the prognostic significance of AML-MRC subtype, adjusted for mutations in the MDS-related gene group (MDS-RG) and cytogenetic abnormalities. Moreover, we aimed to explore the prognostic significance of mutations in each of MDS-RG group individually. Methods We conducted a retrospective cohort study at the University of Maryland Greenebaum Comprehensive Cancer Center. All consecutive AML patients treated between 2013-2021 were included. OS was defined as the time from diagnosis to death and was compared between groups using the multivariable Cox proportional hazards (CPH) model and propensity score-adjusted analysis. Moreover, the OS was compared for AML patients categorized by mutational status for each gene of the MDS-RG group, using unadjusted and adjusted analysis. The following baseline characteristics were used to adjust outcomes: age, gender, ethnicity, comorbidities, performance status, 2016 WHO AML type, 2022 ELN cytogenetic abnormalities risk groups, genetic mutations, and treatments administered. Results Out of 488 AML patients, 222 had myeloid mutation panels at diagnosis and were included in the study. The median age was 64.7 years [IQR 55.7-74.3] and 57% were males. Median follow-up for the whole population was 34.5 months and median OS was 11.9 months (95% CI 9.7-16.8). Frequency of MDS-RG mutations in the whole cohort included: RUNX1: N=42; SRSF2: N=39; ASXL1: N=37; BCOR: N=20; U2AF1: N=15; SF3B1: N=13; STAG2: N=12; EZH2: N=7; and ZRSR2: N=3 patients. When categorizing AML patients by the mutational status of each of the MDS-RGs individually (e.g., ASXL1 mutated AML vs. ASXL1 wild-type AML), patients with mutated genotype were older (~5-10 years), less frequently had de novo AML, and were less frequently treated with intensive chemotherapy. AML patients with mutations in any of MDS-RG group were diagnosed with the 2016 WHO AML-MRC subtype at frequencies ranging from 30 to 60% (e.g., 43% of ASXL1 mutated AML had AML-MRC vs. 20% of ASXL1 wild-type AML had AML-MCR). In the multivariable CPH model (Table 1), AML-MRC was an independent predictor of worse OS (HR: 1.5, 95% CI: 1.1-2.2, P=0.01) after adjustment to covariates, including 2022 ELN cytogenetic abnormality groups and mutations in the MDS-RG group. Only mutated TP53, SRSF2, and ZRSR2 were associated with worse OS (P<0.05). On unadjusted analysis, all patients with mutations in MDS-RGs had a qualitatively lower median OS than patients with wild-type genes, except EZH2, SF3B1and STAG2. Using PS modeling, SRSF2 and EZH2 mutations lower median OS but were not statistically significant. SF3B1 mutation was associated with improved OS (P<0.05). Figure 1 demonstrates adjusted survival curves of AML patients with mutations in any of MDS-RG group treated with anthracycline-based induction or hypomethylating agents +/- venetoclax. Conclusion The 2016 WHO AML-MRC subclass remained an independent predictor of worse OS, after adjustment for cytogenetic abnormalities and mutations in the MDS-RG group. We found that mutated TP53 predicted worse OS, and mutated SF3B1 predicted improved OS. Further multi-institutional studies are needed to examine the prognostic significance of AML-MRC and mutations in the MDS-RG group. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Personalized Prediction Model to Risk Stratify Patients with Therapy-Related Myeloid Neoplasms

Background: Therapy-related myeloid neoplasm (t-MN) is a clinicopathological entity that includes therapy-related myelodysplastic syndrome (t-MDS), therapy-related myelodysplastic syndrome/myeloproliferative neoplasm (t-MDS/MPN), and therapy-related acute myeloid leukemia (t-AML). Given that t-MN encompasses multiple phenotypes, an all-inclusive risk model for t-MN has not been proposed. Moreover, widely used risk stratification tools are limited to a single phenotype. For example, International prognostic scoring system (IPSS), revised-IPSS (IPSS-R) and World Health Organization based prognostic score (WPSS) for MDS and European LeukemiaNet classification for AML). Moreover, prognostic models such as IPSS, IPSS-R and WPSS did not include t-MN counterparts. Our aim was to develop and validate a risk stratification model that uses routinely clinical and cytogenetic factors available at t-MN diagnosis. Methods: We retrospectively analyzed clinicopathological features and outcomes of 653 WHO-defined t-MN patients treated at Mayo Clinic, Rochester (US cohort, n=342) or South Australia MDS Registry (AU cohort; n=311) who had cytogenetics performed at t-MN diagnosis. Karyotypes were classified using the International System for Cytogenetic Nomenclature Criteria. Number of cytogenetic aberrancies were counted (Hasse et al, Leukemia 2019). A random forest survival algorithm was used to build prognostic model in the training cohort (US cohort). The model algorithm randomly bootstraps the original data into two thirds, where the model is developed, and one third, where the model is internally validated. The process is repeated multiple times to assure reproducibility of the final result. The model was subsequently validated in an independent AU cohort. The risk score optimal cut-off was determined using the maximally selected rank statistics. All the statistical analysis was performed using R statistical software. Results: In the US cohort, the most common cytogenetic abnormalities were complex karyotype (CK, 49%), monosomal karyotype (MK, 46%), deletion 7q (del 7q, 36.5%) and deletion 5q (del 5q, 26.5%). The frequency of the most common cytogenetic abnormalities was different in the AU cohort: CK (26.8%), MK (26.2%), del 7q (25.2%) and del 5q (16.0%). Despite the difference, the median overall survival (OS) was not different between the US and AU cohorts (15 vs. 12 months, P =0.81). The US cohort was used to build the prognostic model and included 56 variables (15 clinical and 41 cytogenetic). Variables importance analysis shows the top variables from the most important to the least important that affect OS in the new model (Fig. 1). The variables with the highest impact on OS included the number of chromosomal abnormalities followed by blood counts, CK, and primary cancer type. In contrast, traditionally recognized high-risk features such as bone marrow blast percentage, chromosome 5 and/or 7 abnormalities had modest impact on OS in our model. We next divided the training cohort into high- and low-risk groups based on the risk score derived from the model. In the US cohort, 208 (61%) and 134 (39%) patients were classified as high- and low-risk, respectively with a statistically significant difference in OS (8.42 vs. 40.03 months; P <0.001). The model was validated in the AU cohort. In the AU cohort, there were 174 (56%) patients with high risk and 137 (44%) patients with low risk. The model was very well-calibrated in the validation cohort, with significant median survival difference between the high-risk and low-risk group (8.2 vs. 26.7 months; P <0.001, Fig. 2). The concordance index of the model was 0.64 and 0.69 in the training model and the validation cohorts, respectively. Conclusion: We developed and validated a prognostic model for all t-MN subtypes that incorporates routinely available information and is applicable to the day-to-day practice. We also identified novel factors including chromosomal abnormality number, CBC parameters, and the type of primary disease as those with the highest impact on survival. It is hoped that the incorporation of widely available and standardized testing that accurately identifies patients with extremely poor survival, will help prompt decision making-minimizing toxicities, including financial toxicities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Occupation as a measure of life course socioeconomic position and the risk of oral cancers in India.

Evidence suggests that different indicators of socioeconomic position (SEP) contribute to oral cancer risk. Occupational status, as a measure of SEP, may be able to capture aspects of social hierarchy in societies in which employment is highly correlated with other social structures such as caste systems. Often in such societies, the life course of an individual is also influenced by this hierarchy. However, the influence of life course occupational status on the risk of oral cancer is not well understood. This study aims to identify the life course model that is best supported by the data using life course SEP-as represented by occupation-on oral cancer risk in a population in the South of India. Data from the HeNCe Life study, Indian site were used. Incident oral cancer cases (N=350) were recruited from two major referral hospitals in Kozhikode, Kerala, South India, from 2008 to 2012. Controls (N=371), frequency-matched by age (5 years) and sex were recruited from the outpatient clinics at the same hospitals as the cases. Life grid-based structured interviews collected information on an array of exposures throughout the life course of the participant. Occupation was coded with the 1988 International Standard Classification of Occupations, transformed to the simplified European Socioeconomic Classification, and further dichotomized into advantageous and disadvantageous SEP at three different life periods (childhood, early adulthood and late adulthood). The analysis was conducted using the Bayesian relevant life course exposure model with a Dirichlet noninformative prior and a weakly informative Cauchy prior to the overall lifetime effect and confounders. Participants in disadvantaged SEP throughout their life had 3.6 times higher risk of oral cancer than those in advantaged SEP (OR=3.6; 95% CrI=1.6-7.2), after adjusting for potential confounders. While the crude and sex- and age-adjusted models showed a clear childhood sensitive period for this risk, the model further adjusted for behavioural factors could not distinguish the specific life course period best explained by data. Occupation status alone could provide a similar overarching risk estimate for oral cancer to those obtained from more complex measures of SEP.

Social class and age-earnings trajectories in 14 European countries

In this paper, we seek to contribute to ongoing discussions of the relationship between income and class in analyses of social inequality and mobility. We argue that while class has sometimes been taken as a proxy for long-term earnings levels, it is of greater importance, at least when treated in terms of the EGP schema or the European Socio-Economic Classification (ESEC), in capturing differences in age-earnings trajectories. Moving beyond previous single country studies, we examine how far the theory that underlies ESEC is reflected in men’s age-earnings trajectories across 14 European countries, while also taking into account any effects of their educational qualifications. Modelling data from the 2017 EU-SILC survey, and focussing on men’s full year/full-time equivalent gross annual earnings, we find that although the age-earnings trajectories that are estimated for different classes do reveal some cross-national variation, there are major features, of a theoretically expected kind, that are evident in our pooled sample and that regularly recur in individual countries. Class differences in earnings are at their narrowest for men in the youngest age group that we distinguish but then widen across older age groups. This occurs primarily because the earnings of men in the professional and managerial salariat, and especially in the higher salariat, show a marked rise with age, while the earnings of men in other classes rise far less sharply or remain flat. We also find evidence that these diverging trajectories are primarily shaped by individuals’ class positions independently of their level of educational qualification – however important the latter in determining the class positions that they hold. What can be regarded as the logic of different forms of employment relations lead to a large degree of cross-national commonality in the association that exists between class and earnings at different ages.

Survival prediction optimization of acute myeloid leukaemia based on T-cell function-related genes and plasma proteins.

Interactions between acute myeloid leukaemia (AML) cells and immune cells are postulated to corelate with outcomes of AML patients. However, data on T-cell function-related signature are not included in current AML survival prognosis models. We examined data of RNA matrices from 1611 persons with AML extracted from public databases arrayed in a training and three validation cohorts. We developed an eight-gene T-cell function-related signature using the random survival forest variable hunting algorithm. Accuracy of gene identification was tested in a real-world cohort by quantifying cognate plasma protein concentrations. The model had robust prognostic accuracy in the training and validation cohorts with five-year areas under receiver-operator characteristic curve (AUROC) of 0.67-0.76. The signature was divided into high- and low-risk scores using an optimum cut-off value. Five-year survival in the high-risk groups was 6%-23% compared with 42%-58% in the low-risk groups in all the cohorts (all p values &lt;0.001). In multivariable analyses, a high-risk score independently predicted briefer survival with hazard ratios of death in the range 1.28-2.59. Gene set enrichment analyses indicated significant enrichment for genes involved in immune suppression pathways in the high-risk groups. Accuracy of the gene signature was validated in a real-world cohort with 88 pretherapy plasma samples. In scRNA-seq analyses most genes in the signature were transcribed in leukaemia cells. Combining the gene expression signature with the 2017 European LeukemiaNet classification significantly increased survival prediction accuracy with a five-year AUROC of 0.82 compared with 0.76 (p &lt; 0.001). Our T-cell function-related risk score complements current AML prognosis models.

Influence of the dispersion characteristics for producing thermoregulating nano phase change slurries

Phase Change Dispersions (PCDs) of large colloidal stability were produced by sonication at an energy per liquid volume of ∼ 800 kJ/L, using gum arabic (GA) and sodium dodecyl sulfate (SDS) mixtures as dispersant agent and varying their mass ratios from 0 to 100 (GA/SDS). An important interplay between the PCD base properties and the final phase change slurry (PCS) characteristics was observed, finding that the PCD with the minimum breaking ratio, promotes the PCS with the largest colloidal stability. PCSs from GA/SDS mass ratios of 70/30 and 40/60 were homogeneous, whereas those ones from mass ratios 20/80 or 0/100 generated two phase products. The PCS prepared with a 40/60 of GA/SDS mass ratio was the unique slurry that satisfied the European classification as nanomaterial with a dn0.5 of 94.7 ± 15.0 nm. This homogenous nano-slurry (NPCS) had a solid concentration of 28.1 wt% and large latent heat (32.8 J g−1), exhibiting thermal reversibility, long-term colloidal stability (|ζ| =53.4 ± 1.8 mV freshly and |ζ| =55.86.3 ± 6.3 mV after two years) and Newtonian behavior with low viscosity (10.7 ± 0.3 mPa·s). Besides, observing the encapsulation efficiency, the best reaction was performed producing this nano-slurry with a particle yield of 72.3 % and a PCM content in the capsules close to 50 %.

Defining Long-Term-Care Need Levels for Older Adults: Towards a Standardized European Classification

ABSTRACT International comparisons of long-term care (LTC) are hampered by inconsistencies in how to define the need for care. This is especially relevant for the European Union, whose Aging Working Group, which is tasked to project aging expenditure in the long term, has over time used two competing definitions – one based on inability to perform Activities of Daily Living (ADL) and another based on the more subjective Global Activity Limitation Index (GALI). The inconsistency in measurement, as well as problems in defining the intensity of needs, will acquire growing significance as longevity progresses. This paper investigates how the two measures are linked, by analyzing a large European sample survey where respondents replied to both questions. This allows a calibration of the two measures and an investigation of their areas of overlap and difference. The paper concludes by proposing a simple new 4-scale measure of care needs which, by combining the two metrics, introduces some gradation of the intensity of care. Using a consistent measure incorporating intensity, such as the one proposed, will facilitate international comparisons, improve long-term expenditure projections, and aid policy discussion, including the transfer of best practice.

Update on dermatomyositis.

This review summarizes and comments on current knowledge in dermatomyositis. The 2018 European Neuromuscular Centre classification of dermatomyositis has been challenging by the discovery of clinicopathological features associated with dermatomyositis-specific antibody (DMSA) that were not incorporated in the original criteria. These features include but may not be limited to the presence of perifascicular necrosis in anti-Mi-2 dermatomyositis; presence of diffuse nonperifascicular sarcoplasmic myxovirus resistance protein A expression in anti-MDA5 dermatomyositis; and dermatomyositis sine dermatitis in anti-NXP-2 dermatomyositis. Variations and subclassifications within the same DMSA subtypes are observed: anti-MDA5 dermatomyositis is clinically subcategorized into good, intermediate, and poor prognostic subgroups; concurrent anti-CCAR1 and anti-TIF1-γ positivity identify anti-TIF1-γ-positive patient with a lower risk for cancer-associated myositis. Owing to distinct IFN1-signaling pathway activation in dermatomyositis, JAK-STAT inhibitor - the pathway-targeted therapy, have been studied with promising results in refractory dermatomyositis and some new-onset dermatomyositis. In addition, the potential serum biomarkers for IFN1 pathway activation are being investigated for their performance in monitoring the disease activity and the efficacy of the treatment. DMSA, evidence of prominent IFN1 pathway activation, and risk/severity-associated biomarkers would likely play major roles in future dermatomyositis classification, disease monitoring, and treatment decision.

Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia.

The molecular complexity of acute myeloid leukemia (AML) presents a considerable challenge to implementation of clinical genetic testing for accurate risk stratification. Identification of better biomarkers therefore remains a high priority to enable improving established stratification and guiding risk-adapted therapy decisions. We systematically integrated and analyzed the genome-wide CRISPR-Cas9 data from more than 1,000 in vitro and in vivo knockout screens to identify the AML-specific fitness genes. A prognostic fitness score was developed using the sparse regression analysis in a training cohort of 618 cases and validated in five publicly available independent cohorts (n = 1,570) and our RJAML cohort (n = 157) with matched RNA sequencing and targeted gene sequencing performed. A total of 280 genes were identified as AML fitness genes and a 16-gene AML fitness (AFG16) score was further generated and displayed highly prognostic power in more than 2,300 patients with AML. The AFG16 score was able to distill downstream consequences of several genetic abnormalities and can substantially improve the European LeukemiaNet classification. The multi-omics data from the RJAML cohort further demonstrated its clinical applicability. Patients with high AFG16 scores had significantly poor response to induction chemotherapy. Ex vivo drug screening indicated that patients with high AFG16 scores were more sensitive to the cell-cycle inhibitors flavopiridol and SNS-032, and exhibited strongly activated cell-cycle signaling. Our findings demonstrated the utility of the AFG16 score as a powerful tool for better risk stratification and selecting patients most likely to benefit from chemotherapy and alternative experimental therapies.

Molecular cytogenetics in acute myeloid leukemia in adult patients: practical implications.

Throughout the last 50 years, cytogenetic analyses of pretreatment bone marrow and / or blood samples from patients diagnosed with acute myeloid leukemia (AML) revealed a large number of recurring chromosome aberrations, both structural and numerical. Using standard banding methods and, more recently, molecular cytogenetic techniques, such as fluorescence in situ hybridization, spectral karyotyping, multiplex fluorescence in situ hybridization and comparative genomic hybridization, cytogenetic investigations detect acquired abnormalities that, together with submicroscopic gene mutations and changes in gene expression, strongly influence the clinical features and prognosis of patients with AML. Selected reciprocal translocations and inversions and their molecular counterparts, as well as a number of unbalanced chromosome abnormalities are used, together with bone marrow morphology, immunophenotype, and clinical characteristics, to define separate AML entities in the World Health Organization Classification of Haematolymphoid Tumours. Moreover, cytogenetic findings (and specific gene mutations) are being used in geneticrisk classifications, such as the 2022 European LeukemiaNet classification. Such classifications divide patients into broad prognostic categories: favorable, intermediate, and adverse, which are useful in the management of adults with AML. In this article, I review the present data on recurrent chromosome rearrangements in AML and on correlations between cytogenetic findings and clinical features and treatment outcomes of adult patients diagnosed with AML.

Evaluation of Rituximab for Induction and Maintenance Therapy in Patients 75 Years and Older With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Older patients are underrepresented in studies of rituximab for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Little is known about outcomes and adverse events associated with the use of rituximab therapy among patients 75 years and older with ANCA-associated vasculitis. To examine outcomes and adverse events associated with the use of rituximab therapy in patients 75 years and older with ANCA-associated vasculitis, specifically granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). This multicenter cohort study involved 93 patients 75 years and older with ANCA-associated vasculitis from 36 university and nonuniversity hospitals in France. Data were obtained from the French Vasculitis Study Group database between January 1, 2000, and July 1, 2018, and a call for observation sent to French Vasculitis Study Group members on June 6, 2019. Data analysis was performed from November 15 to December 31, 2021. Inclusion criteria included a diagnosis of GPA or MPA according to European Medicines Agency classification criteria and receipt of treatment with rituximab after age 75 years. Patients were excluded if they were missing relevant clinical or biological data. Data on race and ethnicity were not reported because inclusion of this information was not authorized by the ethics committee. At least 1 infusion of rituximab as induction or maintenance therapy. Occurrence of remission, relapse, drug discontinuation, death, and serious infections (including types of serious infections). Of 238 patients screened, 93 were included (median [IQR] age, 79.4 [76.7-83.1] years; 51 women [54.8%]); 52 patients (55.9%) had a diagnosis of GPA, and 41 (44.1%) had a diagnosis of MPA. Thirty patients (32.3%) received rituximab as induction therapy in combination with high-dose glucocorticoid regimens, 27 (29.0%) received rituximab as maintenance therapy, and 36 (38.7%) received rituximab as both induction and maintenance therapy. The median (IQR) follow-up was 2.3 (1.1-4.0) years. Among 66 patients who received rituximab as induction therapy, 57 (86.4%) achieved remission, and 2 (3.0%) experienced relapses. The incidence of serious infection was significantly higher when rituximab was used as induction therapy vs maintenance therapy (46.6 [95% CI, 24.8-79.7] per 100 patient-years vs 8.4 [95% CI, 3.8-15.9] per 100 patient-years; P = .004). Most infections (12 of 22 [54.5%]) were gram-negative bacterial infections. The incidence of death was 19.7 (95% CI, 7.2-42.9) per 100 patient-years among those who received rituximab as induction therapy and 5.3 (95% CI, 1.9-11.6) per 100 patient-years among those who received rituximab as maintenance therapy. In this cohort study, rituximab therapy was associated with achievement and maintenance of remission in most patients 75 years and older with ANCA-associated vasculitis. The incidence of serious infections and death was high when rituximab was used as induction therapy in combination with high-dose glucocorticoid regimens but not when rituximab was used as maintenance therapy. Efforts might focus on reducing serious infections during the first months of therapy.

Trazodone: applications of the third-generation antidepressant

In the European classifications of antidepressants (AD), the drug is called an antagonist of type 2 serotonin receptors and at the same time a serotonin reuptake inhibitor. In Russian classifications, trazodone is usually referred to as «specific serotonergic antidepressant» or «atypical antidepressant». Trazodone is the only representative in its class. Despite the fact that it was registered in Europe in the 70s, in terms of its receptor properties, good tolerability and safety profile, it belongs to the third generation of ADs and in some respects can be considered more modern than selective serotonin reuptake inhibitors (SSRIs). In terms of overall efficacy, it is comparable to other ADs, but due to the peculiarities of the mechanism of action, it is often effective in cases of depressive and anxiety disorders resistant to other ADs.

Listening to difference: J.G. Herder’s aural theory of cultural diversity in the ‘Treatise on the Origin of Language’ (1772)

ABSTRACT In this article, I develop the concept and practice of ‘listening to difference,’ examining J.G. Herder’s aural theory of cultural diversity as primarily worked out in the ‘Treatise on the Origin of Language’ (1772). I examine the sources Herder critiqued to outline his aural theory of linguistic and cultural difference, which have thus far only been summarily mentioned if at all in scholarship despite the prominence of the ‘Treatise’ in intellectual history and philosophy. These sources comprise the travelogues of seventeenth- and early eighteenth-century French scientists, mathematicians, diplomats, and Jesuit missionaries who described the inadequacy of Romanized orthography to accurately transcribe the sounds and pronunciations of the indigenous peoples they encountered throughout the Americas, Thailand, and China. Herder’s critical readings of travelogues showcased the unintended failures and interruptions in European colonial practices of listening. I argue that it was the French travellers’ failure to erase difference, to transform it into identity or, in other words, into a universalist monolingualism, which produced a consciousness of cultural and linguistic difference, even if repressed. The sounds of the spoken indigenous languages exposed the limits of the paradigms of Catholic and European linguistic classification. Instead, the exemplary technologies for preserving difference in scriptural and listening practices were for Herder the Hebrew alphabet and the oral transmission of poetry in ancient and Indigenous cultures. Listening to difference, as I define it, involves an openness to listening to the voices and sounds of the othered by listeners who recognize their distinct situated, embodied positionalities. It offers alternate possibilities to conceive of human diversity as continually in formation and not as a static or progressive hierarchy.

The reception of European typological language classification among the Turkish language reformers of 1932-1936

The fact that the Turkish language was classified as an agglutinative language bythe traditional European linguistics was accepted, but also challenged by the Turkish language reformers of the 1930s. The underlying reason was that most classifications of the language families were influenced by harsh judgments about the cultural and intellectual level of its speakers as well as on the capability of those languages. Interestingly, the Turks did not question this kind of prejudices towards non-Indo-European languages and their speakers, but they tried to solve this “problem” at alinguistical-theoretical level. There were diverse attempts to deal with this issue, especially between 1932 and 1936.

Pattern of Antibiotic Consumption in Two Italian Production Chains Differing by the Endemic Status for Porcine Reproductive and Respiratory Syndrome.

The aim of this case study was to quantify antibiotic (AB) use in Italian weaning (W) and fattening (F) units differentiated for porcine reproductive and respiratory syndrome (PRRS) occurrence. Farms were classified as either PRRS negative (–) or PRRS positive (+) based on the circulation of the virus among the animals. In all the farms, the modified live PRRS virus (PRRSV) vaccine was provided to all the animals. In the PRRS– farms, the level of circulating antibodies was low, and the disease, in its clinical form, did not occur. In the PRRS+ farms, the level of circulating antibodies against the virus was high, and the disease was recurrent. Data regarding AB consumption were collected from 2017 to 2020, and the active compounds (ACs) were expressed as milligrams of AC/total kilogram of body weight (BW) produced. Each AC was classified into one of four categories according to the European Medicines Agency classification of ABs for prudent and responsible use in animals: Avoid, Restrict, Caution, and Prudence. Data regarding the ACs in each category were analyzed using a linear model that included production phase, PRRS status, and their interaction as factors. Performance parameters, average age of the pigs at the end of each phase, daily live weight gain, feed-to-gain ratio, total losses, cost index, and medication costs were significantly influenced by the PRRS chain. The use of class B ABs was not affected by production phase or PRRS status. Conversely, for class C ABs, interaction between the two factors (p = 0.02) was observed; W/PRRS+ and F/PRRS+ showed the greatest AB use for this class (p = 0.003). For class D ABs, the interaction was significant (p = 0.01); class C and D ABs were used more in the weaning (p = 0.07) than in the fattening phase (p = 0.003). For the weaning phase, the use of class C and D ABs was greater in the PRRS+ than in the PRRS– chain (p < 0.01). In conclusion, PRRS status affected the growth of pigs and economic performance. Moreover, PRRS status significantly influenced the use of ABs during all the growing periods with the greatest impact being on the weaning phase.

Experience of Forest Ecological Classification in Assessment of Vegetation Dynamics

Due to global climate change and increased forest transformation by humans, accounting for the dynamics of forest ecosystems is becoming a central problem in forestry. We reviewed the success of considering vegetation dynamics in the most influential ecological forest classifications in Russia, the European Union, and North America. Out of the variety of approaches to forest classification, only those that are widely used in forestry and forest inventory were selected. It was found that the system of diagnostic signs developed by genetic forest typology based on the time-stable characteristics of habitats as well as the developed concept of dynamic series of cenosis formation allows us to successfully take into account the dynamics of vegetation. While forest dynamics in European classifications is assessed at a theoretical level, it is also possible to assess forest dynamics in practice due to information obtained from EUNIS habitat classification. In ecological classifications in North America, the problem of vegetation dynamics is most fully solved with ecological site description (ESD), which includes potential vegetation and disturbance factors in the classification features. In habitat type classification (HTC) and biogeoclimatic ecosystem classification (BEC), vegetation dynamics is accounted based on testing the diagnostic species and other signs of potential vegetation for resistance to natural and anthropogenic disturbances. Understanding of vegetation–environment associations is fundamental in forming proper forest management methods and improving existing classification structures. We believe that this topic is relevant as part of the ongoing search for new solutions within all significant forest ecological classifications.

Internal Ring Defect Closure Technique in Laparoscopic Mesh Hernioplasty for Indirect Inguinal Hernia.

PurposeThe best way to reduce seroma formation after laparoscopic indirect hernia repair is debated. We noticed that internal ring defect closure in laparoscopic mesh hernioplasty could provide promising outcomes with an effect on diminishing seroma formation. We introduce our closure technique and report our experience.MethodsThis prospective study was conducted from May 2019 to May 2021. Patients with European Hernia Society classification L3 indirect or scrotal hernia were recruited and underwent laparoscopic transabdominal patch plasty (TAPP). Hernia defect closure was performed before mesh deployment. The primary outcomes were seroma formation, postoperative pain, and hernia recurrence. Perioperative data and postoperative complications were also recorded.ResultsConsecutive 77 patients with 89 indirect hernias (including 51 scrotal hernias) were recruited in two regional tertiary hospitals. All operations were successful without open conversion. The mean size of the hernia defect was 3.7 ± 0.5 cm (range, 2.5–5.0 cm). The mean operative time for each hernia repair (peritoneum to peritoneum) was 48.3 ± 10.8 min (range, 33–72 min), and the mean time required for internal ring closure was 6.7 ± 2.2 min (range, 4–10 min). Intraoperative bleeding was minimal. The mean visual analog scale pain score at rest on the first postoperative day was 2.2 (range, 1–4). The average postoperative length of hospital stay was 18 h (range, 14–46 h). During a mean follow-up period of 9.4 months (range, 3–23 months), no hernia recurrence or chronic pain were noted. Seroma formation was detected on six sides of unilateral hernias (6.7%) on postoperative day 7, with a mean volume of 45.8 ml (range, 24–80 ml). All seromas were mild and resolved spontaneously within 3 months, with no need for evacuation or other treatment and without major impact on the final outcome.ConclusionsDefect closure in laparoscopic mesh hernioplasty for large indirect hernias is safe and feasible and can significantly reduce postoperative seroma formation and relative complications. This approach is recommended in large indirect or scrotal hernia repair.

Traduire l’inégale distribution des revenus et des diplômes : Une évaluation de l’efficacité stratificationniste de la nomenclature des PCS, de l’ESeG et de la grille en classes d’emploi

Les nomenclatures professionnelles comptent parmi les principaux outils d’objectivation de la structure d’une société et sont parfois mobilisées pour appréhender les inégalités en son sein. L’enjeu de cet article est de proposer une série d’instruments visant à apprécier leur capacité à rendre compte de l’inégale distribution des ressources entre groupes sociaux. Pour cela, nous nous focalisons sur l’étude de trois nomenclatures : la PCS-2003 (Professions et Catégories Socioprofessionnelles) ainsi que la grille en classes d’emploi de l’INSEE, et la classification européenne ESeG. Après avoir rappelé leurs principes et objectifs, nous présentons les méthodes par lesquelles s’opère habituellement l’évaluation de la qualité des nomenclatures professionnelles et montrons qu’elles ne visent pas à saisir leur pouvoir d’objectivation de la stratification sociale. En nous basant sur les instruments traditionnels d’analyse des inégalités que sont les fractiles, nous proposons alors deux séries d’outils destinés à mesurer l’efficacité des classifications professionnelles à refléter la pente, la forme et l’ étendue des inégalités qui traversent une population. Munis de ces outils et des données de l’enquête Emploi 2017, nous montrons qu’au niveau agrégé des nomenclatures étudiées, c’est la grille en 4 classes d’emploi qui parvient le mieux à restituer l’inégale distribution des revenus et des diplômes entre groupes de populations tandis qu’au niveau détaillé, c’est plutôt la PCS. Nous terminons en avançant quelques propositions de recomposition de certaines catégories de la PCS et de la grille en classes d’emploi afin d’améliorer leur efficacité stratificationniste au niveau détaillé.

Predictors of parenchymal hemorrhage after endovascular treatment in acute ischemic stroke: data from ANGEL-ACT Registry

BackgroundParenchymal hemorrhage (PH) is a troublesome complication after endovascular treatment (EVT).ObjectiveTo investigate the incidence, independent predictors, and clinical impact of PH after EVT in patients with acute ischemic stroke (AIS)...