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Background:Epidemic intelligence (EI) ensures early detection, assessment, and communication of public health threats. Threat reporting defines priorities and mobilize resources for surveillance, prevention, and control. In Portugal, the Directorate-General of Health (DGS) is responsible for EI and publishes a weekly public health threat report (RONDA). Changes in threats in regular threat reports since COVID-19 have not been previously described. We analysed changes in non-COVID threat reporting in the weekly threat report. Methods:Using the DGS Emergency Operations Centre’s threat reporting database, we compared threats reported in RONDAs from 2016 to 2022 in three sequential periods: P1 before COVID-19 (January 2016–March 2020), P2 during acute COVID-19 restrictions (April 2020–February 2022), and P3 in post-acute COVID-19 phase (February 2022–September 2022). We described the monthly average frequency of reports on non-COVID-19 threats in those periods considering different disease groups, geographical focus, and information sources. We estimated expected non-COVID-19 reports on threats using a forecast model fitted to the time series until March 2020 and compared observed and expected values. Results:Non-COVID-19 threats had a decrease in the monthly average frequency of reporting in period 2 (x¯1: 4.7 vs. x¯: 2.3, p< 0.001) compared to period 1. Using the forecast methods, there were 114 fewer non-COVID threats than the 162 expected (−70%) in period 2. In period 3, there were 105 more threats than expected (+256%). The ECDC and the WHO were the most frequent sources of information followed by national Public Health sources. Conclusions:During COVID-19, there was a decrease in reports on non-COVID threats in Portugal. COVID-19 possibly affected global EI, by shifting attention and resources from other threats to the pandemic. However, the number of threats that warrant follow-up and communication is increasing. Further research is necessary to inform the EI research and development agenda, to ensure that all relevant threats are detected, accessed, and communicated according to evolving EI objectives and priorities while resources and preparedness are guaranteed.

Objectives.Several studies have shown that one of the most common causes of collision is driver fatigue since fatigue causes drowsiness while driving and this decreases the driver’s ability to maneuver the vehicle and increases the probability of their nodding off and falling asleep at the wheel. This may be due to a variety of personal reasons and specific factors connected to working conditions. In the present work we therefore intend to develop a predictive model for fatigue in professional drivers using the following indicators: age, gender, personality, burnout, characteristics and job content. Method.The participants were 516 professional drivers from different transport sectors, obtained through non-probabilistic sampling. SPSS version 25.0 was used for data analysis. Results.The predictive capacity of a number of variables that affect drivers by causing fatigue is determined. Fatigue can be predicted through certain variables, with the best predictor being exhaustion (48.8%). Conclusions.This research contributes to a greater knowledge of the factors that produce fatigue in professional drivers. It highlights the importance of designing interventions to reduce the incidence of fatigue, resulting in greater well-being for the driver and a lower incidence of collisions.

Professional drivers are considered prone to health risks. For this reason we have conducted a predictive study to analyze variables that may be predictors of stress in driving. Participating in this study were 372 drivers (93.4% men, 6.6% women) recruited through non-probabilistic sampling. The aim of the study is to develop a prediction model for job stress in professional drivers using the following indicators: personality, impulsiveness, hardy personality, job, age, seat comfort, seat suspension, lumbar support and driving hours. We found that the variables with predictive power over driving stress were: commitment over relaxed driving (ΔR2 = 0.101; β = 0.135), danger prevention (ΔR2 = 0.139; β = 0.342) and fatigue and anxiety (ΔR2 = 0.063; β = −0.227); control over alertness and vigilance (ΔR2 = 0.069; β = 0.278); agreeableness over sensation-seeking (ΔR2 = 0.047; β = −0.268). In conclusion, driver stress can be predicted by certain variables. This study contributes to better understanding of driver stress and promotes safety at the wheel, thus helping to prevent traffic accidents.

A fundamental goal in cancer research is to understand the mechanisms of cell transformation. This is key to developing more efficient cancer detection methods and therapeutic approaches. One milestone towards this objective is the identification of all the genes with mutations capable of driving tumours. Since the 1970s, the list of cancer genes has been growing steadily. Because cancer driver genes are under positive selection in tumorigenesis, their observed patterns of somatic mutations across tumours in a cohort deviate from those expected from neutral mutagenesis. These deviations, which constitute signals of positive selection, may be detected by carefully designed bioinformatics methods, which have become the state of the art in the identification of driver genes. A systematic approach combining several of these signals could lead to a compendium of mutational cancer genes. In this Review, we present the Integrative OncoGenomics(IntOGen) pipeline, an implementation of such an approach to obtain the compendium of mutational cancer drivers. Its application to somatic mutations of more than 28,000 tumours of 66 cancer types reveals 568 cancer genes and points towards their mechanisms of tumorigenesis. The application of this approach to the ever-growing datasets of somatic tumour mutations will support the continuous refinement of our knowledge of the genetic basis of cancer.

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion1,2. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.

Assessing crop diseases at an early stage allows farmers to apply chemicals at the most efficient moment to control the pest and focus on the plants with the highest risk of developing the disease. Moreover, the earlier the assessment the lower the consequences, such as yield reduction, which is crucial to feed the increasing world population. BBR is the first open-source software based on physical and phenological crop parameters that grant the early assessment of botrytis bunch rot disease, caused by Botrytis cinerea, in vineyards using UAV images. This software has been released to improve the current procedure for early botrytis bunch rot assessment, which consists of laborious and time-consuming field inspections. In addition, BBR is easily modifiable by users to implement the workflow in their fields. For future work, the software can be extended to other crops and/or other fungal diseases.

Camelina is an ancient oilseed known for its healthy oil composition and high crude protein content. Efforts have recently been made to reintroduced camelina in Europe and North America. This study aimed to propose an innovative strategy for valorising the camelina meal, a by-product obtained after oil extraction. Specifically, the investigation focused on the hydrolysis of protein directly applied to camelina meal studying two enzymes (Alcalase® and Protamex®) across three Camelina varieties (Calena, Vera and Sonny). Protein hydrolysates were successfully produced, with a maximum weight yield of 47%, and achieved values above 49 g/100 g in crude protein content and 58% in protein yield. The study revealed that Alcalase® and Protamex® produced similar protein molecular weight distribution but exhibited distinct technological properties. The emulsifying capacities of the protein hydrolysates were enhanced by Alcalase®, with the maximum emulsifying activity index reaching 36 m2/s. Conversely, Protamex® decreased the emulsifying capabilities of protein hydrolysates. To evaluate the applicability of the protein hydrolysates obtained, an oil-in-water emulsion was selected as a food application. The results suggested that camelina protein hydrolysates have the potential to serve as a new emulsifier ingredient. Furthermore, no significant differences were observed among the three camelina varieties in terms of protein yields or technological properties.

Evaluar el perfil farmacocinético del gadobutrol en comparación con el Gd-DTPA, en resonancia magnética de mama con contraste (RM-DC). El objetivo secundario es valorar la eficacia diagnóstica en la detección de lesiones adicionales tumorales en RM-DC, y el perfil de seguridad de ambos contrastes.

Valorar, mediante resonancia magnética (RM), las características morfocinéticas, farmacocinéticas y de difusión de las neoplasias de mama con fenotipo triple negativo y analizar si hay relación entre estos parámetros y el tiempo hasta la progresión.

We develop a quantum learning scheme for binary discrimination of coherent states of light. This is a problem of technological relevance for the reading of information stored in a digital memory. In our setting, a coherent light source is used to illuminate a memory cell and retrieve its encoded bit by determining the quantum state of the reflected signal. We consider a situation where the amplitude of the states produced by the source is not fully known, but instead this information is encoded in a large training set comprising many copies of the same coherent state. We show that an optimal global measurement, performed jointly over the signal and the training set, provides higher successful identification rates than any learning strategy based on first estimating the unknown amplitude by means of Gaussian measurements on the training set, followed by an adaptive discrimination procedure on the signal. By considering a simplified variant of the problem, we argue that this is the case even for non-Gaussian estimation measurements. Our results show that, even in absence of entanglement, collective quantum measurements yield an enhancement in the readout of classical information, which is particularly relevant in the operating regime of low-energy signals.

El hallazgo en una biopsia de mama de lesiones proliferativas atípicas, implica la necesidad de cirugía y extirpación de dicha lesión. El objetivo del estudio fue determinar la tasa de escisiones completas mediante el uso del dispositivo Intact®-BLES de lesiones categorizadas B3 en biopsia asistida por vacío (BAV).

En los programas de diagnóstico precoz, se considera sobrediagnóstico al diagnóstico de una enfermedad que sin cribado nunca se hubiera diagnosticado, y como se espera que dicho diagnóstico no cause la muerte, se trata innecesariamente. El sobrediagnóstico es un sesgo del propio cribado y un efecto no deseado de la prevención secundaria y de la mejora de la sensibilidad de las técnicas diagnósticas. A priories difícil de discriminar qué diagnósticos son los clínicamente relevantes y en cuáles se podría evitar el tratamiento. Para minimizar el efecto de sobrediagnóstico, el cribado debe dirigirse a población considerada de riesgo.

Salt-affected soils, both saline and sodic, may develop under both dryland and irrigated conditions, affecting the physical and chemical soil properties, with negative consequences in the environment, in crop production and in animal and human health. Among the development processes of salt-affected soils, the processes of sodification have generally received less attention and are less understood than the development of saline soils. Although in both, hydrological processes are involved in their development, in the case of sodic soils we have to consider some additional chemical and physicochemical reactions, making more difficult their modeling and prediction. This is especially true where we have to consider the effects of the groundwater level and composition. In this contribution there are presented three case studies: one related to the development of sodic soils in the lowlands of the Argentina Pampas, under dry-land conditions with sub-humid temperate climate and pastures for cattle production; the second deals with the development of sodic soils in the Colombia Cauca Valley, under irrigated conditions and tropical sub-humid climate, in lands used for sugarcane cropping dedicated to sugar and ethanol production; and the last one related to the sodification of soils in the Western Plains of Venezuela, under irrigated conditions, sub-humid tropical climate and continuous cropping of rice under flooding. The development of sodicity in the surface soil is partially related to the composition and level of the ground-water, mainly affected in the Argentina case by drainage conditions, in the case of Colombia to the inefficient irrigation and inadequate drainage, and in the case of Venezuela to the soil management and irrigation system. There is shown how the model SALSODIMAR, developed by the author, based on the balance of water and soluble components of both irrigation water and ground-water, under different water and land management conditions, may be successfully adapted for the diagnosis and prediction of the different processes and problems, and for selection of alternatives for their prevention and amelioration.

AbstractFORGE (Fate of Repository Gases) is an international research project supported by funding under the European Commission FP7 Euratom program and lasting four years from 2009 to 2013. The project is dedicated to understanding gas generation and migration as part of the quantitative assessment of a geological repository for radioactive waste. Within the FORGE project, Work Package 1 is dedicated to numerical modeling of a two-phase flow system (hydrogen gas due to corrosion and groundwater) in a geological repository for radioactive waste. Several benchmark exercises were proposed that cover the modeling of a deep geological repository from the disposal cell scale to the repository scale with different codes. During the definition of the exercises, special emphasis was given to the roles of the excavation-disturbed zone and of the interfaces between materials, which could act as a conduit for preferential flow. Some changes were made in the TOUGH2 code to enable the implementation of the prescribed conditions, models, and parameters of the benchmark. The results of the calculations performed with different codes show that TOUGH2 gives comparable results under the numerically challenging conditions defined in the exercise. Some differences were observed resulting from the use of different codes and also from some simplifications in the parameters and models adopted by the participating teams. In this paper, the cell-scale benchmark exercise and the results obtained by the Swiss Federal Nuclear Safety Inspectorate (ENSI) with TOUGH2 will be described, together with some difficulties encountered during the simulation, e.g., convergence problems. The results of other teams participating in the benchmark are in good agreement with the ENSI results.

La densidad mamaria está siendo un aspecto controvertido por las recientes regulaciones a que ha sido sometida. Esta sección docente pretende aclarar el estado de la polémica y proporcionar elementos de decisión ante este nuevo escenario.

Osteoarthritis is the most prevalent joint disease and a frequent cause of joint pain, functional loss, and disability. Osteoarthritis often becomes chronic, and conventional treatments have demonstrated only modest clinical benefits without lesion reversal. Cell-based therapies have shown encouraging results in both animal studies and a few human case reports. We designed a pilot study to assess the feasibility and safety of osteoarthritis treatment with mesenchymal stromal cells (MSCs) in humans and to obtain early efficacy information for this treatment.

We describe the natural history of lupus nephritis (LN) in a historical cohort of 190 white patients with the diagnosis of biopsy-proven LN followed in a single reference center.

The new biodegradable chelating agent imidodisuccinic acid (IDHA) has been studied for its application in agriculture. This study was conducted to compare the efficiency of mixed IDHA and ethylene diamine tetraacetic acid (EDTA) formulations to provide Fe, Mn, Zn, and Cu to green bean (Phaseolus vulgaris ‘Perfección negra polo’) and tomato (Lycopersicum esculentum Mill. ‘Shiren’) plants grown in greenhouses in soil‐less and soil cultures in fertigation conditions. The effect on micronutrient concentrations, SPAD index and fruit yield were investigated. In the green bean experiment, control (no chelate applied) plants showed important micronutrient deficiency symptoms and growth reduction, while IDHA treated plants were healthy. Although EDTA provides micronutrients in higher amounts than IDHA, a chryptogamic infection was observed for this treatment but not for the IDHA one. In the tomato grown on rockwool experiment, increments of SPAD index and Zn concentration are higher in plants treated with IDHA than with EDTA, though for the tomato on soil mulch experiment no differences were found among treatments, even the control. The results are in agreement with previously published studies on the behavior of IDHA. The new chelating agent IDHA can substitute EDTA in hydroponics and fertigation cultures as a chelating agent for micronutrients.

AbstractTwenty-two consecutive children with repaired cleft lip and/or palate [isolated cleft lip (CL) 6, isolated cleft palate (CP) 7, unilateral cleft lip and palate (UCLP) 7, and bilateral cleft lip and palate 2] with a mean age of 27 months underwent spectrographic measures of tape-recorded speech (DSP Sona-Graph digital unit). Controls were 22 age- and sex-matched noncleft children. Data analyzed included (1) the Spanish vocalic variables [a, i, u, e, o]: first formant, second formant, duration, and context; (2) obstruent variables [p, t, k]: burst, voice onset time, and duration, and (3) nasal variables [m]: first formant, second formant, and duration. Statistically significant differences were observed between the CL group and the control group in the first formant of [e] and in the increase of the frequency of the [t] burst. Comparison between UCLP and controls showed differences in the second formant of [a], in the first formant of [o], and in the second formant of [o]. These results suggest a small but significant influence of either the cleft lip or its repair on lip rounding for [o] and [u]. In addition, tongue position differences were most likely responsible for the differences seen with [a] and [e]. Spectrographic differences in the current patients did not contribute to meaningful differences in speech sound development. Individualized care (orthodontics, surgery, speech therapy) in children with cleft lip and/or palate attended at specialized craniofacial units contributes to normalization of speech development.Copyright © 2002 S. Karger AG, Basel

Abstract.: We present three cases of breast lesions labeled as probable intramammary lymph nodes that showed an increase in size on follow-up mammography. Contrast-enhanced MRI was performed and the three lesions showed strong and rapid uptake of the intravenous contrast. Core needle biopsy established the diagnosis of lymphoid hyperplasia in all three patients. Because intramammary lymph nodes affected by benign processes can present findings similar to malignant lesions, the usefulness of contrast-enhanced MRI in these cases is controversial.

We carried out in situ methylation of human chromosomes with the HpaII methylase using [3H]methyl-S-adenosyl-l-methionine as the methyl group carrier. Autoradiographs localising [3H]methyl groups show methylatable CCGG sequences in the R-bands as well as in the short arms of the acrocentric chromosomes that include ribosomal DNA. The strongest labelling was observed over a subset of R-bands, including T-bands. Since methylatable CCGG sequences are representative of the unmethylated fraction of DNA, we suggest that differences in the degree of DNA methylation could be involved in the structure and function of chromosomal bands.

Restriction endonucleases have been used to digest DNA in fixed metaphase chromosomes of animal species. However, constitutive C-heterochromatin of plant species is resistant to these enzymes suggesting that the special structural organization of plant C-bands is an impediment to the activity of restriction endonucleases. In order to test this hypothesis, we have chosen the species Scilla siberica, whose purified satellite DNA, localised at the heterochromatic regions, is extensively digested by HaeIII. In situ treatment with HaeIII alone does not produce significant digestion of heterochromatin, but subsequent treatment with proteinase K results in extensive digestion of heterochromatic regions producing unstained gaps. These results indicate that HaeIII is able to access and cut chromosomal DNA from C-bands, but the DNA fragments remain attached to chromosomal proteins that characterize the complex structure of heterochromatin in this species. Although there are no reasons to suppose that accessibility of chromosomal DNA of S. siberica to restriction enzymes can be impeded, it would be reasonable to think from our results that some special features of heterochromatin organization in plants contribute to the formation of a complex structure that makes chromosomal DNA extraction impossible.

A simple method, using silver impregnation after 2 x SSC pretreatment allowed us to demonstrate axial structures (cores) in the metaphase I bivalents of the neo-XY race of Pycnogaster cucullata under bright-field microscopy. Axial structures can also be shown in DNA-depleted metaphase I bivalents, suggesting that DNA is not essential to demonstrate these elements. Specifically differentiated regions, which coincide with kinetochores, secondary constrictions (including the NOR), and chiasmata were also found. These regions have a characteristic morphology and therefore may be utilized for cytogenetic analysis. The simultaneous visualization of all these regions allowed us to establish their spatial relationships and hence the basic structural organization of the neo-XY sex bivalent in this species.

A method of in situ DNA methylation with the prokaryotic methylase HpaII has been developed on fixed mitotic and meiotic chromosomes of the insect species Baetica ustulata. Incorporation of methyl groups into the chromosomal DNA is revealed by autoradiography using a labelled substrate and by its ability to prevent endonuclease digestion. The method allows direct visualization of clusters of methylatable CCGG sites. The distribution of these clusters in the chromosome complement of Baetica shows two separate domains of heterochromatic DNA which differ in their methylation patterns. Each is distributed at equivalent locations in both homologous and nonhomologous chromosomes. The existence of two compartments, one methylated and the other unmethylated, in the heterochromatic DNA could be interpreted as a remnant of the ancestral echinoderm-like pattern of methylation.

The objective of this study was to assess the usefulness of stereotactic large-core needle biopsy (LCNB) in the management of nonpalpable breast lesions (NBL) and compare it with stereotactic fine-needle aspiration biopsy (SFNA) performed simultaneously in a significant number of cases. From November 1993 through June 1997, 510 consecutive patients with NBL underwent 14-gauge LCNB with 354 women undergoing simultaneous 21-gauge SFNA in the same lesion. Mammographic findings, lesion size, number of core biopsy specimens, complications and diagnoses of both techniques were analysed. Surgical biopsy, tumorectomy or mastectomy was indicated for malignancy or poor correlation between SFNA or LCNB results and clinical or radiological findings. Values of diagnostic accuracy of both LCNB and SFNA were determined. The ratio benign surgical biopsies/malignant surgical biopsies (BB/CB) of the series was calculated. A total of 171 patients underwent surgical treatment; in 31 (18.1 %) a benign process or atypical ductal hyperplasia was the final diagnosis. The ratio BB/CB was 0.22. Sensitivity and specificity were 93.2 and 100 %, respectively, for LCNB, and 77.2 and 92.3 %, respectively, for SFNA with cytological analysis. Large-core needle biopsy provides more accurate diagnosis than SFNA in the management of nonpalpable breast lesions and obviates a surgical diagnostic procedure in a significant number of cases.

Human metaphase chromosomes were treated with the restriction endonuclease Msel, which cuts DNA at TTAA sequences. This enzyme preferentially cuts and extracts DNA from G-bands and thus is the first restriction endonuclease allowing direct R-band visualization. Specific patterns ranging from R+C-like to C-like banding can be induced, depending on the concentration of the enzyme. At intermediate concentrations, only a subset of R-bands are produced, corresponding to GC-rich bands that are especially resistant to heat denaturation (so-called T-bands). These results suggest that compositional differences between chromosomal regions determine the different rates of cleavage by Msel, not only between R- and G-bands but also among different R-bands.

The restriction endonuclease TaqI cleaves DNA at TCGA sites which are very common in human satellite DNAs. However, this enzyme was not used successfully up to now to digest constitutive heterochromatin of human chromosomes, where those highly repetitive DNAs are preferentially located. In this work, we show that TaqI is able to cut and extract DNA from the major heterochromatic regions on chromosomes 1, 9, 15, and 16 which appear as unstained gaps. Yq heterochromatin displays moderate digestion along its entire length but a middle region can be distinguished which is usually more affected. Complete digestion of Yq heterochromatin can be achieved when this block has been previously undercondensed by treating cell cultures with the cytidine analog, 5-azacytidine. Thus, it may be deduced that some factors related to chromatin organization might be involved in the action of TaqI. These results come to reinforce previous data about heterogeneity of Yq heterochromatin, and allow us to subdivide it into three different regions according to their differential response to Taql digestion.

Objective: The purpose of this study was to assess craniofacial growth In children from 10 months to 5 years of age with cleft lip and/or palate and to develop a systematic method of cephalometric measurements.Design: A case-control study.Setting: Craniofacial unit of a teaching hospital for children.Patients: A consecutive series of the first 22 patients with cleft lip and/or palate who underwent early reconstructive treatment [isolated cleft lip (CL) 6; isolated cleft palate (CP) 7; unilateral cleft lip and palate (UCLP) 7; and bilateral complete cleft lip and palate (BCLP) 2] (mean age, 27.9 months) and 22 age- and sex-matched noncleft children.Interventions: Lateral cephalometric headfilms of the children were taken using a pediatric cephalostat.Main Outcome Measures: Cephalometric landmarks were measured according to Ricketts cephalometry.Results: As compared with controls, CL patients had a lingual position and inclination of maxillary and mandibular incisors, an increase of interincisal angle and a decrease of incisor overjet, an increase in facial convexity, and a decrease in facial depth and mandible body length. In CP patients, palatal plane inclination and mandible arch were significantly reduced. In UCLP patients, there was a decrease in molar relation and incisor overbite, an increase in interincisal angle, reduced position and inclination of maxillary incisors and inclination of mandibular incisors, an increase in facial convexity, and lower facial height.Conclusions: Based on the absence of midface growth reduction, these short-term results suggest a tendency toward normal maxillomandibular growth.

The chromosomal location of the ribosomal cistrons 18 + 26S and 5S has been determined in spermatocytes of two cytological races of Pycnogaster cucullata by in situ hybridization using molecular probes from both types of rDNA. A comparative analysis with previous results suggested the existence of more 18 + 26S rDNA sites than active NORs as shown by silver impregnation, but 5S rDNA sites are outside the NORs. Thus, different categories of latent NORs have been shown in this specialised cell type which are discussed in relation to the evolutionary process of differentiation in this species.

We have analyzed the pattern of AluI digestion over time on human chromosomes in order to monitor the evolution of the in situ enzyme action. Short treatments followed by Giemsa staining produce a G-like banding effect, whereas longer treatments produce a C-like banding pattern. However, when Propidium iodide staining is used, it reveals a uniform bright fluorescence after short AluI digestions and C bands when longer treatments are developed. We propose that C banding is the result of a uniform DNA removal in non centromeric regions taking place after a critical time point, the initial G like banding being produced by changes in the DNA-proteins interactions.

Background: Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases. Results: We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 108blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations. Conclusions: The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse.

The distribution of the 2000 copies of the Y-specific repetitive family DYZ2 is controversial since previous reports have mapped these sequences to different sites of the Yqh region. In this work, we have performed non-radioactive in situ hybridization of a cloned DYZ2 fragment at higher stringency conditions on 5-aza-cytidine-enlarged Y chromosomes; the results suggest a non-uniform distribution of these sequences, which are preferentially located at the proximal and distal parts of Yqh, including the C+/Q-heterochromatin at the boundary with the euchromatic region.