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Upon T-cell activation, the levels of the secondary messenger diacylglycerol (DAG) at the plasma membrane need to be controlled to ensure appropriate T-cell receptor signaling and T-cell functions. Extended-Synaptotagmins (E-Syts) are a family of inter-organelle lipid transport proteins that bridge the endoplasmic reticulum and the plasma membrane. In this study, we identify a novel regulatory mechanism of DAG-mediated signaling for T-cell effector functions based on E-Syt proteins. We demonstrate that E-Syts downmodulate T-cell receptor signaling, T-cell-mediated cytotoxicity, degranulation, and cytokine production by reducing plasma membrane levels of DAG. Mechanistically, E-Syt2 predominantly modulates DAG levels at the plasma membrane in resting-state T cells, while E-Syt1 and E-Syt2 negatively control T-cell receptor signaling upon stimulation. These results reveal a previously underappreciated role of E-Syts in regulating DAG dynamics in T-cell signaling.
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Transdução de Sinais , Linfócitos T , Sinaptotagminas/metabolismo , Membrana Celular/metabolismo , Transporte Biológico , Receptores de Antígenos de Linfócitos T/metabolismo , Cálcio/metabolismoRESUMO
Neuroticism/negative emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and well-being. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment to psychiatric illness. Animal research suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to humans has remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to test this hypothesis in an ethnoracially diverse, sex-balanced sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is preferentially associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat (aversive multimodal stimulation), whereas N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to threat-related faces. It is often assumed that different threat paradigms are interchangeable assays of individual differences in brain function, yet this has rarely been tested. Our results revealed negligible associations between BST/Ce reactivity to the anticipation of threat and the presentation of threat-related faces, indicating that the two tasks are nonfungible. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for refining mechanistic research.
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Tonsila do Cerebelo , Emoções , Imageamento por Ressonância Magnética , Neuroticismo , Núcleos Septais , Núcleos Septais/fisiologia , Núcleos Septais/diagnóstico por imagem , Humanos , Masculino , Feminino , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/diagnóstico por imagem , Adulto Jovem , Neuroticismo/fisiologia , Adulto , Emoções/fisiologia , Incerteza , Medo/fisiologia , Medo/psicologia , AdolescenteRESUMO
MOTIVATION: In recent years, the focus of bioinformatics research has moved from individual sequences to collections of sequences. Given the fundamental role of the Burrows-Wheeler Transform (BWT) in string processing, a number of dedicated tools have been developed for computing the BWT of string collections. While the focus has been on improving efficiency, both in space and time, the exact definition of the BWT employed has not been at the center of attention. As we show in this paper, the different tools in use often compute non-equivalent BWT variants: the resulting transforms can differ from each other significantly, including the number r of runs, a central parameter of the BWT. Moreover, with many tools, the transform depends on the input order of the collection. In other words, on the same dataset, the same tool may output different transforms if the dataset is given in a different order. RESULTS: We studied 18 dedicated tools for computing the BWT of string collections and were able to identify 6 different BWT variants computed by these tools. We review the differences between these BWT variants, both from a theoretical and from a practical point of view, comparing them on 8 real-life biological datasets with different characteristics. We find that the differences can be extensive, depending on the datasets, and are largest on collections of many similar short sequences. The parameter r, the number of runs of the BWT, also shows notable variation between the different BWT variants; on our datasets, it varied by a multiplicative factor of up to 4.2. AVAILABILITY: Source code and scripts to replicate the results and download the data used in the article are available at https://github.com/davidecenzato/BWT-variants-for-string-collections. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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BACKGROUND: Extended-spectrum ß-lactamases (ESBLs) producing bacteria have spread worldwide and become a global public health concern. Plasmid-mediated transfer of ESBLs is an important route for resistance acquisition. METHODS: We collected 1345 complete sequences of plasmids containing CTX-Ms from public database. The global transmission pattern of plasmids and evolutionary dynamics of CTX-Ms have been inferred. We applied the pan-genome clustering based on plasmid genomes and evolution analysis to demonstrate the transmission events. FINDINGS: Totally, 48 CTX-Ms genotypes and 186 incompatible types of plasmids were identified. The geographical distribution of CTX-Ms showed significant differences across countries and continents. CTX-M-14 and CTX-M-55 were found to be the dominant genotypes in Asia, while CTX-M-1 played a leading role in Europe. The plasmids can be divided into 12 lineages, some of which forming distinct geographical clusters in Asia and Europe, while others forming hybrid populations. The Inc types of plasmids are lineage-specific, with the CTX-M-1_IncI1-I (Alpha) and CTX-M-65_IncFII (pHN7A8)/R being the dominant patterns of cross-host and cross-regional transmission. The IncI-I (Alpha) plasmids with the highest number, were presumed to form communication groups in Europe-Asia and Asia-America-Oceania, showing the transmission model as global dissemination and regional microevolution. Meanwhile, the main kinetic elements of blaCTX-Ms showed genotypic preferences. ISEcpl and IS26 were most frequently involved in the transfer of CTX-M-14 and CTX-M-65, respectively. IS15 has become a crucial participant in mediating the dissemination of blaCTX-Ms. Interestingly, blaTEM and blaCTX-Ms often coexisted in the same transposable unit. Furthermore, antibiotic resistance genes associated with aminoglycosides, sulfonamides and cephalosporins showed a relatively high frequency of synergistic effects with CTX-Ms. CONCLUSIONS: We recognized the dominant blaCTX-Ms and mainstream plasmids of different continents. The results of this study provide support for a more effective response to the risks associated with the evolution of blaCTX-Ms-bearing plasmids, and lay the foundation for genotype-specific epidemiological surveillance of resistance, which are of important public health implications.
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Antibacterianos , Escherichia coli , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , beta-Lactamases/genética , Escherichia coli/genética , Genômica , Plasmídeos/genéticaRESUMO
Extended defects in wide-bandgap semiconductors have been widely investigated using techniques providing either spectroscopic or microscopic information. Nano-Fourier transform infrared spectroscopy (nano-FTIR) is a nondestructive characterization method combining FTIR with nanoscale spatial resolution (â¼20 nm) and topographic information. Here, we demonstrate the capability of nano-FTIR for the characterization of extended defects in semiconductors by investigating an in-grown stacking fault (IGSF) present in a 4H-SiC epitaxial layer. We observe a local spectral shift of the mid-infrared near-field response, consistent with the identification of the defect stacking order as 3C-SiC (cubic) from comparative simulations based on the finite dipole model (FDM). This 3C-SiC IGSF contrasts with the more typical 8H-SiC IGSFs reported previously and is exemplary in showing that nanoscale spectroscopy with nano-FTIR can provide new insights into the properties of extended defects, the understanding of which is crucial for mitigating deleterious effects of such defects in alternative semiconductor materials and devices.
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Drug-resistant shigellosis is increasing, particularly among men who have sex with men (MSM). During July-October 2022, an extended-spectrum beta-lactamase producing Shigella sonnei cluster of 9 patients was identified in Chicago, of whom 8 were MSM and 6 were festival attendees. The cluster also included 4 domestic travelers to Chicago. Sexual health care for MSM should include shigellosis diagnosis and prevention.
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BACKGROUND: Admission and discharge screening of patients for asymptomatic gut colonization with multidrug-resistant organisms (MDROs) is a traditional approach to active surveillance, but its sensitivity for detecting colonization is uncertain. METHODS: Daily rectal or fecal swab samples and clinical data were collected over 12 months from patients in one 25-bed intensive care unit (ICU) in Chicago, IL USA and tested for the following multidrug-resistant organisms (MDROs): vancomycin-resistant enterococci (VRE); third-generation cephalosporin-resistant Enterobacterales, including extended-spectrum ß-lactamase-producing Enterobacterales (ESBL); and carbapenem-resistant Enterobacterales (CRE). MDRO detection by (1) admission/discharge surveillance cultures or (2) clinical cultures were compared to daily surveillance cultures. Samples underwent 16S rRNA gene sequencing to measure the relative abundance of operational taxonomic units (OTUs) corresponding to each MDRO. RESULTS: Compared with daily surveillance cultures, admission/discharge cultures detected 91% of prevalent MDRO colonization and 63% of incident MDRO colonization among medical ICU patients. Only a minority (7%) of MDRO carriers were identified by clinical cultures. Higher relative abundance of MDRO-associated OTUs and specific antibiotic exposures were independently associated with higher probability of MDRO detection by culture. CONCLUSION: Admission and discharge surveillance cultures underestimated MDRO acquisitions in an ICU. These limitations should be considered when designing sampling strategies for epidemiologic studies that use culture-based surveillance.
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We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antiviral activities. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed a characteristic spin-system motif, indicating the presence of an extended panel of urinary metabolites during the acute viral replication phase. Mass spectrometry additionally enabled the characterization and quantification of the most abundant serum metabolites, showing the potential diagnostic value of the compounds for viral infections. In total, we unveiled ten nucleoside (cytosine- and uracil-based) analogue structures, eight of which were previously unknown in humans allowing us to propose a new extended viperin pathway for the innate production of antiviral compounds. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ, and IL-10, suggest an association with the viperin enzyme contributing to an ancient endogenous innate immune defense mechanism against viral infection.
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COVID-19 , Humanos , Estrutura Molecular , SARS-CoV-2 , Imunidade Inata , Citosina , Redes e Vias Metabólicas , AntiviraisRESUMO
BACKGROUND: Nuclear introns in Euglenida have been understudied. This study aimed to investigate nuclear introns in Euglenida by identifying a large number of introns in Euglena gracilis (E. gracilis), including cis-spliced conventional and nonconventional introns, as well as trans-spliced outrons. We also examined the sequence characteristics of these introns. RESULTS: A total of 28,337 introns and 11,921 outrons were identified. Conventional and nonconventional introns have distinct splice site features; the former harbour canonical GT/C-AG splice sites, whereas the latter are capable of forming structured motifs with their terminal sequences. We observed that short introns had a preference for canonical GT-AG introns. Notably, conventional introns and outrons in E. gracilis exhibited a distinct cytidine-rich polypyrimidine tract, in contrast to the thymidine-rich tracts observed in other organisms. Furthermore, the SL-RNAs in E. gracilis, as well as in other trans-splicing species, can form a recently discovered motif called the extended U6/5' ss duplex with the respective U6s. We also describe a novel type of alternative splicing pattern in E. gracilis. The tandem repeat sequences of introns in this protist were determined, and their contents were comparable to those in humans. CONCLUSIONS: Our findings highlight the unique features of E. gracilis introns and provide insights into the splicing mechanism of these introns, as well as the genomics and evolution of Euglenida.
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Euglena gracilis , Íntrons , Euglena gracilis/genética , Sítios de Splice de RNA , Processamento Alternativo , Splicing de RNARESUMO
The imbalance between organ supply and demand continues to limit the broader benefits of organ transplantation. Machine perfusion (MP) may increase the supply of donor livers by expanding the use of extended-criteria donors. Using the United Network for Organ Sharing/Organ Procurement and Transplantation Network and the Standard Transplant Analysis and Research dataset, we reviewed the effect of MP implementation on the behavior of transplant centers. We identified 15 high-utilizing MP centers that were matched to suitable controls based on volume and geographical proximity. We conducted a differences-in-differences analysis using linear regression to estimate the impact of MP adoption on the transplant centers' donor utilization. We found a significant increase in cold ischemia time and organs with donor warm ischemia time over 30 minutes (P < .05). After removing one outlier center, the analysis showed that these centers through MP accepted overall more donation after circulatory death donors, donation after circulatory death donors over 50 years old, donors with macrovesicular steatosis greater than 30% on liver biopsy, and donor warm ischemia time over 30 minutes (P < .05). MP has allowed centers to expand their use of extended-criteria donors beyond traditional cutoffs and to increase patient access to liver transplantation.
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Patients with end-stage renal disease and iliocaval venous obstruction are normally nonviable recipients of kidney transplantation. We report a case of a 34-year-old male patient who has been receiving hemodialysis as renal replacement therapy for 6 years due to immunoglobulin A nephropathy. Past medical history included multiple central venous catheter infections and catheter-associated thrombosis. Iliac confluence and inferior vena cava occlusion previously excluded the patient from the renal transplantation list. The exhaustion of venous access sites was already documented. After multidisciplinary discussion, the patient was proposed for endovascular iliocaval reconstruction aiming for a future kidney transplant. Iliocaval recanalization was achieved through bilateral femoral access. Inferior vena cava and iliac angioplasty were performed. A dedicated venous stent was deployed in the inferior vena cava, followed by a double-barrel reconstruction of the iliac confluence. Successful iliocaval recanalization was accomplished. Five months after kidney transplantation was performed with a deceased donor graft in the right iliac fossa. The postoperative period was uneventful. After 12 months, the patient remained free from kidney replacement therapies with a serum creatinine level of 1.3 mg/dL. To the best of our knowledge, this is the first clinical description of a successful kidney transplant in a patient with a previous iliocaval reconstruction.
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B cell depletion by the anti-CD20 antibody ocrelizumab is effective in relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS). We investigated immunological changes in peripheral blood of a real-world MS cohort after 6 and 12 months of ocrelizumab. All RRMS and most PPMS patients (15/20) showed treatment response. Ocrelizumab not only reduced CD20+ B cells, but also numbers of CD20+ T cells. Absolute numbers of monocytes, dendritic cells and CD8+ T cells were increased, while CD56hi natural killer cells were reduced after ocrelizumab. The residual B cell population shifted towards transitional and activated, IgA+ switched memory B cells, double negative B cells, and antibody-secreting cells. Delaying the treatment interval by 2-3 months increased mean B cell frequencies and enhanced naive B cell repopulation. Ocrelizumab reduced plasma levels of interleukin(IL)-12p70 and interferon(IFN)-α2. These findings will contribute to understanding ineffective treatment responses, dealing with life-threatening infections and further unravelling MS pathogenesis.
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Anticorpos Monoclonais Humanizados , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Linfócitos T CD8-Positivos , Fatores Imunológicos/uso terapêutico , Interleucina-12 , Sistema ImunitárioRESUMO
Escherichia coli ST131 is a multidrug-resistant lineage associated with the global spread of extended-spectrum ß-lactamase-producing organisms. Particularly, ST131 clade C1 is the most predominant clade in Japan, harboring blaCTX-M-14 at a high frequency. However, the process of resistance gene acquisition and spread remains unclear. Here, we performed whole-genome sequencing of 19 E. coli strains belonging to 12 STs and 12 fimH types collected between 1997 and 2016. Additionally, we analyzed the full-length genome sequences of 96 ST131-H30 clade C0 and C1 strains, including those obtained from this study and those registered in public databases, to understand how ST131 clade C1 acquired and spread blaCTX-M-14. We detected conjugative IncFII plasmids and IncB/O/K/Z plasmids carrying blaCTX-M-14 in diverse genetic lineages of E. coli strains from the 1990s to the 2010s, suggesting that these plasmids played an important role in the spread of blaCTX-M-14. Molecular phylogenetic and molecular clock analyses of the 96 ST131-H30 clade C0 and C1 strains identified 8 subclades. Strains harboring blaCTX-M-14 were clustered in subclades 4 and 5, and it was inferred that clade C1 acquired blaCTX-M-14 around 1993. All 34 strains belonging to subclade 5 possessed blaCTX-M-14 with ISEcp1 upstream at the same chromosomal position, indicating their common ancestor acquired blaCTX-M-14 in a single ISEcp1-mediated transposition event during the early formation of the subclade around 1999. Therefore, both the horizontal transfer of plasmids carrying blaCTX-M-14 to diverse genetic lineages and chromosomal integration in the predominant genetic lineage have contributed to the spread of blaCTX-M-14.
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The last decade has seen significant growth in the application of DNA-based methods for extended antigen typing, and the use of gene sequencing to consider variation in blood group genes to guide clinical care. The challenge for the field now lies in educating professionals, expanding accessibility and standardizing the use of genotyping for routine patient care. Here we discuss applications of genotyping when transfusion is not straightforward including when compatibility cannot be demonstrated by routine methods, when Rh type is unclear, when allo- and auto-antibodies are encountered in stem cell and organ transplantation, for prenatal testing to determine maternal and foetal risk for complications, and Group A subtyping for kidney and platelet donors. We summarize current commercial testing resources and new approaches to testing including high-density arrays and targeted next-generation sequencing (NGS).
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AbstractWhere dramatic sexual displays are involved in attracting a mate, individuals can enhance their performances by manipulating their physical environment. Typically, individuals alter their environment either in preparation for a performance by creating a "stage" or during the display itself by using discrete objects as "props." We examined an unusual case of performative manipulation of an entire stage by male Albert's lyrebirds (Menura alberti) during their complex song and dance displays. We found that males from throughout the species' range shake the entangled forest vegetation of their display platforms, creating a highly conspicuous and stereotypical movement external to their bodies. This "stage shaking" is performed in two different rhythms, with the second rhythm an isochronous beat that matches the beat of the coinciding vocalizations. Our results provide evidence that stage shaking is an integral, and thus likely functional, component of male Albert's lyrebird sexual displays and so highlight an intriguing but poorly understood facet of complex communication.
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Vocalização Animal , Masculino , Animais , Comportamento Sexual Animal , Meio Ambiente , Passeriformes/fisiologia , Comunicação AnimalRESUMO
AbstractMuseum specimens have long served as foundational data sources for ecological, evolutionary, and environmental research. Continued reimagining of museum collections is now also generating new types of data associated with but beyond physical specimens, a concept known as "extended specimens." Field notes penned by generations of naturalists contain firsthand ecological observations associated with museum collections and comprise a form of extended specimens with the potential to provide novel ecological data spanning broad geographic and temporal scales. Despite their data-yielding potential, however, field notes remain underutilized in research because of their heterogeneous, unstandardized, and qualitative nature. We introduce an approach for transforming descriptive ecological notes into quantitative data suitable for statistical analysis. Tests with simulated and real-world published data show that field notes and our transformation approach retain reliable quantitative ecological information under a range of sample sizes and evolutionary scenarios. Unlocking the wealth of data contained within field records could facilitate investigations into the ecology of clades whose diversity, distribution, or other demographic features present challenges to traditional ecological studies, improve our understanding of long-term environmental and evolutionary change, and enhance predictions of future change.
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Evolução Biológica , MuseusRESUMO
In the past, identification of HLA alleles was limited to sequencing the region of the gene coding for the peptide binding groove, resulting in a lack of sequence information in the HLA database, challenging HLA allele assignment software programs. We investigated full-length sequences of 19 HLA class I and 7 HLA class II alleles, and we extended another 47 HLA class I alleles with sequences of 5' and 3' UTR regions that were all not yet available in the IPD-IMGT/HLA database. We resolved 8638 unknown nucleotides in the coding sequence of HLA class I and 2139 of HLA class II. Furthermore, with full-length sequencing of the 26 alleles, more than 90 kb of sequence information was added to the non-coding sequences, whereas extension of the 47 alleles resulted in the addition of 5.5 kb unknown nucleotides to the 5' UTR and > 31.7 kb to the 3' UTR region. With this information, some interesting features were observed, like possible recombination events and lineage evolutionary origins. The continuing increase in the availability of full-length sequences in the HLA database will enable the identification of the evolutionary origin and will help the community to improve the alignment and assignment accuracy of HLA alleles.
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Evolução Biológica , Nucleotídeos , Alelos , Regiões 3' não Traduzidas/genética , Membrana Celular , Nucleotídeos/genéticaRESUMO
We aimed to compare the ability of diffusion tensor imaging and multi-compartment spherical mean technique to detect focal tissue damage and in distinguishing between different connectivity patterns associated with varying clinical outcomes in multiple sclerosis (MS). Seventy-six people diagnosed with MS were scanned using a SIEMENS Prisma Fit 3T magnetic resonance imaging (MRI), employing both conventional (T1w and fluid-attenuated inversion recovery) and advanced diffusion MRI sequences from which fractional anisotropy (FA) and microscopic FA (µFA) maps were generated. Using automated fiber quantification (AFQ), we assessed diffusion profiles across multiple white matter (WM) pathways to measure the sensitivity of anisotropy diffusion metrics in detecting localized tissue damage. In parallel, we analyzed structural brain connectivity in a specific patient cohort to fully grasp its relationships with cognitive and physical clinical outcomes. This evaluation comprehensively considered different patient categories, including cognitively preserved (CP), mild cognitive deficits (MCD), and cognitively impaired (CI) for cognitive assessment, as well as groups distinguished by physical impact: those with mild disability (Expanded Disability Status Scale [EDSS] <=3) and those with moderate-severe disability (EDSS >3). In our initial objective, we employed Ridge regression to forecast the presence of focal MS lesions, comparing the performance of µFA and FA. µFA exhibited a stronger association with tissue damage and a higher predictive precision for focal MS lesions across the tracts, achieving an R-squared value of .57, significantly outperforming the R-squared value of .24 for FA (p-value <.001). In structural connectivity, µFA exhibited more pronounced differences than FA in response to alteration in both cognitive and physical clinical scores in terms of effect size and number of connections. Regarding cognitive groups, FA differences between CP and MCD groups were limited to 0.5% of connections, mainly around the thalamus, while µFA revealed changes in 2.5% of connections. In the CP and CI group comparison, which have noticeable cognitive differences, the disparity was 5.6% for FA values and 32.5% for µFA. Similarly, µFA outperformed FA in detecting WM changes between the MCD and CI groups, with 5% versus 0.3% of connections, respectively. When analyzing structural connectivity between physical disability groups, µFA still demonstrated superior performance over FA, disclosing a 2.1% difference in connectivity between regions closely associated with physical disability in MS. In contrast, FA spotted a few regions, comprising only 0.6% of total connections. In summary, µFA emerged as a more effective tool than FA in predicting MS lesions and identifying structural changes across patients with different degrees of cognitive and global disability, offering deeper insights into the complexities of MS-related impairments.
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Imagem de Tensor de Difusão , Esclerose Múltipla , Substância Branca , Humanos , Feminino , Masculino , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Anisotropia , Adulto , Imagem de Tensor de Difusão/métodos , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/etiologiaRESUMO
PURPOSE: The Clinical Treatment Score post-5 years (CTS5) is an easy-to-use tool estimating the late distant recurrence (LDR) risk in patients with hormone receptor-positive breast cancer after 5 years of endocrine therapy (ET). Apart from evaluating the prognostic value and calibration accuracy of CTS5, the aim of this study is to clarify if this score is able to identify patients at higher risk for LDR who will benefit from extended ET. METHODS: Prognostic power, calibration, and predictive value of the CTS5 was tested in patients of the prospective ABCSG-06 and -06a trials (n = 1254 and 860 patients, respectively). Time to LDR was analyzed with Cox regression models. RESULTS: Higher rates of LDR in the years five to ten were observed in high- and intermediate-risk patients compared to low-risk patients (HR 4.02, 95%CI 2.26-7.15, p < 0.001 and HR 1.93, 95%CI 1.05-3.56, p = 0.035). An increasing continuous CTS5 was associated with increasing LDR risk (HR 2.23, 95% CI 1.74-2.85, p < 0.001). Miscalibration of CTS5 in high-risk patients could be observed. Although not reaching significance, high-risk patients benefitted the most from prolonged ET with an absolute reduction of the estimated 5-year LDR of - 6.1% (95%CI - 14.4 to 2.3). CONCLUSION: The CTS5 is a reliable prognostic tool that is well calibrated in the lower and intermediate risk groups with a substantial difference of expected versus observed LDR rates in high-risk patients. While a numerical trend in favoring prolonged ET for patients with a higher CTS5 was found, a significantly predictive value for the score could not be confirmed. CLINICAL TRIAL REGISTRATION: ABCSG-06 trial (NCT00309491), ABCSG-06A7 1033AU/0001 (NCT00300508).
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Pessoa de Meia-Idade , Prognóstico , Idoso , Quimioterapia Adjuvante/métodos , Recidiva Local de Neoplasia , Adulto , Antineoplásicos Hormonais/uso terapêutico , Tomada de Decisão Clínica , Estudos Prospectivos , Medição de Risco/métodos , Receptores de Estrogênio/metabolismoRESUMO
A recent work (arXiv:2401.04685) has merged N-centered ensembles of neutral and charged electronic ground states with ensembles of neutral ground and excited states, thus providing a general and in-principle exact (so-called extended N-centered) ensemble density functional theory of neutral and charged electronic excitations. This formalism made it possible to revisit the concept of density-functional derivative discontinuity, in the particular case of single excitations from the highest occupied Kohn-Sham (KS) molecular orbital, without invoking the usual "asymptotic behavior of the density" argument. In this work, we address a broader class of excitations, with a particular focus on double excitations. An exact implementation of the theory is presented for the two-electron Hubbard dimer model. A thorough comparison of the true physical ground- and excited-state electronic structures with that of the fictitious ensemble density-functional KS system is also presented. Depending on the choice of the density-functional ensemble as well as the asymmetry of the dimer and the correlation strength, an inversion of states can be observed. In some other cases, the strong mixture of KS states within the true physical system makes the assignment "single excitation" or "double excitation" irrelevant.