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The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells. High-resolution MRI demonstrated concordant lesions indicative of deep gray matter injury. We also observed spinal, ocular, and neuromuscular pathology. Our data show that vascular compromise and neuroprogenitor cell dysfunction are hallmarks of CZS pathogenesis, suggesting novel strategies to prevent and to treat this disease.
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Feto/virologia , Neurônios/patologia , Infecção por Zika virus/patologia , Zika virus/patogenicidade , Animais , Animais Recém-Nascidos , Apoptose , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Calcinose/patologia , Calcinose/veterinária , Feminino , Idade Gestacional , Macaca mulatta , Imageamento por Ressonância Magnética , Necrose , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/virologia , Neurônios/virologia , Gravidez , Índice de Gravidade de Doença , Vasculite/patologia , Vasculite/veterinária , Infecção por Zika virus/veterinária , Infecção por Zika virus/virologiaRESUMO
Asgard archaea are considered to be the closest known relatives of eukaryotes. Their genomes contain hundreds of eukaryotic signature proteins (ESPs), which inspired hypotheses on the evolution of the eukaryotic cell1-3. A role of ESPs in the formation of an elaborate cytoskeleton and complex cellular structures has been postulated4-6, but never visualized. Here we describe a highly enriched culture of 'Candidatus Lokiarchaeum ossiferum', a member of the Asgard phylum, which thrives anaerobically at 20 °C on organic carbon sources. It divides every 7-14 days, reaches cell densities of up to 5 × 107 cells per ml and has a significantly larger genome compared with the single previously cultivated Asgard strain7. ESPs represent 5% of its protein-coding genes, including four actin homologues. We imaged the enrichment culture using cryo-electron tomography, identifying 'Ca. L. ossiferum' cells on the basis of characteristic expansion segments of their ribosomes. Cells exhibited coccoid cell bodies and a network of branched protrusions with frequent constrictions. The cell envelope consists of a single membrane and complex surface structures. A long-range cytoskeleton extends throughout the cell bodies, protrusions and constrictions. The twisted double-stranded architecture of the filaments is consistent with F-actin. Immunostaining indicates that the filaments comprise Lokiactin-one of the most highly conserved ESPs in Asgard archaea. We propose that a complex actin-based cytoskeleton predated the emergence of the first eukaryotes and was a crucial feature in the evolution of the Asgard phylum by scaffolding elaborate cellular structures.
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Citoesqueleto de Actina , Archaea , Eucariotos , Filogenia , Citoesqueleto de Actina/metabolismo , Actinas/classificação , Actinas/genética , Actinas/metabolismo , Archaea/classificação , Archaea/citologia , Archaea/genética , Archaea/crescimento & desenvolvimento , Eucariotos/classificação , Eucariotos/citologia , Eucariotos/metabolismo , Anaerobiose , Ribossomos/metabolismo , Estruturas da Membrana Celular/metabolismo , Proteínas Arqueais/classificação , Proteínas Arqueais/genética , Proteínas Arqueais/metabolismo , Evolução MolecularRESUMO
RNA structural switches are key regulators of gene expression in bacteria, but their characterization in Metazoa remains limited. Here, we present SwitchSeeker, a comprehensive computational and experimental approach for systematic identification of functional RNA structural switches. We applied SwitchSeeker to the human transcriptome and identified 245 putative RNA switches. To validate our approach, we characterized a previously unknown RNA switch in the 3' untranslated region of the RORC (RAR-related orphan receptor C) transcript. In vivo dimethyl sulfate (DMS) mutational profiling with sequencing (DMS-MaPseq), coupled with cryogenic electron microscopy, confirmed its existence as two alternative structural conformations. Furthermore, we used genome-scale CRISPR screens to identify trans factors that regulate gene expression through this RNA structural switch. We found that nonsense-mediated messenger RNA decay acts on this element in a conformation-specific manner. SwitchSeeker provides an unbiased, experimentally driven method for discovering RNA structural switches that shape the eukaryotic gene expression landscape.
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The human cerebrum consists of a precise and stereotyped arrangement of lobes, primary gyri, and connectivity that underlies human cognition [P. Rakic, Nat. Rev. Neurosci. 10, 724-735 (2009)]. The development of this arrangement is less clear. Current models explain individual primary gyrification but largely do not account for the global configuration of the cerebral lobes [T. Tallinen, J. Y. Chung, J. S. Biggins, L. Mahadevan, Proc. Natl. Acad. Sci. U.S.A. 111, 12667-12672 (2014) and D. C. Van Essen, Nature 385, 313-318 (1997)]. The insula, buried in the depths of the Sylvian fissure, is unique in terms of gyral anatomy and size. Here, we quantitatively show that the insula has unique morphology and location in the cerebrum and that these key differences emerge during fetal development. Finally, we identify quantitative differences in developmental migration patterns to the insula that may underlie these differences. We calculated morphologic data in the insula and other lobes in adults (N = 107) and in an in utero fetal brain atlas (N = 81 healthy fetuses). In utero, the insula grows an order of magnitude slower than the other lobes and demonstrates shallower sulci, less curvature, and less surface complexity both in adults and progressively throughout fetal development. Spherical projection analysis demonstrates that the lenticular nuclei obstruct 60 to 70% of radial pathways from the ventricular zone (VZ) to the insula, forcing a curved migration to the insula in contrast to a direct radial pathway. Using fetal diffusion tractography, we identify radial glial fascicles that originate from the VZ and curve around the lenticular nuclei to form the insula. These results confirm existing models of radial migration to the cortex and illustrate findings that suggest differential insular and cerebral development, laying the groundwork to understand cerebral malformations and insular function and pathologies.
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Desenvolvimento Fetal , Córtex Insular , Córtex Insular/anatomia & histologia , Córtex Insular/diagnóstico por imagem , Córtex Insular/crescimento & desenvolvimento , Imagem de Tensor de Difusão , Humanos , Masculino , Feminino , Adulto Jovem , AdultoRESUMO
Protein stability plays a crucial role in a variety of applications, such as food processing, therapeutics, and the identification of pathogenic mutations. Engineering campaigns commonly seek to improve protein stability, and there is a strong interest in streamlining these processes to enable rapid optimization of highly stabilized proteins with fewer iterations. In this work, we explore utilizing a mega-scale dataset to develop a protein language model optimized for stability prediction. ESMtherm is trained on the folding stability of 528k natural and de novo sequences derived from 461 protein domains and can accommodate deletions, insertions, and multiple-point mutations. We show that a protein language model can be fine-tuned to predict folding stability. ESMtherm performs reasonably on small protein domains and generalizes to sequences distal from the training set. Lastly, we discuss our model's limitations compared to other state-of-the-art methods in generalizing to larger protein scaffolds. Our results highlight the need for large-scale stability measurements on a diverse dataset that mirrors the distribution of sequence lengths commonly observed in nature.
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Biologia Computacional , Dobramento de Proteína , Estabilidade Proteica , Proteínas , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , Biologia Computacional/métodos , Bases de Dados de Proteínas , Modelos Moleculares , Algoritmos , Domínios ProteicosRESUMO
We utilized motion-corrected diffusion tensor imaging (DTI) to evaluate microstructural changes in healthy fetal brains during the late second and third trimesters. Data were derived from fetal magnetic resonance imaging scans conducted as part of a prospective study spanning from 2013 March to 2019 May. The study included 44 fetuses between the gestational ages (GAs) of 23 and 36 weeks. We reconstructed fetal brain DTI using a motion-tracked slice-to-volume registration framework. Images were segmented into 14 regions of interest (ROIs) through label propagation using a fetal DTI atlas, with expert refinement. Statistical analysis involved assessing changes in fractional anisotropy (FA) and mean diffusivity (MD) throughout gestation using mixed-effects models, and identifying points of change in trajectory for ROIs with nonlinear trends. Results showed significant GA-related changes in FA and MD in all ROIs except in the thalamus' FA and corpus callosum's MD. Hemispheric asymmetries were found in the FA of the periventricular white matter (pvWM), intermediate zone, and subplate and in the MD of the ganglionic eminence and pvWM. This study provides valuable insight into the normal patterns of development of MD and FA in the fetal brain. These changes are closely linked with cytoarchitectonic changes and display indications of early functional specialization.
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Imagem de Tensor de Difusão , Substância Branca , Feminino , Humanos , Imagem de Tensor de Difusão/métodos , Encéfalo , Estudos Prospectivos , Imagem de Difusão por Ressonância Magnética , Imageamento por Ressonância Magnética , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , AnisotropiaRESUMO
Cleft lip/palate is a common orofacial malformation that often leads to speech/language difficulties as well as developmental delays in affected children, despite surgical repair. Our understanding of brain development in these children is limited. This study aimed to analyze prenatal brain development in fetuses with cleft lip/palate and controls. We examined in utero MRIs of 30 controls and 42 cleft lip/palate fetal cases and measured regional brain volumes. Cleft lip/palate was categorized into groups A (cleft lip or alveolus) and B (any combination of clefts involving the primary and secondary palates). Using a repeated-measures regression model with relative brain hemisphere volumes (%), and after adjusting for multiple comparisons, we did not identify significant differences in regional brain growth between group A and controls. Group B clefts had significantly slower weekly cerebellar growth compared with controls. We also observed divergent brain growth in transient brain structures (cortical plate, subplate, ganglionic eminence) within group B clefts, depending on severity (unilateral or bilateral) and defect location (hemisphere ipsilateral or contralateral to the defect). Further research is needed to explore the association between regional fetal brain growth and cleft lip/palate severity, with the potential to inform early neurodevelopmental biomarkers and personalized diagnostics.
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Fenda Labial , Fissura Palatina , Feminino , Criança , Gravidez , Humanos , Fenda Labial/diagnóstico por imagem , Fenda Labial/cirurgia , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/cirurgia , Encéfalo/diagnóstico por imagem , Encéfalo/anormalidades , FetoRESUMO
CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality, and reduced protective capacity. Despite considerable work interrogating the transcriptional regulation of exhausted CD8 T cells (TEX), the posttranscriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses during chronic viral infection and antagonized exhaustion. miR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and T cell receptor signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion toward a more beneficial memory-like CD8 T cell differentiation state.
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MicroRNAs , Neoplasias , Linfócitos T CD8-Positivos , Humanos , Imunoterapia/métodos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/metabolismo , Infecção PersistenteRESUMO
BACKGROUND: The RTS, S/AS01E malaria vaccine (RTS, S) is recommended for children in moderate-to-high Plasmodium falciparum malaria transmission areas. This phase 2b trial (NCT03276962) evaluates RTS, S fractional- and full-dose regimens in Ghana and Kenya. METHODS: 1500 children aged 5-17 months were randomised (1:1:1:1:1) to receive RTS, S or rabies control vaccine. RTS, S groups received two full RTS, S doses at month (M)0/M1 followed by either full (groups R012-20, R012-14-26) or fractional (1/5) doses (groups Fx012-14-26, Fx017-20-32). RESULTS: At M32 post-first dose, vaccine efficacy (VE) against clinical malaria (all episodes) ranged from 38% (R012-20; 95%CI: 24-49) to 53% (R012-14-26; 95%CI: 42-62). Vaccine impact estimates (cumulative number of malaria cases averted/1000 children vaccinated) were 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional- versus full-dose), in a post-hoc analysis, we also estimated cases averted/1000 RTS, S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), 880 (Fx017-20-32). CONCLUSIONS: VE against clinical malaria was similar in all RTS, S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If borne out through trial end (M50), these observations underscore the means to reduce cost per regimen with a goal of maximising impact and optimising supply.
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Diffusion-weighted Magnetic Resonance Imaging (dMRI) is increasingly used to study the fetal brain in utero. An important computation enabled by dMRI is streamline tractography, which has unique applications such as tract-specific analysis of the brain white matter and structural connectivity assessment. However, due to the low fetal dMRI data quality and the challenging nature of tractography, existing methods tend to produce highly inaccurate results. They generate many false streamlines while failing to reconstruct the streamlines that constitute the major white matter tracts. In this paper, we advocate for anatomically constrained tractography based on an accurate segmentation of the fetal brain tissue directly in the dMRI space. We develop a deep learning method to compute the segmentation automatically. Experiments on independent test data show that this method can accurately segment the fetal brain tissue and drastically improve the tractography results. It enables the reconstruction of highly curved tracts such as optic radiations. Importantly, our method infers the tissue segmentation and streamline propagation direction from a diffusion tensor fit to the dMRI data, making it applicable to routine fetal dMRI scans. The proposed method can facilitate the study of fetal brain white matter tracts with dMRI.
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INTRODUCTION: Suicide rates are elevated after cancer diagnosis. Existential distress caused by awareness of one's impending death is well-described in patients with cancer. The authors hypothesized that suicide risk is associated with cancer prognosis, and the impact of prognosis on suicide risk is greatest for populations with higher baseline suicide risk. METHODS: The authors identified patients (≥16 years old) with newly diagnosed cancers from 2000 to 2019 in the Surveillance, Epidemiology, and End Results database, representing 27% of US cancers. Multiple primary-standardized mortality ratios (SMR) were used to estimate the relative risk of suicide within 6 months of diagnosis compared to the general US population, adjusted for age, sex, race, and year of follow-up. Suicide rates by 20 most common cancer sites were compared with respective 2-year overall survival rates (i.e., prognosis) using a weighted linear regression model. RESULTS: Among 6,754,704 persons diagnosed with cancer, there were 1610 suicide deaths within 6 months of diagnosis, three times higher than the general population (SMR = 3.1; 95% confidence interval, 3.0-3.3). Suicide risk by cancer site was closely associated with overall prognosis (9.5%/percent survival deficit, R2 = 0.88, p < .0001). The association of prognosis with suicide risk became attenuated over time. For men, the risk of suicide increased by 2.8 suicide deaths per 100,000 person-years (p < .0001) versus 0.3 in women (p < .0001). The risk was also higher for persons ≥60 old and for the White (vs. Black) race. CONCLUSIONS: Poorer prognosis was closely associated with suicide risk early after cancer diagnosis and had a greater effect on populations with higher baseline risks of suicide. This model highlights the need for enhanced psychiatric surveillance and continued research in this patient population.
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Neoplasias , Suicídio , Humanos , Masculino , Feminino , Adolescente , Suicídio/psicologia , Neoplasias/diagnóstico , Neoplasias/psicologia , Prognóstico , Risco , Fatores de RiscoRESUMO
BACKGROUND & AIMS: Previous studies have shown an increasing incidence of pancreatic cancer (PC), especially in younger women; however, this has not been externally validated. In addition, there are limited data about contributing factors to this trend. We report age and sex-specific time-trend analysis of PC age-adjusted incidence rates (aIRs) using the National Program of Cancer Registries database without Surveillance Epidemiology and End Results data. METHODS: PC aIR, mortality rates, annual percentage change, and average annual percentage change (AAPC) were calculated and assessed for parallelism and identicalness. Age-specific analyses were conducted in older (≥55 years) and younger (<55 years) adults. PC incidence based on demographics, tumor characteristics, and mortality were evaluated in younger adults. RESULTS: A total of 454,611 patients were diagnosed with PC between 2001 and 2018 with significantly increasing aIR in women (AAPC = 1.27%) and men (AAPC = 1.14%) without a difference (P = .37). Similar results were seen in older adults. However, in younger adults (53,051 cases; 42.9% women), women experienced a greater increase in aIR than men (AAPCs = 2.36%, P < .001 vs 0.62%, P = 0.62) with nonparallel trends (P < .001) and AAPC difference of 1.74% (P < .001). This AAPC difference appears to be due to rising aIR in Blacks (2.23%; P < .001), adenocarcinoma histopathologic subtype (0.89%; P = .003), and location in the head-of-pancreas (1.64%; P < .001). PC mortality was found to be unchanged in women but decreasing in counterpart men (AAPC difference = 0.54%; P = .001). CONCLUSION: Using nationwide data, covering ≈64.5% of the U.S. population, we externally validate a rapidly increasing aIR of PC in younger women. There was a big separation of the incidence trend between women and men aged 15-34 years between 2001 and 2018 (>200% difference), and it did not show slowing down.
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Neoplasias Pancreáticas , Masculino , Humanos , Feminino , Estados Unidos/epidemiologia , Idoso , Incidência , Sistema de Registros , Neoplasias Pancreáticas/epidemiologia , Pâncreas , Neoplasias PancreáticasRESUMO
PURPOSE: To develop a self-navigated motion compensation strategy for 3D radial MRI that can compensate for continuous head motion by measuring rigid body motion parameters with high temporal resolution from the central k-space acquisition point (self-encoded FID navigator) in each radial spoke. METHODS: A forward model was created from low-resolution calibration data to simulate the effect of relative motion between the coil sensitivity profiles and the underlying object on the self-encoded FID navigator signal. Trajectory deviations were included in the model as low spatial-order field variations. Three volunteers were imaged at 3 T using a modified 3D gradient-echo sequence acquired with a Kooshball trajectory while performing abrupt and continuous head motion. Rigid body-motion parameters were estimated from the central k-space signal of each spoke using a least-squares fitting algorithm. The accuracy of self-navigated motion parameters was assessed relative to an established external tracking system. Quantitative image quality metrics were computed for images with and without retrospective correction using external and self-navigated motion measurements. RESULTS: Self-encoded FID navigators achieved mean absolute errors of 0.69 ± 0.82 mm and 0.73 ± 0.87° relative to external tracking for maximum motion amplitudes of 12 mm and 10°. Retrospective correction of the 3D radial data resulted in substantially improved image quality for both abrupt and continuous motion paradigms, comparable to external tracking results. CONCLUSIONS: Accurate rigid body motion parameters can be rapidly obtained from self-encoded FID navigator signals in 3D radial MRI to continuously correct for head movements. This approach is suitable for robust neuroanatomical imaging in subjects that exhibit patterns of large and frequent motion.
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Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Movimento (Física) , Artefatos , EncéfaloRESUMO
OBJECTIVE: Tuberous sclerosis complex (TSC) is associated with focal brain "tubers" and a high incidence of autism spectrum disorder (ASD). The location of brain tubers associated with autism may provide insight into the neuroanatomical substrate of ASD symptoms. METHODS: We delineated tuber locations for 115 TSC participants with ASD (n = 31) and without ASD (n = 84) from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network. We tested for associations between ASD diagnosis and tuber burden within the whole brain, specific lobes, and at 8 regions of interest derived from the ASD neuroimaging literature, including the anterior cingulate, orbitofrontal and posterior parietal cortices, inferior frontal and fusiform gyri, superior temporal sulcus, amygdala, and supplemental motor area. Next, we performed an unbiased data-driven voxelwise lesion symptom mapping (VLSM) analysis. Finally, we calculated the risk of ASD associated with positive findings from the above analyses. RESULTS: There were no significant ASD-related differences in tuber burden across the whole brain, within specific lobes, or within a priori regions derived from the ASD literature. However, using VLSM analysis, we found that tubers involving the right fusiform face area (FFA) were associated with a 3.7-fold increased risk of developing ASD. INTERPRETATION: Although TSC is a rare cause of ASD, there is a strong association between tuber involvement of the right FFA and ASD diagnosis. This highlights a potentially causative mechanism for developing autism in TSC that may guide research into ASD symptoms more generally. ANN NEUROL 2023;93:577-590.
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Transtorno do Espectro Autista , Transtorno Autístico , Esclerose Tuberosa , Humanos , Transtorno do Espectro Autista/patologia , Esclerose Tuberosa/complicações , Encéfalo/patologia , Neuroimagem , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: The use of positron-emission tomography (PET)/computed tomography (CT) in radiation therapy (RT) has increased. Radiation oncologists (RadOncs) have access to PET/CT with a variety of tracers for different tumor entities and use it for target volume definition. The German Society of Nuclear Medicine (DGN) and the German Society of Radiation Oncology (DEGRO) aimed to identify current patterns of care in order to improve interdisciplinary collaboration. METHODS: We created an online survey on participating RadOncs' use of PET tracers for different tumor entities and how they affect RT indication, dose prescription, and target volume definition. Further topics were reimbursement of PET/CT and organizational information (fixed timeslots and use of PET with an immobilization device [planning/RT-PET]). The survey contained 31 questions in German language (yes/no questions, multiple choice [MC] questions, multiple select [MS] questions, and free-text entry options). The survey was distributed twice via the DEGRO member mailing list. RESULTS: During the survey period (May 22-August 7, 2023) a total of 156 RadOncs (13% of respondents) answered the survey. Among these, 59% reported access to diagnostic PET/CT within their organization/clinic and 24% have fixed timeslots for their patients. 37% of survey participants can perform RT-PET and 29% have the option of providing a dedicated RT technician for planning PET. Besides [18F]-fluorodeoxyglucose (FDG; mainly used in lung cancer: 95%), diagnostic prostate-specific membrane antigen (PSMA)-PET/CT for RT of prostate cancer is routinely used by 44% of participants (by 64% in salvage RT). Use of amino acid PET in brain tumors and somatostatin receptor PET in meningioma is low (19 and 25%, respectively). Scans are reimbursed through private (75%) or compulsory (55%) health insurance or as part of indications approved by the German Joint Federal Committee (Gemeinsamer Bundesausschuss; 59%). 98% of RadOncs agree that PET impacts target volume definition and 62% think that it impacts RT dose prescription. DISCUSSION: This is the first nationwide survey on the role of PET/CT for RT planning among RadOncs in Germany. We find high acceptance of PET results for treatment decisions and target volume definition. Planning PET comes with logistic challenges for different healthcare settings (e.g., private practices vs. university hospitals). The decision to request PET/CT is often based on the possibility of reimbursement. CONCLUSION: PET/CT has become an important tool for RadOncs, with several indications. However, access is still limited at several sites, especially for dedicated RT-PET. This study aims to improve interdisciplinary cooperation and adequate implementation of current guidelines for the treatment of various tumor entities.
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AIM: The optimal management for early recurrent prostate cancer following radical prostatectomy (RP) in patients with negative prostate-specific membrane antigen positron-emission tomography (PSMA-PET) scan is an ongoing subject of debate. The aim of this study was to evaluate the outcome of salvage radiotherapy (SRT) in patients with biochemical recurrence with negative PSMA PET finding. METHODS: This retrospective, multicenter (11 centers, 5 countries) analysis included patients who underwent SRT following biochemical recurrence (BR) of PC after RP without evidence of disease on PSMA-PET staging. Biochemical recurrence-free survival (bRFS), metastatic-free survival (MFS) and overall survival (OS) were assessed using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predefined predictors of survival outcomes. RESULTS: Three hundred patients were included, 253 (84.3%) received SRT to the prostate bed only, 46 (15.3%) additional elective pelvic nodal irradiation, respectively. Only 41 patients (13.7%) received concomitant androgen deprivation therapy (ADT). Median follow-up after SRT was 33 months (IQR: 20-46 months). Three-year bRFS, MFS, and OS following SRT were 73.9%, 87.8%, and 99.1%, respectively. Three-year bRFS was 77.5% and 48.3% for patients with PSA levels before PSMA-PET ≤ 0.5 ng/ml and > 0.5 ng/ml, respectively. Using univariate analysis, the International Society of Urological Pathology (ISUP) grade > 2 (p = 0.006), metastatic pelvic lymph nodes at surgery (p = 0.032), seminal vesicle involvement (p < 0.001), pre-SRT PSA level of > 0.5 ng/ml (p = 0.004), and lack of concomitant ADT (p = 0.023) were significantly associated with worse bRFS. On multivariate Cox proportional hazards, seminal vesicle infiltration (p = 0.007), ISUP score >2 (p = 0.048), and pre SRT PSA level > 0.5 ng/ml (p = 0.013) remained significantly associated with worse bRFS. CONCLUSION: Favorable bRFS after SRT in patients with BR and negative PSMA-PET following RP was achieved. These data support the usage of early SRT for patients with negative PSMA-PET findings.
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Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Prognóstico , Antígeno Prostático Específico , Glândulas Seminais/patologia , Estudos Retrospectivos , Antagonistas de Androgênios , Recidiva Local de Neoplasia/patologia , Prostatectomia , Tomografia por Emissão de Pósitrons , Terapia de Salvação , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodosRESUMO
PURPOSE: Despite growing evidence for bilateral pelvic radiotherapy (whole pelvis RT, WPRT) there is almost no data on unilateral RT (hemi pelvis RT, HPRT) in patients with nodal recurrent prostate cancer after prostatectomy. Nevertheless, in clinical practice HPRT is sometimes used with the intention to reduce side effects compared to WPRT. Prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA-PET/CT) is currently the best imaging modality in this clinical situation. This analysis compares PSMA-PET/CT based WPRT and HPRT. METHODS: A propensity score matching was performed in a multi-institutional retrospective dataset of 273 patients treated with pelvic RT due to nodal recurrence (214 WPRT, 59 HPRT). In total, 102 patients (51 in each group) were included in the final analysis. Biochemical recurrence-free survival (BRFS) defined as prostate specific antigen (PSA) < post-RT nadir + 0.2ng/ml, metastasis-free survival (MFS) and nodal recurrence-free survival (NRFS) were calculated using the Kaplan-Meier method and compared using the log rank test. RESULTS: Median follow-up was 29 months. After propensity matching, both groups were mostly well balanced. However, in the WPRT group there were still significantly more patients with additional local recurrences and biochemical persistence after prostatectomy. There were no significant differences between both groups in BRFS (p = .97), MFS (p = .43) and NRFS (p = .43). After two years, BRFS, MFS and NRFS were 61%, 86% and 88% in the WPRT group and 57%, 90% and 82% in the HPRT group, respectively. Application of a boost to lymph node metastases, a higher RT dose to the lymphatic pathways (> 50 Gy EQD2α/ß=1.5 Gy) and concomitant androgen deprivation therapy (ADT) were significantly associated with longer BRFS in uni- and multivariate analysis. CONCLUSIONS: Overall, this analysis presents the outcome of HPRT in nodal recurrent prostate cancer patients and shows that it can result in a similar oncologic outcome compared to WPRT. Nevertheless, patients in the WPRT may have been at a higher risk for progression due to some persistent imbalances between the groups. Therefore, further research should prospectively evaluate which subgroups of patients are suitable for HPRT and if HPRT leads to a clinically significant reduction in toxicity.
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Concentrations of dissolved nitrogen in seawater can affect the resilience of the cnidarian-dinoflagellate symbiosis to climate change-induced bleaching. However, it is not yet known how the assimilation and translocation of the various nitrogen forms change during heat stress, nor how the symbiosis responds to nutrient depletion, which may occur due to increasing water stratification. Here, the tropical scleractinian coral Stylophora pistillata, in symbiosis with dinoflagellates of the genus Symbiodinium, was grown at different temperatures (26°C, 30°C and 34°C), before being placed in nutrient-replete or -depleted seawater for 24â h. The corals were then incubated with 13C-labelled sodium bicarbonate and different 15N-labelled nitrogen forms (ammonium, urea and dissolved free amino acids) to determine their assimilation rates. We found that nutrient depletion inhibited the assimilation of all nitrogen sources studied and that heat stress reduced the assimilation of ammonium and dissolved free amino acids. However, the host assimilated over 3-fold more urea at 30°C relative to 26°C. Overall, both moderate heat stress (30°C) and nutrient depletion individually decreased the total nitrogen assimilated by the symbiont by 66%, and combined, they decreased assimilation by 79%. This led to the symbiotic algae becoming nitrogen starved, with the C:N ratio increasing by over 3-fold at 34°C, potentially exacerbating the impacts of coral bleaching.
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Antozoários , Dinoflagellida , Resposta ao Choque Térmico , Simbiose , Antozoários/fisiologia , Antozoários/metabolismo , Animais , Dinoflagellida/fisiologia , Dinoflagellida/metabolismo , Resposta ao Choque Térmico/fisiologia , Nutrientes/metabolismo , Nitrogênio/metabolismo , Compostos de Nitrogênio/metabolismo , Água do Mar/química , Temperatura Alta , Aminoácidos/metabolismoRESUMO
BACKGROUND: There are no consensus definitions for evaluating kidney function recovery after acute kidney injury (AKI) and acute kidney disease (AKD), nor is it clear how recovery varies across populations and clinical subsets. We present a federated analysis of four population-based cohorts from Canada, Denmark and Scotland, 2011-18. METHODS: We identified incident AKD defined by serum creatinine changes within 48 h, 7 days and 90 days based on KDIGO AKI and AKD criteria. Separately, we applied changes up to 365 days to address widely used e-alert implementations that extend beyond the KDIGO AKI and AKD timeframes. Kidney recovery was based on resolution of AKD and a subsequent creatinine measurement below 1.2× baseline. We evaluated transitions between non-recovery, recovery and death up to 1 year; within age, sex and comorbidity subgroups; between subset AKD definitions; and across cohorts. RESULTS: There were 464 868 incident cases, median age 67-75 years. At 1 year, results were consistent across cohorts, with pooled mortalities for creatinine changes within 48 h, 7 days, 90 days and 365 days (and 95% confidence interval) of 40% (34%-45%), 40% (34%-46%), 37% (31%-42%) and 22% (16%-29%) respectively, and non-recovery of kidney function of 19% (15%-23%), 30% (24%-35%), 25% (21%-29%) and 37% (30%-43%), respectively. Recovery by 14 and 90 days was frequently not sustained at 1 year. Older males and those with heart failure or cancer were more likely to die than to experience sustained non-recovery, whereas the converse was true for younger females and those with diabetes. CONCLUSION: Consistently across multiple cohorts, based on 1-year mortality and non-recovery, KDIGO AKD (up to 90 days) is at least prognostically similar to KDIGO AKI (7 days), and covers more people. Outcomes associated with AKD vary by age, sex and comorbidities such that older males are more likely to die, and younger females are less likely to recover.
Assuntos
Injúria Renal Aguda , Rim , Masculino , Feminino , Humanos , Idoso , Creatinina , Estudos de Coortes , Doença Aguda , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Chronic kidney disease (CKD) is a growing global health concern. Identifying individuals in routine clinical care with new-onset CKD at high risk of rapid progression of the disease is imperative to guide allocation of prophylactic interventions, but community-based data are limited. We aimed to examine the risk of rapid progression, kidney failure, hospitalization and death among adults with incident CKD stage G3 and to clarify the association between predefined risk markers and rapid CKD progression. METHODS: Using plasma creatinine measurements for the entire Danish population from both hospitals and primary care, we conducted a nationwide, population-based cohort study, including adults in Denmark with incident CKD stage G3 in 2017-2020. We estimated 3-year risks of rapid progression (defined by a confirmed decline in estimated glomerular filtration rate of ≥5 mL/min/1.73 m2/year), kidney failure, all-cause hospitalization and death. To examine risk markers, we constructed a heat map showing the risk of rapid progression based on predefined markers: albuminuria, sex, diabetes and hypertension/cardiovascular disease. RESULTS: Among 133 443 individuals with incident CKD stage G3, the 3-year risk of rapid progression was 14.6% [95% confidence interval (CI) 14.4-14.8]. The 3-year risks of kidney failure, hospitalization and death were 0.3% (95% CI 0.3-0.4), 53.3% (95% CI 53.0-53.6) and 18.1% (95% CI 17.9-18.4), respectively. In the heat map, the 3-year risk of rapid progression ranged from 7% in females without albuminuria, hypertension/cardiovascular disease or diabetes, to 46%-47% in males and females with severe albuminuria, diabetes and hypertension/cardiovascular disease. CONCLUSION: This population-based study shows that CKD stage G3 is associated with considerable morbidity in a community-based setting and underscores the need for optimized prophylactic interventions among such patients. Moreover, our data highlight the potential of using easily accessible markers in routine clinical care to identify individuals who are at high risk of rapid progression.