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1.
Eur J Radiol ; 143: 109939, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34479124

RESUMO

INTRODUCTION: To investigate the value of contrast-enhanced CT findings - splenic and aortic radiodensities and their ratios (spleno-aortic ratio) - in predicting the prognosis of critical care unit patients (CCU). METHODS: One hundred thirteen continuous CCU patients with an acute deterioration (Group A: 37 women, age: 67.2 ± 14.0 years) were included in the retrospective study. Radiodensities of the spleen and aorta were evaluated by two radiologists separately. The spleno-aortic ratio was calculated. Matthews correlation coefficient (MCC) was used in conjunction with receiver operating characteristic analysis (ROC) to assess if and which parameter was most suitable for short-term mortality prediction. The intra-class correlation coefficient assessed consensus across readers. To validate the results for the best predictor, a second cohort was evaluated (Group B: 354 CT scans). RESULTS: The portal venous spleno-aortic ratio was best suited to predict 72-hour mortality (AUC = 0.91). A threshold ratio ≤0.53 predicted short-term mortality with a high sensitivity (80.95%) and specificity (96.74%, MCC = 0.79). The post-test probability was 85%, assuming a pre-test probability of 18.6% (72-hour mortality rate). ICCs of HU measurements in the aorta, spleen, and its ratios showed high interrater agreement (ICC: 0.92-0.99). In a control cohort, a threshold ratio ≤0.53 predicted CCU patients outcome satisfactorily (SENS = 83.93%, SPEC = 97.65%, PPV = 87.00%, NPV = 97.00%). CONCLUSIONS: The portal venous spleno-aortic ratio serves as a distinctive imaging feature to predict short-term mortality. For CCU patients with a cut-off portal venous spleno-aortic ratio ≤0.53, the risk of dying within three days after CT scan is approximately twenty times higher.


Assuntos
Aorta , Baço , Idoso , Idoso de 80 Anos ou mais , Cuidados Críticos , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Baço/diagnóstico por imagem
2.
Commun Biol ; 4(1): 1069, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521987

RESUMO

Primary visual cortex (V1) in humans is known to represent both veridically perceived external input and internally-generated contents underlying imagery and mental rotation. However, it is unknown how the brain keeps these contents separate thus avoiding a mixture of the perceived and the imagined which could lead to potentially detrimental consequences. Inspired by neuroanatomical studies showing that feedforward and feedback connections in V1 terminate in different cortical layers, we hypothesized that this anatomical compartmentalization underlies functional segregation of external and internally-generated visual contents, respectively. We used high-resolution layer-specific fMRI to test this hypothesis in a mental rotation task. We found that rotated contents were predominant at outer cortical depth bins (i.e. superficial and deep). At the same time perceived contents were represented stronger at the middle cortical bin. These results identify how through cortical depth compartmentalization V1 functionally segregates rather than confuses external from internally-generated visual contents. These results indicate that feedforward and feedback manifest in distinct subdivisions of the early visual cortex, thereby reflecting a general strategy for implementing multiple cognitive functions within a single brain region.

3.
Neuroimage ; 240: 118365, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34233220

RESUMO

Looking for objects within complex natural environments is a task everybody performs multiple times each day. In this study, we explore how the brain uses the typical composition of real-world environments to efficiently solve this task. We recorded fMRI activity while participants performed two different categorization tasks on natural scenes. In the object task, they indicated whether the scene contained a person or a car, while in the scene task, they indicated whether the scene depicted an urban or a rural environment. Critically, each scene was presented in an "intact" way, preserving its coherent structure, or in a "jumbled" way, with information swapped across quadrants. In both tasks, participants' categorization was more accurate and faster for intact scenes. These behavioral benefits were accompanied by stronger responses to intact than to jumbled scenes across high-level visual cortex. To track the amount of object information in visual cortex, we correlated multi-voxel response patterns during the two categorization tasks with response patterns evoked by people and cars in isolation. We found that object information in object- and body-selective cortex was enhanced when the object was embedded in an intact, rather than a jumbled scene. However, this enhancement was only found in the object task: When participants instead categorized the scenes, object information did not differ between intact and jumbled scenes. Together, these results indicate that coherent scene structure facilitates the extraction of object information in a task-dependent way, suggesting that interactions between the object and scene processing pathways adaptively support behavioral goals.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34254137

RESUMO

OBJECTIVES: The Cox-maze IV is the gold standard for surgical ablation of atrial fibrillation (AF). A heart-team hybrid approach using selected epicardial thoracoscopic surgical ablations and completion endocardial ablations to replicate the Cox-maze IV lesion set has gained popularity and early results have been promising. We herein report our single-centre long-term clinical outcomes using the heart-team hybrid approach with 455 patients. METHODS: From 1 March 2013 to 1 July 2019, we prospectively collected data on all patients referred to our heart team for rhythm-control strategy for AF. Baseline characteristics, procedural complications and long-term freedom from AF (FFAF) both on and off anti-arrhythmic drug therapy were analysed. Ambulatory monitoring (>7 days) was obtained at 3 months and annually thereafter. RESULTS: Four hundred and fifty-five patients completed the hybrid approach. Four hundred and forty-five (97.8%) patients had non-paroxysmal AF (long-standing persistent AF n = 249, 54.7%; persistent AF n = 196, 43.1%; paroxysmal AF n = 10, 2.2%). Average duration of AF was 5.9 ± 6.1 years. Average left atrial diameter was 4.8 ± 0.8 cm. FFAF at 3, 12, 24 and 36 months was 92%, 87%, 81% and 72%, respectively. FFAF without the use of anti-arrhythmic medications was 75%, 81%, 76% and 66%. Any surgical complications occurred in 28 (6.1%) patients. CONCLUSIONS: A heart-team hybrid strategy for the treatment of AF is safe and effective. In a predominantly non-paroxysmal population with AF, at the 3-year follow-up, FFAF in patients on and off anti-arrhythmic drugs approaches that of patients who had the Cox-maze IV.

5.
J Am Chem Soc ; 143(28): 10524-10529, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34232035

RESUMO

A novel, one-step N-dehydrogenation of amides to enamides is reported. This reaction employs the unlikely combination of LiHMDS and triflic anhydride, which serves as both the electrophilic activator and the oxidant, and is characterized by its simple setup and broad substrate scope. The synthetic utility of the formed enamides was readily demonstrated in a range of downstream transformations.

7.
PLoS Biol ; 19(5): e3001241, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33951043

RESUMO

The study of unconscious processing requires a measure of conscious awareness. Awareness measures can be either subjective (based on participant's report) or objective (based on perceptual performance). The preferred awareness measure depends on the theoretical position about consciousness and may influence conclusions about the extent of unconscious processing and about the neural correlates of consciousness. We obtained functional magnetic resonance imaging (fMRI) measurements from 43 subjects while they viewed masked faces and houses that were either subjectively or objectively invisible. Even for objectively invisible (perceptually indiscriminable) stimuli, we found significant category information in both early, lower-level visual areas and in higher-level visual cortex, although representations in anterior, category-selective ventrotemporal areas were less robust. For subjectively invisible stimuli, similar to visible stimuli, there was a clear posterior-to-anterior gradient in visual cortex, with stronger category information in ventrotemporal cortex than in early visual cortex. For objectively invisible stimuli, however, category information remained virtually unchanged from early visual cortex to object- and category-selective visual areas. These results demonstrate that although both objectively and subjectively invisible stimuli are represented in visual cortex, the extent of unconscious information processing is influenced by the measurement approach. Furthermore, our data show that subjective and objective approaches are associated with different neural correlates of consciousness and thus have implications for neural theories of consciousness.


Assuntos
Conscientização/fisiologia , Visão Ocular/fisiologia , Percepção Visual/fisiologia , Adolescente , Adulto , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Córtex Cerebral/fisiologia , Estado de Consciência/fisiologia , Feminino , Substância Cinzenta/fisiologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Estimulação Luminosa/métodos , Córtex Visual/fisiologia , Adulto Jovem
8.
J Neurosci ; 41(26): 5687-5698, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34031162

RESUMO

The successful recognition of familiar persons is critical for social interactions. Despite extensive research on the neural representations of familiar faces, we know little about how such representations unfold as someone becomes familiar. In three EEG experiments on human participants of both sexes, we elucidated how representations of face familiarity and identity emerge from different qualities of familiarization: brief perceptual exposure (Experiment 1), extensive media familiarization (Experiment 2), and real-life personal familiarization (Experiment 3). Time-resolved representational similarity analysis revealed that familiarization quality has a profound impact on representations of face familiarity: they were strongly visible after personal familiarization, weaker after media familiarization, and absent after perceptual familiarization. Across all experiments, we found no enhancement of face identity representation, suggesting that familiarity and identity representations emerge independently during face familiarization. Our results emphasize the importance of extensive, real-life familiarization for the emergence of robust face familiarity representations, constraining models of face perception and recognition memory.SIGNIFICANCE STATEMENT Despite extensive research on the neural representations of familiar faces, we know little about how such representations unfold as someone becomes familiar. To elucidate how face representations change as we get familiar with someone, we conducted three EEG experiments where we used brief perceptual exposure, extensive media familiarization, or real-life personal familiarization. Using multivariate representational similarity analysis, we demonstrate that the method of familiarization has a profound impact on face representations, and emphasize the importance of real-life familiarization. Additionally, familiarization shapes representations of face familiarity and identity differently: as we get to know someone, familiarity signals seem to appear before the formation of identity representations.

9.
Org Lett ; 23(6): 2094-2098, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33635665

RESUMO

A formal enone α-arylation is described. This metal-free transformation relies on the I(III)-mediated skeletal reorganization of silyl enol ethers and features mild conditions, good yields, and high stereoselectivities for ß-substituted enones.

10.
Neurology ; 96(9): e1272-e1277, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33408145

RESUMO

OBJECTIVE: To investigate the efficacy of tenecteplase (TNK), a genetically modified variant of alteplase with greater fibrin specificity and longer half-life than alteplase, prior to endovascular thrombectomy (EVT) in patients with basilar artery occlusion (BAO). METHODS: To determine whether TNK is associated with better reperfusion rates than alteplase prior to EVT in BAO, clinical and procedural data of consecutive patients with BAO from the Basilar Artery Treatment and Management (BATMAN) registry and the Tenecteplase vs Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) trial were retrospectively analyzed. Reperfusion >50% or absence of retrievable thrombus at the time of the initial angiogram was evaluated. RESULTS: We included 110 patients with BAO treated with IV thrombolysis prior to EVT (mean age 69 [SD 14] years; median NIH Stroke Scale score 16 [interquartile range (IQR) 7-32]). Nineteen patients were thrombolysed with TNK (0.25 mg/kg or 0.40 mg/kg) and 91 with alteplase (0.9 mg/kg). Reperfusion >50% occurred in 26% (n = 5/19) of patients thrombolysed with TNK vs 7% (n = 6/91) thrombolysed with alteplase (risk ratio 4.0, 95% confidence interval 1.3-12; p = 0.02), despite shorter thrombolysis to arterial puncture time in the TNK-treated patients (48 [IQR 40-71] minutes) vs alteplase-treated patients (110 [IQR 51-185] minutes; p = 0.004). No difference in symptomatic intracranial hemorrhage was observed (0/19 [0%] TNK, 1/91 [1%] alteplase; p = 0.9). CONCLUSIONS: TNK may be associated with an increased rate of reperfusion in comparison with alteplase before EVT in BAO. Randomized controlled trials to compare TNK with alteplase in patients with BAO are warranted. CLINICALTRIALSGOV IDENTIFIERS: NCT02388061 and NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that TNK leads to higher reperfusion rates in comparison with alteplase prior to EVT in patients with BAO.


Assuntos
Procedimentos Endovasculares/métodos , Fibrinolíticos/uso terapêutico , Tenecteplase/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Insuficiência Vertebrobasilar/tratamento farmacológico , Insuficiência Vertebrobasilar/cirurgia , Idoso , Idoso de 80 Anos ou mais , Angiografia Cerebral , Feminino , Fibrina/efeitos dos fármacos , Fibrinolíticos/farmacocinética , Meia-Vida , Humanos , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/epidemiologia , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/cirurgia , Masculino , Pessoa de Meia-Idade , Reperfusão , Estudos Retrospectivos , Tenecteplase/farmacocinética , Ativador de Plasminogênio Tecidual/farmacocinética , Resultado do Tratamento
11.
J Neurointerv Surg ; 13(3): 221-225, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32527939

RESUMO

BACKGROUND: To assess whether thrombus surface morphology has an impact on first pass reperfusion in contact aspiration (CA) and stent retriever (SR) thrombectomy. METHODS: From January 2016 to December 2018, consecutive stroke patients with an occlusion of the middle cerebral artery and thrombectomy (CA or SR) were examined in this retrospective study. We assessed patients' characteristics, procedural data and clinical outcome. Thrombus surface on pretreatment digital subtraction angiography (DSA) was categorized into regular versus irregular phenotype by blinded three-reader-consensus. Primary outcome was successful reperfusion (modified treatment in cerebral ischemia (mTICI) 2b-3) after first pass. Data analysis was stratified according to thrombectomy technique and thrombus phenotype. RESULTS: Among 203 patients (76 years (IQR 65.5-81.9), 47.3% male, National Institutes of Health Stroke Scale Score 16 (IQR 12-20)), 155 patients were treated primarily with CA and 48 with SR. 40% (n=62/155) CA and 41.7% (n=20/48) SR-treated patients had a regular thrombus phenotype. In the CA group, successful reperfusion after first pass was more frequently obtained in patients with regular compared with irregular phenotype (69.4% (n=43/62) vs 34.4% (n=32/93); P<0.0001). In contrast, in the SR group, reperfusion after first pass was achieved in 35% (n=7/20; P=0.01) of patients with regular phenotypes. In the CA group, median number of passes (1 (1-2) vs 2 (1-4); P<0.00001) and time from reaching the thrombus to reperfusion (19±27 vs 38±36 min; P=0.0001) were lower among patients with a regular phenotype. CONCLUSION: Direct CA is associated with higher rates of successful first pass reperfusion in patients with a regular thrombus phenotype in pretreatment DSA.


Assuntos
Isquemia Encefálica/cirurgia , Paracentese/métodos , Reperfusão/métodos , Stents , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Idoso , Idoso de 80 Anos ou mais , Angiografia Digital/métodos , Isquemia Encefálica/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Stents/efeitos adversos , Acidente Vascular Cerebral/diagnóstico por imagem , Trombose/diagnóstico por imagem , Trombose/cirurgia , Resultado do Tratamento
12.
Neurology ; 96(3): e343-e351, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33144517

RESUMO

OBJECTIVE: To determine whether thrombectomy is safe in children up to 24 hours after onset of symptoms when selected by mismatch between clinical deficit and infarct. METHODS: A secondary analysis of the Save ChildS Study (January 2000-December 2018) was performed, including all pediatric patients (<18 years) diagnosed with arterial ischemic stroke who underwent endovascular recanalization at 27 European and United States stroke centers. Patients were included if they had a relevant mismatch between clinical deficit and infarct. RESULTS: Twenty children with a median age of 10.5 (interquartile range [IQR] 7-14.6) years were included. Of those, 7 were male (35%), and median time from onset to thrombectomy was 9.8 (IQR 7.8-16.2) hours. Neurologic outcome improved from a median Pediatric NIH Stroke Scale score of 12.0 (IQR 8.8-20.3) at admission to 2.0 (IQR 1.2-6.8) at day 7. Median modified Rankin Scale (mRS) score was 1.0 (IQR 0-1.6) at 3 months and 0.0 (IQR 0-1.0) at 24 months. One patient developed transient peri-interventional vasospasm; no other complications were observed. A comparison of the mRS score to the mRS score in the DAWN and DEFUSE 3 trials revealed a higher proportion of good outcomes in the pediatric compared to the adult study population. CONCLUSIONS: Thrombectomy in pediatric ischemic stroke in an extended time window of up to 24 hours after onset of symptoms seems safe and neurologic outcomes are generally good if patients are selected by a mismatch between clinical deficit and infarct. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for children with acute ischemic stroke with a mismatch between clinical deficit and infarct size, thrombectomy is safe.


Assuntos
Embolectomia , AVC Isquêmico/cirurgia , Seleção de Pacientes , Trombectomia , Adolescente , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
13.
Abdom Radiol (NY) ; 46(5): 2107-2114, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33306145

RESUMO

PURPOSE: To investigate whether adrenal gland radiodensities alone or set in relation to either the inferior vena cava (IVC) or the spleen can predict hospital mortality in intensive care unit patients. METHODS: One hundred thirty-three intensive care patients (90 males, age: 66.3 ± 14.5 years) with an acute clinical deterioration were included in this retrospective analysis. CT attenuation (Hounsfield units) of adrenal glands, IVC, and spleen was evaluated by 2 radiologists separately. Adrenal-to-IVC and adrenal-to-spleen ratios were calculated. Receiver operating characteristic (ROC) analysis, combined with the Matthews correlation coefficient (MCC) as a classifier, was used to assess which parameter is the most suitable for short-term, intermediate-term, and overall mortality prediction. Interrater agreement was assessed using intraclass correlation coefficient (ICC). RESULTS: The highest discriminative power to distinguish between deceased and survivors was found for the adrenal gland-to-spleen ratio for the 72-h mortality. A threshold of > 1.4 predicted 72-h mortality with a sensitivity of 79.31% and a specificity of 98.08% (area und the curve (AUC) = 0.94; p < 0.0001; MCCs = 0.81). The positive likelihood ratio was 41; the positive predictive value was 92.20%. Adrenal gland-to-spleen ratio was also best suited to predict the 24-h and overall mortality. ICCs of HU measurements in adrenal gland, IVC, and spleen indicated a high interrater agreement (ICC 0.95-0.99). CONCLUSIONS: To conclude, the adrenal-to-spleen ratio in CT in portal venous phase may serve as an imaged-based predictor for short, intermediate, and overall mortality and as reproducible prognostic marker for patient outcome.


Assuntos
Glândulas Suprarrenais , Baço , Glândulas Suprarrenais/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Baço/diagnóstico por imagem
14.
ACS Cent Sci ; 6(11): 1869-1889, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33274267

RESUMO

Over the past several decades, macrocyclic compounds have emerged as increasingly significant therapeutic candidates in drug discovery. Their pharmacological activity hinges on their rotationally restricted three-dimensional orientation, resulting in a unique conformational preorganization and a high enthalpic gain as a consequence of high-affinity macrocycle-protein binding interactions. Synthetic access to macrocyclic drug candidates is therefore crucial. From a synthetic point of view, the efficiency of macrocyclization events commonly suffers from entropic penalties as well as undesired intermolecular couplings (oligomerization). Although over the past several decades ring-closing metathesis, macrolactonization, or macrolactamization have become strategies of choice, the toolbox of organic synthesis provides a great number of versatile transformations beyond the aforementioned. This Outlook focuses on a selection of examples employing what we term unconventional macrocyclizations toward the synthesis of natural products or analogues.

15.
Materials (Basel) ; 13(22)2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33182632

RESUMO

Martensitic steels are tempered to increase the toughness of the metastable martensite, which is brittle in the as-quenched state, and to achieve a more stable microstructure. During the tempering of steels, several particular overlapping effects can arise. Classical dilatometric investigations can only detect effects by monitoring the integral length change of the sample. Additional in-situ diffractometry allowed a differentiation of the individual effects such as transformation of retained austenite and formation of cementite during tempering. Additionally, the lattice parameters of martensite and therefrom the tetragonality was analyzed. Two low-alloy steels with carbon contents of 0.4 and 1.0 wt.% and a high-alloy 5Cr-1Mo-steel with 0.4 wt.% carbon were investigated by dilatometry and in-situ diffractometry. In this paper, microstructural effects during tempering of the investigated steels are discussed by a comparative study of dilatometric and diffractometric experiments. The influence of the chemical composition on the tempering behavior is illustrated by comparing the determined effects of the three steels. The kinetics of tempering is similar for the low-alloy steels and shifted to much higher temperatures for the high-alloy steel. During tempering, the tetragonality of martensite in the steel with 1.0 wt% carbon shifts towards a low carbon behavior, as in the steels with 0.4 wt.% carbon.

16.
Sci Rep ; 10(1): 16852, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033356

RESUMO

When we see a face, we rapidly form an impression of its attractiveness. Here, we investigated how rapidly representations of facial attractiveness emerge in the human brain. In an EEG experiment, participants viewed 100 face photographs and rated them for their attractiveness. Using time-resolved representational similarity analysis on the EEG data, we reveal representations of facial attractiveness after 150-200 ms of cortical processing. Interestingly, we show that these representations are related to individual participants' personal attractiveness judgments, suggesting that already early perceptual representations of facial attractiveness convey idiosyncratic attractiveness preferences. Further, we show that these early representations are genuinely related to attractiveness, as they are neither explained by other high-level face attributes, such as face sex or age, nor by features extracted by an artificial deep neural network model of face processing. Together, our results demonstrate early, individually specific, and genuine representations of facial attractiveness, which may underlie fast attractiveness judgments.


Assuntos
Beleza , Encéfalo/fisiologia , Face/fisiologia , Expressão Facial , Reconhecimento Facial/fisiologia , Julgamento/fisiologia , Percepção Visual/fisiologia , Adulto , Eletroencefalografia , Feminino , Humanos , Masculino , Rede Nervosa/fisiologia , Estimulação Luminosa , Fotografação , Adulto Jovem
17.
Chemistry ; 26(67): 15509-15512, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035360

RESUMO

A synthetically convenient approach for the direct α-deuteration of amides is reported. This mechanistically unusual process relies on a retro-ene-type process, triggered by the addition of deuterated dimethyl sulfoxide to a keteniminium intermediate, generated through electrophilic amide activation. The transformation displays broad functional-group tolerance and high deuterium incorporation.

18.
BMJ ; 371: m3734, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087345

RESUMO

OBJECTIVE: To assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model. DESIGN: Investigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13). SETTING: Charité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union). PARTICIPANTS: Recipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9). INTERVENTIONS: CD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48. MAIN OUTCOME MEASURES: The primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio. RESULTS: For all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire. CONCLUSIONS: The application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies. TRIAL REGISTRATION: NCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).


Assuntos
Imunossupressão/métodos , Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Linfócitos T Reguladores/transplante , Tacrolimo/administração & dosagem , Adulto , Aloenxertos/imunologia , Estudos de Viabilidade , Feminino , Alemanha , Sobrevivência de Enxerto/imunologia , Humanos , Infusões Intravenosas , Rim/imunologia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Resultado do Tratamento , Suspensão de Tratamento
19.
Artigo em Inglês | MEDLINE | ID: mdl-32986177

RESUMO

PURPOSE: Optimal stroke prevention strategies for patients with atrial fibrillation (AF) who experience a major bleed are poorly defined. We sought to estimate the effectiveness and safety of oral anticoagulation (OAC) represcription after an OAC contraindication. METHODS: TREAT-AF is a retrospective cohort study of patients with newly diagnosed AF (2004-2012), treated in the Veterans Health Administration. From this cohort, we identified patients with a contraindication to OAC after AF diagnoses, defined as incident intracranial bleeding, non-intracranial bleeding requiring hospitalization, or unrepaired cerebral aneurysm or aortic dissection. We used multivariate Cox proportional hazards to estimate the association of OAC prescription in the 90 days following OAC contraindication to ischemic stroke and rebleeding. RESULTS: Among 167,190 patients with newly diagnosed AF (70 ± 11 years, 1.7% female, CHA2DS2-VASc 2.7 ± 1.7), 19,285 patients (11.5%) had an incident bleed (n = 18,342) or an unrepaired cerebral aneurysm or aortic dissection (n = 943). For OAC-contraindicated patients with a CHA2DS2-VASc ≥2 (N = 16,194), OAC was represcribed in 4075 patients (25%) and was associated with a higher risk of non-intracranial bleeding (HR 1.49; 95% CI 1.37-1.61; p < 0.0001) but no difference in intracranial bleeding. There was a trend toward decreased stroke risk (HR 0.85; 95% CI 0.71-1.02; p 0.09). CONCLUSIONS: Development of contraindication to OAC after diagnosis of AF is common (11.5%), with most events requiring hospitalization. OAC reinitiation was associated with non-intracranial bleeding risk, with a trend toward reduced stroke risk. These data suggest that stroke prevention approaches after major bleeding events could be beneficial if bleeding risk can be successfully mitigated.

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