RESUMO
Background: There are no high-quality data to guide long-term mycophenolate mofetil (MMF) dosing in kidney transplant recipients (KTRs) to balance the long-term risks of allograft rejection with that of infections and malignancy. At our center, KTRs are managed with either a "preemptive" dose reduction strategy, where the MMF dose is reduced after the first year before the development of adverse events, or with a "reactive" dosing strategy, where they are maintained on the same MMF dose and only reduced if they develop an adverse event. We hypothesized that a preemptive MMF dosing strategy after the first year of transplantation is associated with decreased infections without increasing alloimmune complications. Methods: We conducted a retrospective cohort study of all KTRs receiving MMF from January 1, 2015, to December 31, 2020. The primary outcome was the incidence of infections requiring hospitalization. Results: One hundred forty-two KTRs met the inclusion criteria, of whom 44 (31%) were in the preemptive group and 98 (69%) were in the reactive group. The median follow-up was 4 y (interquartile range, 3.8-4.0). Multivariable analysis showed that a preemptive MMF dose reduction strategy was associated with a lower risk of infections requiring hospitalization (adjusted hazard ratio = 0.39; 95% confidence interval, 0.16-0.92). There was no difference in graft loss, rejection, or estimated glomerular filtration rate slope. Conclusions: Preemptive MMF dose reduction in KTRs may be an effective strategy to prevent infections without increasing the risk of allograft rejection. Randomized clinical trials are needed to confirm these findings.
RESUMO
Motivationally salient stimuli, such as those associated with reward, can automatically gain attentional prioritisation - even when individuals are motivated to ignore such stimuli. This 'attentional bias for reward' has often been interpreted as evidence for involuntary Pavlovian 'sign tracking' behaviour. The prioritisation of reward-signalling distractors may additionally reflect a drive to gain information about the state of the world, irrespective of the particular reward that is being signalled. In the current study we assessed whether forewarning participants on each trial as to the upcoming features of a distractor would reduce reward-related attentional capture. This manipulation reduces the information provided by the distractor, without affecting the magnitude of the signalled reward. Using eye tracking in Experiment 1, we found that reward-related attentional capture was virtually eliminated when participants were informed of the upcoming distractor colour (relative to the baseline condition when no information was provided). In Experiment 2, using a response-time version of the task, we again found a significant reduction in reward-related attentional capture when participants received information about the colour of an upcoming distractor, or information about the value of the upcoming reward. Finally, in Experiment 3 we assessed whether participants were using the pre-trial information to strategically inhibit attention to the upcoming distractor colour. The results of these experiments are discussed within the context of information-seeking accounts of reward-related attentional capture effects.
RESUMO
Our prior experiences shape the way that we prioritize information from the environment for further processing, analysis, and action. We show in three experiments that this process of attentional prioritization is critically modulated by the degree of uncertainty in these previous experiences. Participants completed a visual search task in which they made a saccade to a target to earn a monetary reward. The color of a color-singleton distractor in the search array signaled the reward outcome(s) that were available, with different degrees of variance (uncertainty). Participants were never required to look at the colored distractor, and doing so would slow their response to the target. Nevertheless, across all experiments, participants were more likely to look at distractors associated with high outcome variance versus low outcome variance. This pattern was observed when all distractors had equal expected value (Experiment 1), when the difference in variance was opposed by a difference in expected value (i.e., the high-variance distractor had a low expected value, and vice versa: Experiment 2), and when high- and low-variance distractors were paired with the maximum-value outcome on an equal proportion of trials (Experiment 3). Our findings demonstrate that experience of prediction error plays a fundamental role in guiding "attentional exploration," wherein priority is driven by the potential for a stimulus to reduce future uncertainty through a process of learning, as opposed to maximizing current information gain. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Assuntos
Atenção , Humanos , Atenção/fisiologia , Incerteza , Feminino , Masculino , Adulto , Adulto Jovem , Recompensa , Tempo de Reação/fisiologiaRESUMO
OBJECTIVES: The surgical training of gynecologic oncology (GO) fellows is critical to providing excellent care to women with gynecologic cancers. We sought to evaluate changes in techniques and surgical volumes over an 18-year period among established GO fellowships across the US. METHODS: We emailed surveys to 30 GO programs that had trained fellows for at least 18 years. Surveys requested the number of surgical cases performed by a fellow for seventeen surgical procedures over each of five-time intervals. A One-Way Analysis of Variance was conducted for each procedure, averaged across institutions, to examine whether each procedure significantly changed over the 18-year span. RESULTS: 14 GO programs responded and were included in the analysis using SPSS. We observed a significant increase in the use of minimally invasive (MIS) procedures (robotic hysterectomy (p < .001), MIS pelvic (p = .001) and MIS paraaortic lymphadenectomy (p = .008). There was a concurrent significant decrease in corresponding "open" procedures. There was a significant decrease in all paraaortic lymphadenectomies. Complex procedures (such as bowel resection) remained stable. However, there was a wide variation in the number of cases reported with extremely small numbers for some critical procedures. CONCLUSIONS: The experience of GO fellows has shifted toward increased use of MIS. While these trends in care are appropriate, they do not diminish the need in many patients for complex open procedures. These findings should help spur the development of innovative training to maintain the ability to provide these core, specialty-defining procedures safely.
Assuntos
Bolsas de Estudo , Procedimentos Cirúrgicos em Ginecologia , Ginecologia , Oncologia , Humanos , Feminino , Bolsas de Estudo/tendências , Bolsas de Estudo/estatística & dados numéricos , Ginecologia/educação , Ginecologia/tendências , Procedimentos Cirúrgicos em Ginecologia/educação , Procedimentos Cirúrgicos em Ginecologia/tendências , Oncologia/educação , Oncologia/tendências , Neoplasias dos Genitais Femininos/cirurgia , Estados Unidos , Histerectomia/educação , Histerectomia/tendências , Histerectomia/estatística & dados numéricos , Histerectomia/métodos , Educação de Pós-Graduação em Medicina/tendências , Educação de Pós-Graduação em Medicina/métodos , Inquéritos e QuestionáriosRESUMO
Attentional prioritisation of stimuli in the environment plays an important role in overt choice. Previous research shows that prioritisation is influenced by the magnitude of paired rewards, in that stimuli signalling high-value rewards are more likely to capture attention than stimuli signalling low-value rewards; and this attentional bias has been proposed to play a role in addictive and compulsive behaviours. A separate line of research has shown that win-related sensory cues can bias overt choices. However, the role that these cues play in attentional selection is yet to be investigated. Participants in this study completed a visual search task in which they responded to a target shape in order to earn reward. The colour of a distractor signalled the magnitude of reward and type of feedback on each trial. Participants were slower to respond to the target when the distractor signalled high reward compared to when the distractor signalled low reward, suggesting that the high-reward distractors had increased attentional priority. Critically, the magnitude of this reward-related attentional bias was further increased for a high-reward distractor with post-trial feedback accompanied by win-related sensory cues. Participants also demonstrated an overt choice preference for the distractor that was associated with win-related sensory cues. These findings demonstrate that stimuli paired with win-related sensory cues are prioritised by the attention system over stimuli with equivalent physical salience and learned value. This attentional prioritisation may have downstream implications for overt choices, especially in gambling contexts where win-related sensory cues are common.
Assuntos
Viés de Atenção , Sinais (Psicologia) , Humanos , Tempo de Reação , Atenção , Aprendizagem , RecompensaRESUMO
It is critical to understand the laws of quantum mechanics in transformative technologies for computation and quantum information science applications to enable the ongoing second quantum revolution calls. Recently, spin qubits based on point defects have gained great attention, since these qubits can be initiated, selectively controlled, and read out with high precision at ambient temperature. The major challenge in these systems is controllably generating multiqubit systems while properly coupling the defects. To address this issue, we began by tackling the engineering challenges these systems present and understanding the fundamentals of defects. In this regard, we controllably generate defects in MoS2 and WS2 monolayers and tune their physicochemical properties via proton irradiation. We quantitatively discovered that the proton energy could modulate the defects' density and nature; higher defect densities were seen with lower proton irradiation energies. Three distinct defect types were observed: vacancies, antisites, and adatoms. In particular, the creation and manipulation of antisite defects provides an alternative way to create and pattern spin qubits based on point defects. Our results demonstrate that altering the particle irradiation energy can regulate the formation of defects, which can be utilized to modify the properties of 2D materials and create reliable electronic devices.
RESUMO
Self-generated overt actions are preceded by a slow negativity as measured by electroencephalogram, which has been associated with motor preparation. Recent studies have shown that this neural activity is modulated by the predictability of action outcomes. It is unclear whether inner speech is also preceded by a motor-related negativity and influenced by the same factor. In three experiments, we compared the contingent negative variation elicited in a cue paradigm in an active vs. passive condition. In Experiment 1, participants produced an inner phoneme, at which an audible phoneme whose identity was unpredictable was concurrently presented. We found that while passive listening elicited a late contingent negative variation, inner speech production generated a more negative late contingent negative variation. In Experiment 2, the same pattern of results was found when participants were instead asked to overtly vocalize the phoneme. In Experiment 3, the identity of the audible phoneme was made predictable by establishing probabilistic expectations. We observed a smaller late contingent negative variation in the inner speech condition when the identity of the audible phoneme was predictable, but not in the passive condition. These findings suggest that inner speech is associated with motor preparatory activity that may also represent the predicted action-effects of covert actions.
Assuntos
Eletroencefalografia , Fala , Humanos , Fala/fisiologia , Eletroencefalografia/métodos , Variação Contingente Negativa/fisiologiaRESUMO
Purpose: In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population.Patients and Methods: Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were randomly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II).Results: Seven hundred ninety-two eligible patients were enrolled onto the study. Prognostic factors were similar in the two treatment groups. Gastrointestinal, renal, and metabolic toxicity, as well as grade 4 leukopenia, were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II. Neurologic toxicity was similar in both regimens. Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval [CI], 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02).Conclusion: In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel.
RESUMO
OBJECTIVE: We sought to document current surgical practices among gynecologic oncologists in the United States. METHODS: In March/April 2020, we conducted a cross-sectional survey among members of the Society of Gynecologic Oncology to identify gynecologic oncology practice trends in the United States. The survey collected demographic data and queried participants on types of surgical procedures performed and chemotherapy use. Univariant and multivariant analyses were used to evaluate the association between surgeon practice type, region of practice, working with gynecologic oncology fellows, time in practice, and dominant surgical modality of practice on performance of specific procedures. RESULTS: Among 1199 gynecologic oncology surgeons who were emailed the survey, 724 completed the survey (60.4% response rate). Of these respondents, 170 (23.5%) were within 6 years of fellowship graduation, 368 (50.8%) identified as female; and 479 (66.2%) worked in an academic setting. Surgeons who worked with gynecologic oncology fellows were more likely to perform bowel surgery, upper abdominal surgery, complex upper abdominal surgery, and prescribe chemotherapy. Surgeons who were ≥ 13 years out from fellowship graduation were more likely to perform bowel surgery and complex abdominal surgery and less likely to prescribe chemotherapy and perform sentinel lymph node dissections (P < 0.05). CONCLUSIONS: These findings highlight the variation in surgical procedures performed by gynecologic oncologists in the United States. These data support that there are practice variations that would benefit from further investigation.
Assuntos
Ginecologia , Oncologistas , Feminino , Humanos , Estados Unidos , Estudos Transversais , Excisão de Linfonodo , Inquéritos e QuestionáriosRESUMO
We study the nanoscale patterns that form on the surface of a rotating sample of an elemental material that is bombarded with a broad noble gas ion beam for angles of incidence θ just above the critical angle for pattern formation θ_{c}. The pattern formation depends crucially on the ion energy E. In simulations carried out in the low-energy regime in which sputtering is negligible, we find disordered arrays of nanoscale mounds (nanodots) that coarsen in time. Disordered arrays of nanodots also form in the high-energy regime in which there is substantial sputtering, but no coarsening occurs close to the threshold angle. Finally, for values of E just above the sputter yield threshold, nanodot arrays with an extraordinary degree of hexagonal order emerge for a range of parameter values, even though there is a broad band of linearly unstable wavelengths. This finding might prove to be useful in applications in which highly ordered nanoscale patterns are needed.
RESUMO
OBJECTIVES: There is considerable variation in ordering practices for the initial laboratory evaluation of monoclonal gammopathies (MGs) despite clear society guidelines to include serum free light chain (sFLC) testing. We assessed the ability of a clinical decision support (CDS) alert to improve guideline compliance and analyzed its clinical impact. METHODS: We designed and deployed a targeted CDS alert to educate and prompt providers to order an sFLC assay when ordering serum protein electrophoresis (SPEP) testing. RESULTS: The alert was highly effective at increasing the co-ordering of SPEP and sFLC testing. Preimplementation, 62.8% of all SPEP evaluations included sFLC testing, while nearly 90% of evaluations included an sFLC assay postimplementation. In patients with no prior sFLC testing, analysis of sFLC orders prompted by the alert led to the determination that 28.9% (800/2,769) of these patients had an abnormal κ/λ ratio. In 452 of these patients, the sFLC assay provided the only laboratory evidence of a monoclonal protein. Moreover, within this population, there were numerous instances of new diagnoses of multiple myeloma and other MGs. CONCLUSIONS: The CDS alert increased compliance with society guidelines and improved the diagnostic evaluation of patients with suspected MGs.
Assuntos
Sistemas de Apoio a Decisões Clínicas , Mieloma Múltiplo , Paraproteinemias , Humanos , Paraproteinemias/diagnóstico , Cadeias Leves de ImunoglobulinaRESUMO
The phenomenon of sensory self-suppression - also known as sensory attenuation - occurs when a person generates a perceptible stimulus (such as a sound) by performing an action (such as speaking). The sensorimotor control system is thought to actively predict and then suppress the vocal sound in the course of speaking, resulting in lowered cortical responsiveness when speaking than when passively listening to an identical sound. It has been hypothesized that auditory hallucinations in schizophrenia result from a reduction in self-suppression due to a disruption of predictive mechanisms required to anticipate and suppress a specific, self-generated sound. It has further been hypothesized that this suppression is evident primarily in theta band activity. Fifty-one people, half of whom had a diagnosis of schizophrenia, were asked to repeatedly utter a single syllable, which was played back to them concurrently over headphones while EEG was continuously recorded. In other conditions, recordings of the same spoken syllables were played back to participants while they passively listened, or were played back with their onsets preceded by a visual cue. All participants experienced these conditions with their voice artificially shifted in pitch and also with their unaltered voice. Suppression was measured using event-related potentials (N1 component), theta phase coherence and power. We found that suppression was generally reduced on all metrics in the patient sample, and when voice alteration was applied. We additionally observed reduced theta coherence and power in the patient sample across all conditions. Visual cueing affected theta coherence only. In aggregate, the results suggest that sensory self-suppression of theta power and coherence is disrupted in schizophrenia.
Assuntos
Córtex Auditivo , Esquizofrenia , Humanos , Esquizofrenia/complicações , Fala , Potenciais Evocados Auditivos , Potenciais EvocadosRESUMO
Attention, the mechanism that prioritizes stimuli in the environment for further processing, plays an important role in behavioral choice. In the present study, we investigated the automatic orienting of attention to cues that signal reward. Such attentional capture occurs despite negative consequences, and we investigated whether this counterproductive and reflexive behavior would persist following outcome devaluation. Thirsty participants completed a visual search task in which the color of a distractor stimulus in the search display signaled whether participants would earn water or potato chips for making a rapid eye movement to a diamond target, but looking at the colored distractor was punished by omission of the signaled reward. Nevertheless, participants looked at the water-signaling distractor more frequently than the chip-signaling distractor. Half the participants then drank water ad libitum before continuing with the visual search task. Although the water was now significantly less desirable for half of the participants, there was no difference between groups in the tendency for the water-signaling distractor to capture attention. These findings suggest that once established, counterproductive attentional bias to signals of reward persists even when those outcomes are no longer valuable. This suggests a "habit-like" attentional mechanism that prioritizes reward stimuli in the environment for further action, regardless of whether those stimuli are aligned with current goals or currently desired.
Assuntos
Sinais (Psicologia) , Recompensa , Hábitos , Humanos , Tempo de ReaçãoRESUMO
Existing research demonstrates different ways in which attentional prioritization of salient nontarget stimuli is shaped by prior experience: Reward learning renders signals of high-value outcomes more likely to capture attention than signals of low-value outcomes, whereas statistical learning can produce attentional suppression of the location in which salient distractor items are likely to appear. The current study combined manipulations of the value and location associated with salient distractors in visual search to investigate whether these different effects of selection history operate independently or interact to determine overall attentional prioritization of salient distractors. In Experiment 1, high-value and low-value distractors most frequently appeared in the same location; in Experiment 2, high-value and low-value distractors typically appeared in distinct locations. In both experiments, effects of distractor value and location were additive, suggesting that attention-promoting effects of value and attention-suppressing effects of statistical location-learning independently modulate overall attentional priority. Our findings are consistent with a view that sees attention as mediated by a common priority map that receives and integrates separate signals relating to physical salience and value, with signal suppression based on statistical learning determined by physical salience, but not incentive salience.
Assuntos
Atenção , Aprendizagem , Humanos , Tempo de Reação , RecompensaRESUMO
Preformed donor-specific antibodies are associated with a higher risk of rejection and worse graft survival in organ transplantation. However, in heart transplantation, the risk and benefit balance between high mortality on the waiting list and graft survival may allow the acceptance of higher immunologic risk donors in broadly sensitized recipients. Transplanting donor-recipient pairs with a positive complement dependent cytotoxic (CDC) crossmatch carries the highest risk of hyperacute rejection and immediate graft loss and is usually avoided in kidney transplantation. Herein we report the first successful simultaneous heart-kidney transplant with a T- and B-cell CDC crossmatch positive donor using a combination of rituximab, intravenous immunoglobulin, plasmapheresis, bortezomib and rabbit anti-thymocyte globulin induction followed by eculizumab therapy for two months post-transplant. In the year following transplantation, both allografts maintained stable graft function (all echocardiographic left ventricular ejection fractions ≥ 65%, eGFR>60) and showed no histologic evidence of antibody-mediated rejection. In addition, the patient has not developed any severe infections including cytomegalovirus or BK virus infection. In conclusion, a multitarget immunosuppressive regimen can allow for combined heart/kidney transplantation across positive CDC crossmatches without evidence of antibody-mediated rejection or significant infection. Longer follow-up will be needed to further support this conclusion.
RESUMO
Stimuli that signal large reward have an increased likelihood of capturing attention and gaze relative to stimuli that signal small or no reward, even when capture counterproductively prevents reward delivery. These findings suggest that a stimulus's signaling relationship with reward (the contingency between stimulus presentation and reward delivery) is a potent influence on selective attention. Recent studies have also implicated a stimulus's response relationship with reward (the contingency between orienting to a stimulus and reward delivery) in reducing capture by signals of reward. Here we show that this response pathway modulates capture by encouraging a reactive, goal-directed distractor suppression process. In a rewarded visual search task, participants demonstrated an oculomotor preference away from a distractor that had a negative response relationship with high reward (looking at the distractor caused reward omission) and toward a distractor that had no such negative response relationship, providing evidence for the role of the response relationship in suppressing capture by reward-related distractors. Analysis of the temporal dynamics of eye movements suggests that this distractor suppression process operates via a reactive mechanism of rapid disengagement (Experiment 1). Consistent with a goal-directed mechanism, the influence of the response relationship was eliminated when reward was unavailable (Experiment 2). These findings highlight the multifaceted role of stimulus-reward relationships in attentional selection. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Assuntos
Atenção , Objetivos , Humanos , Motivação , Tempo de Reação , RecompensaRESUMO
High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7-independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.
Assuntos
Proteína Proto-Oncogênica N-Myc/fisiologia , Metástase Neoplásica , Neuroblastoma/patologia , Proteínas de Ligação a RNA/fisiologia , Ribossomos/fisiologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neuroblastoma/etiologiaRESUMO
The molecular mechanisms that govern the choreographed timing of organ development remain poorly understood. Our investigation of the role of the Lin28a and Lin28b paralogs during the developmental process of branching morphogenesis establishes that dysregulation of Lin28a/b leads to abnormal branching morphogenesis in the lung and other tissues. Additionally, we find that the Lin28 paralogs, which regulate post-transcriptional processing of both mRNAs and microRNAs (miRNAs), predominantly control mRNAs during the initial phases of lung organogenesis. Target mRNAs include Sox2, Sox9, and Etv5, which coordinate lung development and differentiation. Moreover, we find that functional interactions between Lin28a and Sox9 are capable of bypassing branching defects in Lin28a/b mutant lungs. Here, we identify Lin28a and Lin28b as regulators of early embryonic lung development, highlighting the importance of the timing of post-transcriptional regulation of both miRNAs and mRNAs at distinct stages of organogenesis.