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Cytarabine Pharmacogenomics and Outcomes Among Children and Young Adults With Acute Myeloid Leukemia
Get PDFImportance: Therapeutic responses in acute myeloid leukemia (AML) demonstrate considerable variability both across and within established risk stratifications and age groups. Moreover, significant racial disparities persist, with Black patients experiencing inferior survival outcomes compared with their White counterparts. Objective: To validate the association of the previously reported 10 single nucleotide variant (SNV)–based ara-C pharmacogenomics score (ACS10) with survival outcomes in a large cohort of pediatric AML patients; to evaluate whether ACS10 remains relevant in an adolescent and young adult (AYA) population of patients with AML treated with similar intensive induction chemotherapy protocols; and to assess the association of ACS10 with race and treatment outcomes in both cohorts. Design, Setting, and Participants: This cohort study included patients from the Children’s Oncology Group’s AAML1031 trial, a multicenter, open-label randomized clinical trial that enrolled pediatric patients with newly diagnosed, treatment-naive primary AML from June 2011 to July 2017 (aged 0 to 29.5 years) and from the Alliance for Clinical Trials in Oncology frontline protocols, which included AYA patients from 9 different trials that enrolled patients with newly diagnosed AML from 1992 to 2010. Data were analyzed from September 2022 to March 2025. Exposures: Patients in the AAML1031 trial were randomized to 2 arms, standard chemotherapy alone or standard chemotherapy with the addition of bortezomib. Patients in the Alliance for Clinical Trials in Oncology cohorts were treated with similar intensive induction chemotherapy protocols. Main Outcomes and Measures: ACS10 scores were evaluated for association with outcomes according to race, treatment arm, and hematopoietic stem cell transplant (HSCT) status. Results: The study included 1086 patients with AML. There were 717 patients from the pediatric AML cohort (median [range] age, 9.6 [0.04-29.2 years]; 379 [53%] male; 33 [5%] Asian, 84 [12%] Black, and 522 [73%] White) and 369 AYA patients with AML from the Alliance for Clinical Trials in Oncology group (median [range] age, 30 [17-39] years; 196 [53%] male; 7 [2%] Asian, 32 [9%] Black, and 288 [78%] White). Within the standard treatment arm of AAML1031, patients in the low ACS10 group had significantly worse event-free survival (EFS) compared with those in the high ACS10 group (all patients: hazard ratio [HR], 1.42; 95% CI, 1.05-1.95; P = .02; non-HSCT cohort: HR, 1.48; 95% CI, 1.06-2.07; P = .02). The ACS10 score remained significantly associated with EFS in multivariable analysis after adjusting for age, race, risk group and white blood cell count, within the standard treatment arm (HR, 1.44; 95% CI, 1.03-2.02; P = .03). In the Alliance for Clinical Trials in Oncology AYA non-HSCT cohort, the low ACS10 score group had significantly inferior overall survival (OS) and a higher point estimate for EFS compared with patients with a high ACS10 score (OS: HR, 1.50; 95% CI, 1.05-2.14; P = .03; EFS: HR, 1.32; 95% CI, 0.95-1.83; P = .10). A higher number of early deaths was observed in the low ACS10 group compared with the high ACS10 group, but the difference was not statistically significant (death within 30 days of treatment initiation: 6 of 112 [5%] vs 2 of 257 [1%]; P = .07). Across both cohorts, a low ACS10 score was significantly more abundant in Black patients compared with White patients (eg, in Alliance for Clinical Trials in Oncology cohort, 27 of 32 Black patients [84%] had low ACS10 scores compared with 64 of 288 White patients [22%]; P Conclusions and Relevance: In this study of 717 pediatric and 369 AYA patients with AML, the ACS10 score was associated with EFS in pediatric and AYA patients when treated with a standard induction regimen. There was a higher abundance of low ACS10 scores in Black patients, and Black patients treated with augmented therapy (ie, the addition of bortezomib) seemed to have improved outcomes. Integrating the ACS10 score into a prospective clinical trial to personalize induction therapy based on an individual’s genetic profile has the potential to improve treatment outcomes.</p
An implantable, intracerebral osmotic pump for convection-enhanced drug delivery in glioblastoma multiforme
No full textBackground: Glioblastoma multiforme (GBM; WHO Grade 4) is an aggressive brain tumor that invariably recurs after surgical resection, chemoradiation, and adjuvant chemotherapy. Treatment is limited, in part, because the blood-brain barrier (BBB) restricts entry of chemotherapeutic agents to the brain. Introducing drugs directly into the brain circumvents the BBB, but diffusion of these typically large drug molecules within brain parenchyma is limited. Convection-enhanced delivery (CED), based on the principles of bulk flow, can achieve drug distribution over a wider area to target residual cancer cells and thus remains a promising technique for treating GBM and other neuro-oncologic pathologies. Here, we propose a new method that combines direct brain delivery and CED using a fully implantable, microfluidic pump placed at the time of initial resection surgery. Methods: In this initial proof-of-concept study, we evaluated the function of a 3D-printed pump in an in vitro system and in vivo in a rat C6 glioma model. Results: In vitro osmosis-driven distribution of a high molecular-weight marker dye extended up to 18 mm from the pump with minimal reflux, including under simulations of increased intracranial pressure. In vivo, MRI imaging demonstrated wide distribution of superparamagnetic iron oxide particles from a pump implanted after the resection of a C6 glioma. Histological staining indicated that pump implantation did not cause additional inflammatory changes compared to controls. Conclusion: This preliminary study demonstrated the feasibility of using an implantable, osmosis-driven pump to bypass the BBB and provide targeted delivery for treatment of GBM.</p
A Portfolio Approach to Massively Parallel Bayesian Optimization
Get PDFOne way to reduce the time of conducting optimization studies is to evaluate designs in parallel rather than just one-at-a-time. For expensive-to-evaluate black-boxes, batch versions of Bayesian optimization have been proposed. They work by building a surrogate model of the black-box to simultaneously select multiple designs via an infill criterion. Still, despite the increased availability of computing resources that enable large-scale parallelism, the strategies that work for selecting a few tens of parallel designs for evaluations become limiting due to the complexity of selecting more designs. It is even more crucial when the black-box is noisy, necessitating more evaluations as well as repeating experiments. Here we propose a scalable strategy that can keep up with massive batching natively, focused on the exploration/exploitation trade-off and a portfolio allocation. We compare the approach with related methods on noisy functions, for mono and multi-objective optimization tasks. These experiments show orders of magnitude speed improvements over existing methods with similar or better performance
Delivering Guideline-Concordant Care for Patients With High-Risk HPV and Normal Cytologic Findings
Get PDFImportance: As US health care systems shift to human papillomavirus (HPV)–based cervical cancer screening, more patients are receiving positive high-risk non–16/18 genotype HPV results and negative for intraepithelial lesion or malignancy (NILM) cytological findings. Risk-based management guidelines recommend 2 consecutive negative annual results to return to routine screening. Objective: To quantify patterns of surveillance testing and associated outcomes for patients after an HPV-positive results and NILM cytologic findings. Design, Setting, and Participants: This cohort study analyzed patients in the METRICS (Multi-level Optimization of the Cervical Cancer Screening Process in Diverse Settings and Populations) cohort of the PROSPR II (Population-Based Research to Optimize the Screening Process) Cervical Consortium. Population-based data were obtained from 3 diverse health care systems (Mass General Brigham [MGB] in Massachusetts, Kaiser Permanente Washington [KPWA] in Washington, and Parkland Health [PH] in Texas) in the METRICS cohort. Participants were patients aged 21 to 65 years who received an HPV-positive (non-16/18 or pooled genotypes) result and NILM cytologic finding from January 2010 to August 2018 and were followed up through December 2019. Data analyses were performed between April 2021 and November 2024. Main Outcomes and Measures: Test receipt and outcomes delivered within 16 months after the index result (round 1 surveillance). Results: The final sample across the 3 health care systems comprised 13 158 female patients (3228 Hispanic or Latine [24.5%], 1990 non-Hispanic African American or Black [15.1%], 749 non-Hispanic Asian [5.7%], and 6559 non-Hispanic White [49.8%] individuals). Sociodemographic characteristics varied by site, with more non-Hispanic White (2277 [63.7%] and 4061 [61.2%]) and commercially insured patients (3137 [87.8%] and 4365 [65.7%]) at KPWA and MGB, and more Hispanic or Latine (1664 [56.5%]) and uninsured patients (2352 [79.9%]) at PH. During round 1 surveillance, 43.7% of patients were tested, of whom 18.2% (2394) had HPV-negative results and NILM cytologic findings and 25.5% (3351) had abnormal results. Many patients remained in the cohort and were untested through round 1 surveillance (overall: 49.4% [6505]; across sites: 39.0% [1395] to 69.4% [2043]), while fewer exited the cohort (overall: 6.9% [908]; across sites: 0.2% [12] to 24.6% [879]). Groups with lower odds of timely testing were younger adults (aged 25-29 vs 30-39 years: adjusted odds ratio [AOR], 0.65; 95% CL, 0.53-0.81), non-Hispanic African American or Black compared with non-Hispanic White patients (AOR, 0.78; 95% CL, 0.68-0.89), and those with Medicaid compared with commercial insurance (AOR, 0.81; 95% CL, 0.72-0.91), while those with a primary care clinician were more likely to have timely testing (AOR, 1.44; 95% CL, 1.21-1.70). Cancer was diagnosed in 10 patients (0.2%) untested in round 1 surveillance compared with 0 cancers in those with an HPV-negative results and NILM cytologic findings. Conclusions and Relevance: This cohort study found that among patients with HPV-positive results and NILM cytologic findings, less than half received a surveillance cotest during the guideline-recommended time frame. Health care systems should monitor annual surveillance and gather evidence on interventions to optimize the delivery of surveillance testing.</p
A comparison of MRI and intraoperative measurements to determine interspinous spacer device size
Get PDFPurpose: To determine whether preoperative magnetic resonance imaging (MRI) can reliably determine intraoperative measurements in the Vertiflex Interspinous Spacer (ISS) procedure. Methods: Patients who underwent Vertiflex ISS with Lumbar Spinal Stenosis (LSS) and a preoperative MRI available in picture archiving and communication system (PACS) between January 2013 to February 2023 were identified retrospectively from the University of Chicago Medical Center Database. An experienced board-certified pain specialist and well-trained 2nd-year medical student independently performed measurements of the interspinous space where Vertiflex ISSs of various sizes are inserted. MRI measurements were taken blinded to intraoperative measurement and ISS implant size used in the procedure. Pearson's correlation, paired T-test, intraclass correlation coefficients (ICC), absolute agreement, and 2-way random effects model were used to determine the relationships between MRI, intraoperative measurement, and ISS size. Results: A total of 79 patients who underwent the Vertiflex ISS procedure were included in the study. Median Vertiflex ISS size was 10 mm (10-12), mean intraoperative measurement was 11.40 mm (±1.23), and mean MRI measurement was 11.24 mm (±1.44). Mean differences were not significant in intraoperative and MRI measurements (p = 0.271). Pearson's correlation between ISS size and intraoperative measurement was 0.807 (p Conclusions: Measuring interspinous space on MRI yielded, on average, a value smaller than the intraoperative measurement in Vertiflex ISS procedures, but the mean differences were not significant. Good agreement and moderate reliability were found between observer MRI and surgeon intraoperative measurements, suggesting MRI can evaluate the intraoperative space for the Vertiflex ISS procedure. Preoperative MRI measurement may help decrease complications by aiding in surgical decision-making through providing a reference for intraoperative measurements. Further prospective study is necessary to determine if preoperative MRI measurement can predict and potentially replace the need for intraoperative measurement.</p
Deborah A. Starr <i>Togo Mizrahi and the Making of Egyptian Cinema</i>. Stanford, Calif.: University of California Press, 2020. 252 pp.
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Influence of Intrinsic Point Defects Incorporated from Growth Surface on Atomic Interdiffusion and Unintentional Compositional Gradient in AlGaN/AlN Heterointerfaces
Get PDFWe investigate theoretically the formation mechanisms of the unintentional compositional gradient layer occurring at AlGaN/AlN heterointerfaces during metal–organic chemical vapor deposition (MOCVD). The study of heterointerface morphology is crucial for developing AlGaN deep-ultraviolet light-emitting laser diodes. After studying the stability of the surface reconstructions with intrinsic point defects in their subsurface layers using an ab initio-based approach, we inspect the impact of defects on the atomic interdiffusion at the heterointerfaces by Monte Carlo simulation. The relationship between MOCVD conditions and the type of dominant intrinsic point defects is clarified. We find that (i) cation and anion vacancy complexes are dominant in the subsurface layers above 1000 °C and (ii) they accumulate near the AlGaN/AlN heterointerface during growth, causing cation interdiffusion, i.e., the formation of compositional gradient layers. Controlling the type of intrinsic point defects incorporated during the surface growth in MOCVD is a key factor in preserving atomically flat heterointerfaces
Regional climate change: consensus, discrepancies, and ways forward
Get PDFClimate change has emerged across many regions. Some observed regional climate changes, such as amplified Arctic warming and land-sea warming contrasts have been predicted by climate models. However, many other observed regional changes, such as changes in tropical sea surface temperature and monsoon rainfall are not well simulated by climate model ensembles even when taking into account natural internal variability and structural uncertainties in the response of models to anthropogenic radiative forcing. This suggests climate model predictions may not fully reflect what our future will look like. The discrepancies between models and observations are not well understood due to several real and apparent puzzles and limitations such as the “signal-to-noise paradox” and real-world record-shattering extremes falling outside of the possible range predicted by models. Addressing these discrepancies, puzzles and limitations is essential, because understanding and reliably predicting regional climate change is necessary in order to communicate effectively about the underlying drivers of change, provide reliable information to stakeholders, enable societies to adapt, and increase resilience and reduce vulnerability. The challenges of achieving this are greater in the Global South, especially because of the lack of observational data over long time periods and a lack of scientific focus on Global South climate change. To address discrepancies between observations and models, it is important to prioritize resources for understanding regional climate predictions and analyzing where and why models and observations disagree via testing hypotheses of drivers of biases using observations and models. Gaps in understanding can be discovered and filled by exploiting new tools, such as artificial intelligence/machine learning, high-resolution models, new modeling experiments in the model hierarchy, better quantification of forcing, and new observations. Conscious efforts are needed toward creating opportunities that allow regional experts, particularly those from the Global South, to take the lead in regional climate research. This includes co-learning in technical aspects of analyzing simulations and in the physics and dynamics of regional climate change. Finally, improved methods of regional climate communication are needed, which account for the underlying uncertainties, in order to provide reliable and actionable information to stakeholders and the media
Do empirically-derived personality subtypes relate to cognitive inflexibility in anorexia nervosa and bulimia nervosa?
Get PDFBackground: Accruing evidence suggests that personality-based approaches to eating disorder classification may offer several advantages over current diagnostic models, with prior research consistently identifying three personality-based groups characterized by either (1) high levels of impulsivity and dysregulation (termed the "undercontrolled" group), (2) high levels of rigidity and avoidance (termed the "overcontrolled" group), or (3) relatively normative levels of personality functioning (termed the "low psychopathology" group). Cognitive inflexibility (i.e., difficulty adjusting thoughts or behaviors) has theorized relevance to eating disorders. However, prior research has frequently failed to observe differences in cognitive inflexibility across eating disorder diagnostic groups. The present study aimed to identify personality-based groups in an eating disorder sample, and then to examine the relations between these groups and behavioral measures of cognitive inflexibility. Method: 83 men and women who met DSM-5 criteria for anorexia nervosa or bulimia nervosa completed self-report questionnaires to assess trait-level approach/avoidance behaviors and impulsivity, as well as behavioral tasks assessing attentional set-shifting and reversal learning, two facets of cognitive inflexibility. Results: Latent profile analysis of measures assessing approach/avoidance behaviors and impulsivity supported a three-class model replicating the undercontrolled, overcontrolled, and low psychopathology groups. Notably, the low psychopathology group was characterized by elevated reward responding. One-way ANOVAs indicated that the low psychopathology group demonstrated heightened perseverative errors (an indicator of impaired reversal learning) relative to the other groups. No group differences were observed for attentional set-shifting errors or probabilistic switch errors. Discussion: Findings from the present study provide additional support for personality-based classification approaches identifying undercontrolled, overcontrolled, and low psychopathology eating disorder groups. Results also suggest that reward-related processes may contribute to disorder maintenance in the low psychopathology group, indicating potentially meaningful targets for intervention.</p
Individualized models of social judgments and context-dependent representations
Get PDFHow individuals view the world is critical to understanding human behavior. Yet, almost all research within perception and judgment has drawn inferences from group-level behavior, with little work focused on understanding how the individual perceives their world. However, for complex judgments (e.g., trustworthiness), most of the meaningful variance is due to factors specific to the individual. Here we showcase a data-driven reverse correlation method for visualizing any perceptually-derived stereotype at the individual level. We show that our method (1) produces photorealistic and reliable results related to a broad range of judgments, (2) produces valid, psychologically-aligned representations of what individuals are imagining “in their mind’s eye”, and (3) is capable of capturing visual representations sensitive enough to examine context-dependent categories (e.g., a trustworthy individual to babysit your children vs. to fix your car). Across all studies, we highlight the theoretical implications and utility of developing idiosyncratic models of visual perception