Disentangling periodic and aperiodic resting EEG correlates of personality.

Previous studies of resting electroencephalography (EEG) correlates of personality traits have conflated periodic and aperiodic sources of EEG signals. Because these are associated with different underlying neural dynamics, disentangling them can avoid measurement confounds and clarify findings. In a large sample (n = 300), we investigated how disentangling these activities impacts findings related to two research programs within personality neuroscience. In Study 1 we examined associations between Extraversion and two putative markers of reward sensitivity-Left Frontal Alpha asymmetry (LFA) and Frontal-Posterior Theta (FPT). In Study 2 we used machine learning to predict personality trait scores from resting EEG. In both studies, power within each EEG frequency bin was quantified as both total power and separate contributions of periodic and aperiodic activity. In Study 1, total power LFA and FPT correlated negatively with Extraversion (r ∼ -0.14), but there was no relation when LFA and FPT were derived only from periodic activity. In Study 2, all Big Five traits could be decoded from periodic power (r ∼ 0.20), and Agreeableness could also be decoded from total power and from aperiodic indices. Taken together, these results show how separation of periodic and aperiodic activity in resting EEG may clarify findings in personality neuroscience. Disentangling these signals allows for more reliable findings relating to periodic EEG markers of personality, and highlights novel aperiodic markers to be explored in future research.

Clinical outcomes of patients with acute myeloid leukemia and cardiovascular disease.

Incidence of both acute myeloid leukemia (AML) and cardiovascular disease (CVD) increases with age. We evaluated whether pre-existing CVD impacts clinical outcomes in AML. We retrospectively evaluated 291 consecutive adult AML patients treated at our institution, 2014-2020. Pretreatment comorbidities were identified by chart review. Outcomes included complete remission (CR) and CR with incomplete count recovery (CRi) rates, disease-free survival (DFS), overall survival (OS) and incidence of cardiovascular adverse events. CVD was present in 34% of patients at AML diagnosis. CVD patients had worse performance status (p=0.03) and more commonly had secondary AML (p=0.03) and received hypomethylating (HMA) agent-based therapy (72% vs 38%, p< 0.001). CVD (0.45 vs 0.71, p<0.001) and diabetes mellitus (HR= 0.24, 95% CI: 0.08 - 0.8, p= 0.01) were associated with lower probability of achieving CR/CRi. Accounting for age, performance status (PS), complex karyotype, secondary disease and treatment, CVD patients had shorter OS (HR=1.5, 95% CI: 1.1-2.2, p=0.002), with 1- and 3-year OS 44% vs 67% and 25% vs 40%, respectively, but there was no difference in cumulative incidence of relapse between patients with vs without CVD. Thus, CVD is an independent risk factor for lower response rate and shorter survival in AML patients.

Olanzapine within steroid-sparing antiemetic regimen to prevent chemotherapy-induced nausea and vomiting in patients with acute leukemia receiving multi-day intensive chemotherapy.

INTRODUCTION: Olanzapine use for chemotherapy-induced nausea and vomiting (CINV) in hematological malignancies, for multi-day chemotherapy, and with a steroid-sparing antiemetic strategy is poorly understood. This study investigated if olanzapine is associated with improved prevention of CINV when added to a steroid-sparing antiemetic regimen in patients with acute leukemia receiving intensive, moderately emetogenic, multi-day chemotherapy. METHODS: This was a single-center, retrospective cohort study in patients with acute leukemia. Patients who received olanzapine for CINV prevention were compared to those who did not. All patients received a 5-HT3 antagonist. Adult patients receiving moderately emetogenic, multi-day, intensive chemotherapy for acute leukemia were included. Patients were excluded if they received steroids greater than physiological doses during the study period. The primary endpoint was the complete response of CINV (no emesis or rescue antiemetic usage). RESULTS: This study included 58 patients, 12 patients received olanzapine and 46 patients were in the control group. Baseline demographics were similar. In the study population, 89.7% had acute myeloid leukemia, median age was 54 (interquartile range 42-63) years, 34.5% were female, 27.6% had prior CINV. Complete response of CINV was similar between groups, 4 (33.3%) and 15 (32.6%) patients in the olanzapine and control groups, respectively. Safety events were similar between groups. CONCLUSION: Patients with acute leukemia receiving multi-day intensive chemotherapy are at high risk for CINV. The limited data in this study suggests that olanzapine use within a steroid-sparing antiemetic regimen was well tolerated and associated with similar incidence and severity of CINV compared to the control group.

Myeloid madness: assessing diagnostic inconsistency between the new WHO and ICC schemes for myelodysplastic/myeloproliferative neoplasms.

The classification of haematological neoplasms recently underwent revision, generating two separate schemes-the International Consensus Classification and the fifth edition of the WHO classification. The new division into separate classification systems presents challenges for haematopathologists, haematologists/oncologists and patients. While it is too early to assess the full clinical impact, we sought to identify diagnostic discordance which may arise from applying separate classification schemes in myeloid neoplasia, and particularly in the challenging category of myelodysplastic syndrome/myeloproliferative neoplasms. A review of 64 such cases found 1 case with a significant discrepancy between the WHO and International Consensus Classification systems, and 9 cases with nominal discrepancies. Confusion from the use of conflicting diagnostic terms represents a potential source of patient harm, increased pathologist workload and burnout and erosion of clinician and patient trust.

Acceptability and Usability of the Family Gene Toolkit for Swiss and Korean Families Harboring BRCA1/BRAC2 Pathogenic Variants: A Web-Based Platform for Cascade Genetic Testing.

The study adapted the Family Gene Toolkit and developed a customized web application for Swiss and Korean families harboring BRCA1 or BRCA2 pathogenic variants to support family communication of genetic testing results and promote cascade genetic testing among at-risk relatives. In the first step, narrative data from 68 women with BRCA1/BRCA2 pathogenic variants and clinician feedback informed a culturally sensitive adaptation of the content consistent with current risk management guidelines. In the second step, the Information Technology team developed the functions and the interface of the web application that will host the intervention. In the third step, a new sample of 18 women from families harboring BRCA1/BRCA2 pathogenic variants tested the acceptability and usability of the intervention using "think-aloud" interviews and a questionnaire. Participants expressed high levels of satisfaction with the intervention. They provided positive feedback for the information regarding active coping, strategies to enhance family communication, interactive elements, and illustrative stories. They reported that the information was useful and the web application was easy to navigate. Findings suggest that the Family Gene Toolkit is well-designed and can increase rates of cascade testing among at-risk relatives. Its efficacy will be tested in a subsequent randomized trial.

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

Approach to the Treatment of Philadelphia Chromosome-Negative B-cell ALL in Older Adults: Is Age Becoming just a Number?

PURPOSE OF REVIEW: Despite progress in the treatment of pediatric B-cell acute lymphoblastic leukemia (ALL) and PH + ALL, fewer advancements have been for older adults with PH-negative B-cell ALL. Treatment of this population is mired by higher incidence of poor risk biologic features, increased incidence of medical comorbidities, and higher rates of treatment-related mortality (TRM). Here, we review the difficulties in managing elderly patients with PH-negative ALL. RECENT FINDINGS: The development of novel agents has brought additional tools to the armamentarium of drugs and has changed the landscape of treatment. More recent clinical trials and future clinical trials focus on blinatumomab, inotuzomab ozogamicin (IO), and/or chimeric antigen receptor T-cell (CAR-T) either alone or integrated with dose-reduced chemotherapy regimens. The introduction of novel agents/therapies and incorporation into our current treatment paradigms may finally offer an avenue to improve the dismal outcomes seen in this population.

Therapy-related B-lymphoblastic leukemia after multiple myeloma.

New therapies for multiple myeloma have improved outcomes, but are associated with therapy-related hematologic malignancies. We report eight patients with therapy-related B-lymphoblastic leukemias (t-B-ALL) in the setting of therapy for multiple myeloma, which included lenalidomide maintenance. A subset of patients had pancytopenia and low-level marrow involvement by acute leukemia, an unusual finding in de novo B-ALL. One patient died of chemotherapy complications; the other seven responded. No patient died of B-ALL (median follow up of 1.0 years). Our series suggests that t-B-ALL is clonally unrelated to myeloma, presents with diverse cytogenetic abnormalities, and responds well to B-ALL therapy.

Safety, Outcomes, and T-Cell Characteristics in Patients with Relapsed or Refractory MDS or CMML Treated with Atezolizumab in Combination with Guadecitabine.

PURPOSE: We hypothesized that resistance to hypomethylating agents (HMA) among patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) would be overcome by combining a programmed death-ligand 1 antibody with an HMA. PATIENTS AND METHODS: We conducted a Phase I/II, multicenter clinical trial for patients with MDS not achieving an International Working Group response after at least 4 cycles of an HMA ("refractory") or progressing after a response ("relapsed") with 3+ or higher risk MDS by the revised International Prognostic Scoring System (IPSS-R) and CMML-1 or -2. Phase I consisted of a 3+3 dose-escalation design beginning with guadecitabine at 30 mg/m2 and escalating to 60 mg/m2 Days 1 to 5 with fixed-dose atezolizumab: 840 mg intravenously Days 8 and 22 of a 28-day cycle. Primary endpoints were safety and tolerability; secondary endpoints were overall response rate (ORR) and survival. RESULTS: Thirty-three patients, median age 73 (range 54-85), were treated. Thirty patients had MDS and 3 had CMML, with 30% relapsed and 70% refractory. No dose-limiting toxicities were observed in Phase I. There were 3 (9%) deaths in ≤ 30 days. Five patients (16%) came off study for drug-related toxicity. Immune-related adverse events (IRAE) occurred in 12 (36%) patients (4 grade 3, 3 grade 2, and 5 grade1). ORR was 33% [95% confidence interval (CI), 19%-52%] with 2 complete remission (CR), 3 hematologic improvement, 5 marrow CR, and 1 partial remission. Median overall survival was 15.1 (95% CI, 8.5-25.3) months. CONCLUSIONS: Guadecitabine with atezolizumab has modest efficacy with manageable IRAEs and typical cytopenia-related safety concerns for patients with relapsed or refractory MDS and CMML.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of 1-Aryl-1H-pyrazole-Fused Curcumin Analogues as Anticancer Agents.

Addressing the growing burden of cancer and the shortcomings of chemotherapy in cancer treatment are the current research goals. Research to overcome the limitations of curcumin and to improve its anticancer activity via its heterocycle-fused monocarbonyl analogues (MACs) has immense potential. In this study, 32 asymmetric MACs fused with 1-aryl-1H-pyrazole (7a-10h) were synthesized and characterized to develop new curcumin analogues. Subsequently, via initial screening for cytotoxic activity, nine compounds exhibited potential growth inhibition against MDA-MB-231 (IC50 2.43-7.84 µM) and HepG2 (IC50 4.98-14.65 µM), in which seven compounds showing higher selectivities on two cancer cell lines than the noncancerous LLC-PK1 were selected for cell-free in vitro screening for effects on microtubule assembly activity. Among those, compounds 7d, 7h, and 10c showed effective inhibitions of microtubule assembly at 20.0 µM (40.76-52.03%), indicating that they could act as microtubule-destabilizing agents. From the screening results, three most potential compounds, 7d, 7h, and 10c, were selected for further evaluation of cellular effects on breast cancer MDA-MB-231 cells. The apoptosis-inducing study indicated that these three compounds could cause morphological changes at 1.0 µM and could enhance caspase-3 activity (1.33-1.57 times) at 10.0 µM in MDA-MB-231 cells, confirming their apoptosis-inducing activities. Additionally, in cell cycle analysis, compounds 7d and 7h at 2.5 µM and 10c at 5.0 µM also arrested MDA-MB-231 cells in the G2/M phase. Finally, the results from in silico studies revealed that the predicted absorption, distribution, metabolism, excretion, and the toxicity (ADMET) profile of the most potent MACs might have several advantages in addition to potential disadvantages, and compound 7h could bind into (ΔG -10.08 kcal·mol-1) and access wider space at the colchicine-binding site (CBS) than that of colchicine or nocodazole via molecular docking studies. In conclusion, our study serves as a basis for the design of promising synthetic compounds as anticancer agents in the future.

AI-Based Soft Module for Safe Human-Robot Interaction towards 4D Printing.

Soft robotic modules have potential use for therapeutic and educational purposes. To do so, they need to be safe, soft, smart, and customizable to serve individuals' different preferences and personalities. A safe modular robotic product made of soft materials, particularly silicon, programmed by artificial intelligence algorithms and developed via additive manufacturing would be promising. This study focuses on the safe tactile interaction between humans and robots by means of soft material characteristics for translating physical communication to auditory. The embedded vibratory sensors used to stimulate touch senses transmitted through soft materials are presented. The soft module was developed and verified successfully to react to three different patterns of human-robot contact, particularly users' touches, and then communicate the type of contact with sound. The study develops and verifies a model that can classify different tactile gestures via machine learning algorithms for safe human-robot physical interaction. The system accurately recognizes the gestures and shapes of three-dimensional (3D) printed soft modules. The gestures used for the experiment are the three most common, including slapping, squeezing, and tickling. The model builds on the concept of how safe human-robot physical interactions could help with cognitive and behavioral communication. In this context, the ability to measure, classify, and reflect the behavior of soft materials in robotic modules represents a prerequisite for endowing robotic materials in additive manufacturing for safe interaction with humans.

B cell-mediated regulatory mechanisms control tumor-promoting intestinal inflammation.

Mechanisms underlying tumor-promoting inflammatory processes in colitis-associated colorectal cancer (CAC) remain largely elusive. Here, we provide genetic evidence for distinct B cell-mediated immunoregulatory mechanisms that protect from chronic colitis versus CAC. We demonstrate an inherent capacity of interleukin-10 (IL-10)-producing B cells to differentiate into immunoglobulin A (IgA) plasma cells (PCs) upon Toll-like receptor (TLR) activation. Our data show that B cell-derived IL-10 is essential to limit pathogenic T helper type 1 (Th1)/Th17 T cell responses during chronic colitis, while IgA PCs derived from IL-10+ B cells are being implicated in restraining tumorigenesis during CAC. Formation of a tumor-protective intestinal environment was associated with clonal expansion of specific types of colonic IgA PCs and development of an altered microbiota that attenuated CAC. We thus propose that regulatory B cell-mediated immunomodulation entails temporal release of IL-10, which is superseded by the generation of specific IgA affecting the microbial community, thereby controlling chronic inflammation and tumorigenesis in a distinctive but interrelated manner.

Impact of FLT3-ITD Insertion Length on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study.

The prognostic significance of the length of internal tandem duplication (ITD) insertions in mutant FLT3 genes in acute myeloid leukemia (AML) is controversial. We conducted a retrospective study to evaluate the correlation between the ITD base-pair (bp) insertion length and clinical outcomes. The mutational status of the FLT3 gene was evaluated in 402 of 467 consecutive AML patients treated at the University of Maryland Greenebaum Comprehensive Cancer Center between 2013 and 2020; 77 had FLT3-ITD mutations. Patients were divided into three cohorts based on bp insertion length (<30 (0−33rd percentile), 30−53 (34th−66th percentile),and >53 (>66th percentile)). The median overall survival (OS) of patients was 16.5 months (confidence interval (CI) 7.3-NA), 18.5 months (CI 7.3-NA), and 21.9 months (CI 19.1-NA) (p = 0.03) for the <30, 30−53, and >53 bp insertion length cohorts, respectively. The adjusted median event-free survival (EFS) for the ITD insertion lengths >30, 30−53, and >53 bp was 11.1 months (CI 2.8−16.5), 5.2 months (CI 2.9−12.6), and 9.1 months (CI 5.4-NA) (p = 0.5), respectively. Complete remission (CR) rates were 64% (<30 inserted bp), 55% (30−53 inserted bp), and 79% (>53 inserted bp) (p = 0.23). For patients treated with gilteritinib and midostaurin, the unadjusted median OS was not statistically significantly different between cohorts.

Lowering platelet count threshold to 10,000/µL for peripherally inserted central catheter placement safely conserves blood products.

Despite the low risk of peripherally inserted central catheter (PICC) insertion-related bleeding, the practice of administering prophylactic platelets varies greatly. Limiting unnecessary blood product transfusions reduces transfusion-related adverse events, financial cost, and delays in care. We assessed the impact of lowering prophylactic platelet administration threshold on blood product utilization patterns and bleeding events. This quasi-experimental study was conducted in an urban academic tertiary medical center. The study population included patients with platelet counts ≥ 10,000/µL and < 50,000/µL undergoing PICC placement in 2018 and 2019 when the minimum platelet thresholds were 50,000/µL and 10,000/µL, respectively. The primary outcome was blood product utilization and the secondary outcome was PICC insertion-related bleeding complications. Thirty-five patients using the 10,000/µL (10 K) platelet threshold and 46 patients using the 50,000/µL (50 K) platelet threshold were enrolled. The 50 K group received more platelets before PICC insertion (0.870 ± 0.885 and 0.143 ± 0.430 pools of platelets-per-person, p < 0.001). No patients experienced clinically significant bleeding. Immediately following PICC insertion, minor bleeding occurred in five patients (two [4.3%] and three [8.6%] in the 50 K and 10 K groups, respectively). Bleeding rates between the two cohorts did not differ (p = 0.647). Lowering the minimum platelet threshold from 50,000/µL to 10,000/µL resulted in less prophylactic platelet and total blood product administration with no appreciable difference in PICC insertion-related bleeding.

Mobility of antimicrobial resistance across serovars and disease presentations in non-typhoidal Salmonella from animals and humans in Vietnam.

Non-typhoidal Salmonella (NTS) is a major cause of bacterial enterocolitis globally but also causes invasive bloodstream infections. Antimicrobial resistance (AMR) hampers the treatment of these infections and understanding how AMR spreads between NTS may help in developing effective strategies. We investigated NTS isolates associated with invasive disease, diarrhoeal disease and asymptomatic carriage in animals and humans from Vietnam. Isolates included multiple serovars and both common and rare phenotypic AMR profiles; long- and short-read sequencing was used to investigate the genetic mechanisms and genomic backgrounds associated with phenotypic AMR profiles. We demonstrate concordance between most AMR genotypes and phenotypes but identified large genotypic diversity in clinically relevant phenotypes and the high mobility potential of AMR genes (ARGs) in this setting. We found that 84 % of ARGs identified were located on plasmids, most commonly those containing IncHI1A_1 and IncHI1B(R27)_1_R27 replicons (33%), and those containing IncHI2_1 and IncHI2A_1 replicons (31%). The vast majority (95%) of ARGS were found within 10 kbp of IS6/IS26 elements, which provide plasmids with a mechanism to exchange ARGs between plasmids and other parts of the genome. Whole genome sequencing with targeted long-read sequencing applied in a One Health context identified a comparatively limited number of insertion sequences and plasmid replicons associated with AMR. Therefore, in the context of NTS from Vietnam and likely for other settings as well, the mechanisms by which ARGs move contribute to a more successful AMR profile than the specific ARGs, facilitating the adaptation of bacteria to different environments or selection pressures.

Outcomes of Newly Diagnosed Acute Myeloid Leukemia Patients Treated With Hypomethylating Agents With or Without Venetoclax: A Propensity Score-Adjusted Cohort Study.

There is a deficiency of real-world data on the impact of combining venetoclax (VEN) with hypomethylating agents (HMAs) in newly diagnosed acute myeloid leukemia (AML) patients. We conducted a single-center, propensity-adjusted retrospective cohort study to compare composite complete remission (CCR) rates, median overall survival (m-OS) and median event-free survival (m-EFS). A total of 170 adult AML patients were treated with first-line azacitidine (AZA) or decitabine (DEC) +/- VEN. Median age was 71 years and 99 (58%) were male. Median follow-up in HMA and HMA-VEN groups was 79 and 21 months. Treatments included AZA alone (n=35, 21%), DEC alone (n=84, 49%), AZA-VEN (n=24, 14%) and DEC-VEN (n=27, 16%). VEN improved CCR rates to HMAs overall (52% vs. 27%, P<0.05) and to AZA (54% vs. 10%, P<0.05), but not to DEC (43% vs. 32%, P=0.35); it did not improve OS, and only improved EFS for AZA (10.5 vs. 3.8 months, P<0.05). CCR rates were lower with AZA than with DEC (13% vs. 33%, P<0.05), but OS and EFS were not different statistically. CCR rates did not differ for AZA-VEN vs. DEC-VEN (CCR: 58% vs. 52%, P=0.66), but OS and EFS were longer for AZA-VEN (m-OS: 12.3 vs. 2.2 months, P<0.05; m-EFS: 9.2 vs. 2.1 months, P<0.05). Our analysis showed that combining VEN with AZA in newly diagnosed AML patients improved outcomes, but combining VEN with DEC did not. AZA-VEN was associated with improved outcomes compared to DEC-VEN. Further studies are needed to test the benefit of combining VEN with DEC.

Impact of IDH1 c.315C>T SNP on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study.

Acute myeloid leukemia (AML) is the common type of acute leukemia in adults. Definitive prognostic significance of variants of unknown significance lacks for many commonly mutated genes, including the isocitrate dehydrogenase 1 (IDH1) synonymous single nucleotide polymorphism (SNP) variant c.315C>T. In this retrospective cohort study of 248 AML patients at the University of Maryland Greenebaum Comprehensive Cancer Center, we show that the IDH1 c.315C>T SNP, previously reported to be associated with poor prognosis by other studies with conflicting data, does not confer worse prognosis, with a median overall survival (OS) of 17.1 months compared to 15.1 months for patients without this SNP (P=0.57). The lack of negative effect on prognosis by IDH1 SNP c.315C>T is consistent with the absence of amino acid alteration (p.Gly105Gly).