Outcomes of Patients With Newly Diagnosed AML and Hyperleukocytosis.

PURPOSE: AML presenting with hyperleukocytosis is associated with poor outcomes. We aim to understand the factors associated with early mortality and overall survival (OS) to help guide management and improve early mortality. METHODS: We retrospectively reviewed data from 129 consecutive patients with newly diagnosed AML and a WBC count ≥100 × 109/L between January 2010 and April 2020. Logistic regression models estimated odds ratios for 4-week mortality. Cox proportional hazard models estimated hazard ratios for OS. RESULTS: The median age was 65 years (range, 23-86); the median WBC was 146 × 109/L (range, 100-687). Seventy-five (58%) patients had clinical leukostasis (CL). FLT3, NPM1, and RAS pathway mutations were detected in 63%, 45%, and 27% of patients, respectively. Cytoreduction consisted of hydroxyurea in 124 (96%) patients, cytarabine in 69 (54%), and leukapheresis in 31 (24%). The cumulative 4-week and 8-week mortality rates were 9% and 13%, respectively, all in patients age 65 years and older. By multivariate analysis, older age, CL, and thrombocytopenia <40 × 109/L were independently associated with a higher 4-week mortality rate. After a median follow-up of 49.4 months, the median OS was 14.3 months (95% CI, 7 to 21.6), with 4-year OS of 29%. Age 65 years and older, CL, tumor lysis syndrome, elevated LDH ≥2,000 U/L, elevated lactate ≥2.2 mmol/L, and poor-risk cytogenetics were independent factors associated with worse OS. CONCLUSION: Hyperleukocytosis is a life-threatening hematologic emergency. Early recognition and intervention including cytoreduction, blood product support, antibiotics, and renal replacement therapy may help mitigate the risk of morbidity and early mortality.

Predicting Goal Attainment in Process-Oriented Behavioral Interventions Using a Data-Driven System Identification Approach.

Behavioral interventions (such as those developed to increase physical activity, achieve smoking cessation, or weight loss) can be represented as dynamic process systems incorporating a multitude of factors, ranging from cognitive (internal) to environmental (external) influences. This facilitates the application of system identification and control engineering methods to address questions such as: what drives individuals to improve health behaviors (such as engaging in physical activity)? In this paper, the goal is to efficiently estimate personalized, dynamic models which in turn will lead to control systems that can optimize this behavior. This problem is examined in system identification applied to the Just Walk study that aimed to increase walking behavior in sedentary adults. The paper presents a Discrete Simultaneous Perturbation Stochastic Approximation (DSPSA)-based modeling of the Goal Attainment construct estimated using AutoRegressive with eXogenous inputs (ARX) models. Feature selection of participants and ARX order selection is achieved through the DSPSA algorithm, which efficiently handles computationally expensive calculations. DSPSA can search over large sets of features as well as regressor structures in an informed, principled manner to model behavioral data within reasonable computational time. DSPSA estimation highlights the large individual variability in motivating factors among participants in Just Walk, thus emphasizing the importance of a personalized approach for optimized behavioral interventions.

Did childhood adversity increase the vulnerability of university students to the negative mental health impact of the COVID-19 pandemic?

OBJECTIVE: To examine a potential synergistic effect of history of childhood adversity and COVID-19 pandemic exposure on the association with mental health concerns in undergraduate students. Participants: We used U-Flourish Survey data from 2019 (pre-pandemic) and 2020 (during-pandemic) first-year cohorts (n = 3,149) identified at entry to a major Canadian University. METHODS: Interactions between childhood adversity (physical and sexual abuse, and peer bullying) and COVID-19 pandemic exposure regarding mental health concern (depressive and anxiety symptoms, suicidality, and non-suicidal self-harm) were examined on an additive scale. RESULTS: We found a positive additive interaction between physical abuse and pandemic exposure in relation to suicidality (combined effect was greater than additive effect (risk difference 0.54 vs. 0.36)). Conversely, less than additive interactions between peer bullying and pandemic regarding depression and anxiety were observed. CONCLUSIONS: Childhood adversities have diverse reactions to adult stressor depending on the nature of the childhood adversity and the mental health outcomes.

Improved Access to Potent Anticancer Tubulysins and Linker-Functionalized Payloads Via an All-On-Resin Strategy.

Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide-drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on simplifying their structures, e. g., by using small tertiary amide N-substituents (Me, Et, Pr) on the tubuvaline residue. Cumbersome solution-phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p-Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all-on-resin strategy permitting a loss-free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on-resin tubulysin derivatization with, e. g., a maleimido-Val-Cit-PABQ linker, which is a notable progress for the payload-PABQ-linker technology. The strategy also allows tubulysin diversification of the internal amide N-substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker-attachment and functionalization.

Recent Developments in Magnetic Hyperthermia Therapy (MHT) and Magnetic Particle Imaging (MPI) in the Brain Tumor Field: A Scoping Review and Meta-Analysis.

Magnetic hyperthermia therapy (MHT) is a promising treatment modality for brain tumors using magnetic nanoparticles (MNPs) locally delivered to the tumor and activated with an external alternating magnetic field (AMF) to generate antitumor effects through localized heating. Magnetic particle imaging (MPI) is an emerging technology offering strong signal-to-noise for nanoparticle localization. A scoping review was performed by systematically querying Pubmed, Scopus, and Embase. In total, 251 articles were returned, 12 included. Articles were analyzed for nanoparticle type used, MHT parameters, and MPI applications. Preliminary results show that MHT is an exciting treatment modality with unique advantages over current heat-based therapies for brain cancer. Effective application relies on the further development of unique magnetic nanoparticle constructs and imaging modalities, such as MPI, that can enable real-time MNP imaging for improved therapeutic outcomes.

Circumscribing Laser Cuts Attenuate Seizure Propagation in a Mouse Model of Focal Epilepsy.

In partial onset epilepsy, seizures arise focally in the brain and often propagate. Patients frequently become refractory to medical management, leaving neurosurgery, which can cause neurologic deficits, as a primary treatment. In the cortex, focal seizures spread through horizontal connections in layers II/III, suggesting that severing these connections can block seizures while preserving function. Focal neocortical epilepsy is induced in mice, sub-surface cuts are created surrounding the seizure focus using tightly-focused femtosecond laser pulses, and electrophysiological recordings are acquired at multiple locations for 3-12 months. Cuts reduced seizure frequency in most animals by 87%, and only 5% of remaining seizures propagated to the distant electrodes, compared to 80% in control animals. These cuts produced a modest decrease in cortical blood flow that recovered and left a ≈20-µm wide scar with minimal collateral damage. When placed over the motor cortex, cuts do not cause notable deficits in a skilled reaching task, suggesting they hold promise as a novel neurosurgical approach for intractable focal cortical epilepsy.

Establishing Geriatric Opiate Use Patterns in Trauma.

Introduction: There is evidence that providers often overprescribe opiates in the postoperative period. Despite an ever-growing geriatric population, there is little research detailing current opiate usage in older patients after trauma. This population presents a unique set of challenges for pain management and prescription drug dependence due to sensitivity, a narrow therapeutic window, and high rates of pre-existing polypharmacy.Objective: Assess the use of narcotics in geriatric trauma patients with various injury patterns to establish a reference point for future intervention for reduction in narcotic dependence.Methods: We created a database of trauma patients' age ≥65 years admitted to a single level 1 trauma center in the Southeastern United States during the 2019 calendar year. Information gathered included patient factors, injury patterns, operative intervention, pain medications prescribed during hospitalization and at discharge, total and average daily morphine milligram equivalents (MME) inpatient and outpatient, and requests/prescriptions for narcotics at follow-up.Results: In 2019, there were 475 patients aged ≥65 admitted to our level 1 trauma center for acute traumatic injuries. 219 of those patients required operative intervention. Average total inpatient MME for this cohort was 169.0 with average daily MME of 22.89. The average total prescribed MME upon discharge was 79.27. There were 29 patients documented to request narcotic prescription refill at time of clinic follow-up, 27 of whom were prescribed a narcotic medication at follow-up.Conclusion: This dataset establishes a reference point for opiate use in geriatric trauma patients to facilitate further research for mitigation of risk in this population.

Bone marrow-restricted aberrant myeloperoxidase expression in B-acute lymphoblastic leukemia: A diagnostic dilemma and mimicry of mixed phenotype acute leukemia.

Myeloperoxidase (MPO) is the most specific marker of the myeloid lineage, essential for diagnosing acute myeloid leukemia and mixed phenotype acute leukemia with myeloid components. In this regard, we present a unique case of B-acute lymphoblastic leukemia (B-ALL) with isolated MPO expression in bone marrow blasts detected by flow cytometry and immunohistochemistry, while peripheral blood blasts were negative for MPO expression. In this report, our discussion encompasses diagnostic pitfalls from a laboratory testing perspective in similar cases and includes a literature review. Furthermore, we emphasize the necessity of conducting a comprehensive analysis for the accurate diagnosis of MPO-positive B-ALL cases.

Magnetic Hyperthermia Therapy for High-Grade Glioma: A State-of-the-Art Review.

Magnetic hyperthermia therapy (MHT) is a re-emerging treatment modality for brain tumors where magnetic nanoparticles (MNPs) are locally delivered to the brain and then activated with an external alternating magnetic field (AMF) to generate localized heat at a site of interest. Due to the recent advancements in technology and theory surrounding the intervention, clinical and pre-clinical trials have demonstrated that MHT may enhance the effectiveness of chemotherapy and radiation therapy (RT) for the treatment of brain tumors. The future clinical success of MHT relies heavily on designing MNPs optimized for both heating and imaging, developing reliable methods for the local delivery of MNPs, and designing AMF systems with integrated magnetic particle imaging (MPI) for use in humans. However, despite the progression of technological development, the clinical progress of MHT has been underwhelming. This review aims to summarize the current state-of-the-art of MHT and offers insight into the current barriers and potential solutions for moving MHT forward.

Gut Microbiota Signatures with Potential Clinical Usefulness in Colorectal and Non-Small Cell Lung Cancers.

The application of bacterial metagenomic analysis as a biomarker for cancer detection is emerging. Our aim was to discover gut microbiota signatures with potential utility in the diagnosis of colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). A prospective study was performed on a total of 77 fecal samples from CRC and NSCLC patients and controls. DNA from stool was analyzed for bacterial genomic sequencing using the Ion Torrent™ technology. Bioinformatic analysis was performed using the QIIME2 pipeline. We applied logistic regression to adjust for differences attributable to sex, age, and body mass index, and the diagnostic accuracy of our gut signatures was compared with other previously published results. The feces of patients affected by different tumor types, such as CRC and NSCLC, showed a differential intestinal microbiota profile. After adjusting for confounders, Parvimonas (OR = 53.3), Gemella (OR = 6.01), Eisenbergiella (OR = 5.35), Peptostreptococcus (OR = 9.42), Lactobacillus (OR = 6.72), Salmonella (OR = 5.44), and Fusobacterium (OR = 78.9) remained significantly associated with the risk of CRC. Two genera from the Ruminococcaceae family, DTU089 (OR = 20.1) and an uncharacterized genus (OR = 160.1), were associated with the risk of NSCLC. Our two panels had better diagnostic capacity for CRC (AUC = 0.840) and NSLC (AUC = 0.747) compared to the application of two other published panels to our population. Thus, we propose a gut bacteria panel for each cancer type and show its potential application in cancer diagnosis.

MousePZT: A simple, reliable, low-cost device for vital sign monitoring and respiratory gating in mice under anesthesia.

Small animal studies in biomedical research often require anesthesia to reduce pain or stress experienced by research animals and to minimize motion artifact during imaging or other measurements. Anesthetized animals must be closely monitored for the safety of the animals and to prevent unintended effects of altered physiology on experimental outcomes. Many currently available monitoring devices are expensive, invasive, or interfere with experimental design. Here, we present MousePZT, a low-cost device based on a simple piezoelectric sensor, with a custom circuit and computer software that allows for measurements of both respiratory rate and heart rate in a non-invasive, minimal contact manner. We find the accuracy of the MousePZT device in measuring respiratory and heart rate matches those of commercial systems. Using the widely-used gas isoflurane and injectable ketamine/xylazine combination, we also demonstrate that changes in respiratory rate are more easily detected and can precede changes in heart rate associated with variations in anesthetic depth. Additional circuitry on the device outputs a respiration-locked trigger signal for respiratory-gating of imaging or other data acquisition and has high sensitivity and specificity for detecting respiratory cycles. We provide detailed instruction documents and all necessary microcontroller and computer software, enabling straightforward construction and utilization of this device.

Tuning Local Atomic Structures in MoS2 Based Catalysts for Electrochemical Nitrate Reduction.

In recent years, there has been a substantial surge in the investigation of transition-metal dichalcogenides such as MoS2 as a promising electrochemical catalyst. Inspired by denitrification enzymes such as nitrate reductase and nitrite reductase, the electrochemical nitrate reduction catalyzed by MoS2 with varying local atomic structures is reported. It is demonstrated that the hydrothermally synthesized MoS2 containing sulfur vacancies behaves as promising catalysts for electrochemical denitrification. With copper doping at less than 9% atomic ratio, the selectivity of denitrification to dinitrogen in the products can be effectively improved. X-ray absorption characterizations suggest that two sulfur vacancies are associated with one copper dopant in the MoS2 skeleton. DFT calculation confirms that copper dopants replace three adjacent Mo atoms to form a trigonal defect-enriched region, introducing an exposed Mo reaction center that coordinates with Cu atom to increase N2 selectivity. Apart from the higher activity and selectivity, the Cu-doped MoS2 also demonstrates remarkably improved tolerance toward oxygen poisoning at high oxygen concentration. Finally, Cu-doped MoS2 based catalysts exhibit very low specific energy consumption during the electrochemical denitrification process, paving the way for potential scale-up operations.

Development and Independent Validation of a Prognostic Gene Expression Signature Based on RB1, PTEN, and TP53 in Metastatic Hormone-sensitive Prostate Cancer Patients.

BACKGROUND: Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC). OBJECTIVE: To study the clinical implications of TSG mRNA expression in mHSPC patients. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective biomarker study in mHSPC patients. TSGlow status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSGwt for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis. RESULTS AND LIMITATIONS: A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSGlow (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSGlow was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSGlow patients, while a significant benefit was observed for ADT + D in the TSGwt group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART. CONCLUSIONS: TSGlow expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted. PATIENT SUMMARY: The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.

Batch Fabrication of Microelectrode Arrays with Glassy Carbon Microelectrodes and Interconnections for Neurochemical Sensing: Promises and Challenges.

Flexible multielectrode arrays with glassy carbon (GC) electrodes and metal interconnection (hybrid MEAs) have shown promising performance in multi-channel neurochemical sensing. A primary challenge faced by hybrid MEAs fabrication is the adhesion of the metal traces with the GC electrodes, as prolonged electrical and mechanical stimulation can lead to adhesion failure. Previous devices with GC electrodes and interconnects made of a homogeneous material (all GC) demonstrated exceptional electrochemical stability but required miniaturization for enhanced tissue integration and chronic electrochemical sensing. In this study, we used two different methods for the fabrication of all GC-MEAs on thin flexible substrates with miniaturized features. The first method, like that previously reported, involves a double pattern-transfer photolithographic process, including transfer-bonding on temporary polymeric support. The second method requires a double-etching process, which uses a 2 µm-thick low stress silicon nitride coating of the Si wafer as the bottom insulator layer for the MEAs, bypassing the pattern-transfer and demonstrating a novel technique with potential advantages. We confirmed the feasibility of the two fabrication processes by verifying the practical conductivity of 3 µm-wide 2 µm-thick GC traces, the GC microelectrode functionality, and their sensing capability for the detection of serotonin using fast scan cyclic voltammetry. Through the exchange and discussion of insights regarding the strengths and limitations of these microfabrication methods, our goal is to propel the advancement of GC-based MEAs for the next generation of neural interface devices.

Recent Advances in Photoinduced Modification of Amino Acids, Peptides, and Proteins.

The chemical modification of biopolymers like peptides and proteins is a key technology to access vaccines and pharmaceuticals. Similarly, the tunable derivatization of individual amino acids is important as they are key building blocks of biomolecules, bioactive natural products, synthetic polymers, and innovative materials. The high diversity of functional groups present in amino acid-based molecules represents a significant challenge for their selective derivatization Recently, visible light-mediated transformations have emerged as a powerful strategy for achieving chemoselective biomolecule modification. This technique offers numerous advantages over other methods, including a higher selectivity, mild reaction conditions and high functional-group tolerance. This review provides an overview of the most recent methods covering the photoinduced modification for single amino acids and site-selective functionalization in peptides and proteins under mild and even biocompatible conditions. Future challenges and perspectives are discussed beyond the diverse types of photocatalytic transformations that are currently available.

Response to Marabotto et al.

Biopsies have important value in assessing for nonerosive reflux disease.

Diversification of a Novel α-Galactosyl Ceramide Hotspot Boosts the Adjuvant Properties in Parenteral and Mucosal Vaccines.

The development of potent adjuvants is an important step for improving the performance of subunit vaccines. CD1d agonists, such as the prototypical α-galactosyl ceramide (α-GalCer), are of special interest due to their ability to activate iNKT cells and trigger rapid dendritic cell maturation and B-cell activation. Herein, we introduce a novel derivatization hotspot at the α-GalCer skeleton, namely the N-substituent at the amide bond. The multicomponent diversification of this previously unexplored glycolipid chemotype space permitted the introduction of a variety of extra functionalities that can either potentiate the adjuvant properties or serve as handles for further conjugation to antigens toward the development of self-adjuvanting vaccines. This strategy led to the discovery of compounds eliciting enhanced antigen-specific T cell stimulation and a higher antibody response when delivered by either the parenteral or the mucosal route, as compared to a known potent CD1d agonist. Notably, various functionalized α-GalCer analogues showed a more potent adjuvant effect after intranasal immunization than a PEGylated α-GalCer analogue previously optimized for this purpose. Ultimately, this work could open multiple avenues of opportunity for the use of mucosal vaccines against microbial infections.

Acceptability and utility of digital well-being and mental health support for university students: A pilot study.

AIM: To assess the acceptability and explore the utility of a novel digital platform designed as a student-facing well-being and mental health support. METHODS: An adapted version of i-spero® was piloted as a student-facing well-being support and as part of routine university-based mental health care. In both pathways, student participants completed baseline demographics and brief validated measures of well-being and mental health. Weekly measures of anxiety (GAD-7) and depression (PHQ-9) and a Week 8 Experience Survey were also scheduled. Integrated mixed methods analysis was used to assess acceptability and explore the utility of these platforms. RESULTS: Students in the well-being (n = 120) and care pathways (n = 121) were mostly female and between 19 and 22 years of age. Baseline screen positive rates for anxiety and depression were high in both the well-being (68%) and care pathways (80%). There was a substantial drop in adherence over Week 1 (50% well-being; 40% care) followed by minor attrition up to Week 8. Anxiety and depressive symptom levels improved from baseline in students who dropped out after Week 1 (p ≤ .06). The student experience was that i-spero® improved their emotional self-awareness, understanding of progress in care, and knowledge about when to seek help. Most students agreed (>75%) that i-spero® should form part of regular university student wellness support. CONCLUSIONS: Digital well-being and mental health support seems acceptable to university students; however, engagement and persistence are areas for further development. Such digital tools could make a positive contribution to an evidence-based stepped approach to student well-being and mental health support.

Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group.

Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.