Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus-specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis.

To enhance protective cytomegalovirus (CMV)-specific T cells in immunosuppressed recipients of an allogeneic hematopoietic cell transplant (HCT), we evaluated post-HCT impact of vaccinating healthy HCT donors with Triplex. Triplex is a viral vectored recombinant vaccine expressing three immunodominant CMV antigens. The vector is modified vaccinia Ankara (MVA), an attenuated, non-replicating poxvirus derived from the vaccinia virus strain Ankara. It demonstrated tolerability and immunogenicity in healthy adults and HCT recipients, in whom it also reduced CMV reactivation. Here, we report feasibility, safety, and immunological outcomes of a pilot phase 1 trial (NCT03560752 at ClinicalTrials.gov) including 17 CMV-seropositive recipients who received an HCT from a matched related donor (MRD) vaccinated with 5.1 × 108 pfu/ml of Triplex before cell harvest (median 15, range 11-28 days). Donor and recipient pairs who committed to participation in the trial resulted in exceptional adherence to the protocol. Triplex was well-tolerated with limited adverse events in donors and recipients, who all engrafted with full donor chimerism. On day 28 post-HCT, levels of functional vaccinia- and CMV-specific CD137+ CD8+ T cells were significantly higher (p < .0001 and p = .0174, respectively) in recipients of Triplex vaccinated MRD than unvaccinated MRD (control cohort). Predominantly, central and effector memory CMV-specific T-cell responses continued to steadily expand through 1-year follow-up. CMV viremia requiring antivirals developed in three recipients (18%). In summary, this novel approach represents a promising strategy applicable to different HCT settings for limiting the use of antiviral prophylaxis, which can impair and delay CMV-specific immunity, leading to CMV reactivation requiring treatment.

Validated HPLC-UV method for quantification of paxalisib, a pan PI3K and mTOR inhibitor in mouse plasma: Application to a pharmacokinetic study in mice.

Paxalisib is a pan-PI3K and mTOR inhibitor, currently entering into Phase II clinical trials as a potential drug to treat glioblastoma patients. We report the development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of paxalisib in mouse plasma as per the US Food and Drug Administration regulatory guidelines. From the mouse plasma, paxalisib and the internal standard (IS; filgotinib) were extracted using ethyl acetate as an extraction solvent. The chromatographic separation of paxalisib and the IS was accomplished on a Symmetry C18 (250 × 4.6 mm, 5.0 µm) column maintained at 40°C using 10 mm ammonium formate and acetonitrile in gradient conditions at a 0.8 ml/min flow-rate. The injection volume was 20 µl. The elution was monitored using a photo-diode array detector set at λmax 280 nm. Paxalisib and the IS eluted at 6.5 and 5.9 min, respectively with a total run time of 10 min. The calibration curve was linear over the range of 111-4,989 ng/ml. Inter- and intraday precision and accuracy, stability studies, dilution integrity and incurred sample reanalysis were investigated and the results met the acceptance criteria. The validated HPLC method was extended to assess the pharmacokinetic parameters of paxalisib in mice.

Cytokine gene polymorphisms are associated with response to blinatumomab in B-cell acute lymphoblastic leukemia.

Blinatumomab is a bispecific T cell-engaging antibody approved for treatment of relapsed/refractory (r/r) ALL, with 40%-50% complete response (CR)/CR with incomplete count recovery (CRi). Cytokine release syndrome (CRS) as a major adverse effect after blinatumomab therapy. Here, we evaluated the possible association between single-nucleotide polymorphisms (SNPs) in cytokine genes, disease response, and CRS in r/r ALL patients who received blinatumomab between 2012 and 2017 at our center (n = 66), using patients' archived DNA samples. With a median duration of 9.5 months (range: 1-37), 37 patients (56.1%) achieved CR/CRi, 54 (81.8%) experienced CRS (G1: n = 35, G2: n = 14, G3: n = 5), and 9 (13.6%) developed neurotoxicity. By multivariable analysis, after adjusting for high disease burden, one SNP on IL2 (rs2069762), odds ratio (OR) = 0.074 (95% CI: NE-0.43, P = .01) and one SNP on IL17A (rs4711998), OR = 0.28 (95% CI: 0.078-0.92, P = .034) were independently associated with CR/CRi. None of the analyzed SNPs were associated with CRS. To our knowledge, this is the first study demonstrating a possible association between treatment response to blinatumomab and SNPs. Our hypothesis-generated data suggest a potential role for IL-17 and IL-2 in blinatumomab response and justify a larger confirmatory study, which may lead to personalized blinatumomab immunotherapy for B-ALL.

Stereoselective pharmacokinetics and tissue distribution of levodropropizine after administration of pure levodropropizine and the rac-dropropizine to Sprague-Dawley rats.

Levodropropizine (LDP) is a non-opioid anti-tussive. The stereoselective pharmacokinetics and tissue distribution (TD) of LDP vs. dextrodropropizine (DDP) have been characterized after oral and intravenous (IV) administration of LDP and rac-dropropozine in rats.Oral/IV doses of 50/5.0 mg/kg and 25/2.5 rac-dropropizine and LDP were employed. TD study focused on tissues such as liver, lung and kidney. Blood samples were collected for pharmacokinetic and TD evaluation. Validated methods were used to quantitate LDP, DDP and rac-dropropizine.No stereoselectivity in pharmacokinetics was observed between LDP vs. DDP following rac-dropropizine. However, LDP pharmacokinetics after LDP administration (oral/IV) appeared to be different compared to LDP derived from rac-dropropizine.TD data were similar between the two enantiomers regardless of oral/IV rac-dropropizine administration. When LDP alone was administered, levels were comparable to those derived for LDP from rac-dropropizine after oral/IV. However, in the lung and kidney tissues, the exposure after oral dosing was higher for LDP alone as compared to LDP from rac-dropropizine.In summary, complete characterization of stereoselective pharmacokinetics and TD of rac-dropropizine has been reported after oral/IV routes. It was evident that the presence of DDP, increased the plasma/tissue exposure of LDP which was evident after oral rac-dropropizine dosing.

Early Outcomes With HeartWare HVAD as Bridge to Transplant in Children: A Single Institution Experience.

The HeartWare HVAD has been used as a bridge to cardiac transplantation in the pediatric population. We describe outcomes following HeartWare HVAD implantation at a single center. A retrospective chart review was performed of all HeartWare HVAD implants performed at our institution between May 2013 and March 2015. Eight children between the ages of 9 and 17 years underwent HVAD implantation as a bridge to transplant (N = 7 cardiomyopathy, N = 1 complex single ventricle). There was one operative death in the complex single ventricle patient. Seven patients (87%) were successfully bridged to transplant. Median time of support was 24.5 days (range, 6-91 days). All transplanted patients are alive and well at a median follow-up of 448 days. Our results demonstrated that mechanical support with HeartWare HVAD is feasible in patients of varying sizes (from older children to adolescents).

Characterization of Event Related Desynchronization in Chronic Stroke Using Motor Imagery Based Brain Computer Interface for Upper Limb Rehabilitation.

OBJECTIVE: Motor imagery-based brain-computer interface (MI-BCI) is a promising novel mode of stroke rehabilitation. The current study aims to investigate the feasibility of MI-BCI in upper limb rehabilitation of chronic stroke survivors and also to study the early event-related desynchronization after MI-BCI intervention. METHODS: Changes in the characteristics of sensorimotor rhythm modulations in response to a short brain-computer interface (BCI) intervention for upper limb rehabilitation of stroke-disabled hand and normal hand were examined. The participants were trained to modulate their brain rhythms through motor imagery or execution during calibration, and they played a virtual marble game during the feedback session, where the movement of the marble was controlled by their sensorimotor rhythm. RESULTS: Ipsilesional and contralesional activities were observed in the brain during the upper limb rehabilitation using BCI intervention. All the participants were able to successfully control the position of the virtual marble using their sensorimotor rhythm. CONCLUSIONS: The preliminary results support the feasibility of BCI in upper limb rehabilitation and unveil the capability of MI-BCI as a promising medical intervention. This study provides a strong platform for clinicians to build upon new strategies for stroke rehabilitation by integrating MI-BCI with various therapeutic options to induce neural plasticity and recovery.

Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.

While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).

Signal Selection Technique based on Statistical Approach for Enhanced Detection of Single-trial Auditory Evoked Potentials.

Volume conduction from insignificant neuronal sources in the brain poses a challenge to the detection and classification of single-trial low amplitude evoked potentials in electroencephalograph (EEG). This work presents a statistical signal selection method for enhanced detection of single-trial EEG auditory evoked potential (AEP) elicited in the brain in response to subjects' own name audio stimulus. The proposed method comprises of a signal selection stage based on a statistical analysis followed by a support vector machine (SVM)-based classifier. The EEG signals recorded from the Fp1 electrode of 24 subjects are used to generate a classifier-dependent feature vector. With the selected one-quarter of AEP signals, a single-trial classification accuracy of 70.59% is obtained. To the best of our knowledge, this is the first study that reports the classification of single-trial AEPs evoked by subjects' own-name audio stimulus versus familiar-name audio stimulus.

A Phase-based EEG Epoch Selection Method for Decoding Bi-directional Hand Movement Imagination in Stroke Patients.

Electroencephalogram (EEG) based non-invasive Brain Computer Interface (BCI) system is gaining significant attention as a promising solution for stroke rehabilitation. Accurate selection of informative EEG time segment, that accommodates the specific neural activity patterns associated with the underlying mental task can help to improve the efficacy of the BCI system. In this work, we propose a phase-based EEG epoch selection algorithm to extract the discriminative EEG time segment corresponding to bi-directional hand motor imagery. The imagined center-out hand movement in two directions is decoded using the selected epoch of the EEG, recorded from 16 stroke patients with hemiparesis and specifically hand weakness. Phase Lock Value (PLV) EEG features extracted from the selected EEG epoch is used as discriminative feature for binary classification of imagined hand movement direction using Linear Discriminant Analysis. The use of selected EEG epoch yielded an improvement of 11.5% and 11.7% in the average direction classification accuracy of calibration and feedback session data respectively, compared to the baseline method employing the whole EEG signal. In addition to improvement in decoding accuracy, the epoch selection also yielded an average Information Transfer Rate (ITR) of 39.8±24.6 bits per minute, which is 86% improvement compared to the baseline method.Clinical Relevance- The proposed Motor Imagery (MI)-BCI system may be of clinical relevance as an active rehabilitation tool for stroke-affected patients, to enhance neural plasticity and recovery of centre-out activities of affected hand and forms a strong platform for MI-BCI coupled with exoskeletons or prosthesis rehabilitation.

Creation of a Neo-Mitral Valve With Right Atrial Appendage Tissue in an Infant.

Mitral valve replacement in neonates and infants is a challenging operation with few good options. Neo-mitral valve reconstruction with right atrial appendage (RAA) may overcome some of the limitations of existing options.

Functional SARS-CoV-2-specific T cells of donor origin in allogeneic stem cell transplant recipients of a T-cell-replete infusion: A prospective observational study.

In the current post-pandemic era, recipients of an allogeneic hematopoietic stem cell transplant (HCT) deserve special attention. In these vulnerable patients, vaccine effectiveness is reduced by post-transplant immune-suppressive therapy; consequently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) is often associated with elevated morbidity and mortality. Characterizing SARS-CoV-2 adaptive immunity transfer from immune donors to HCT recipients in the context of immunosuppression will help identify optimal timing and vaccination strategies that can provide adequate protection to HCT recipients against infection with evolving SARS-CoV-2 variants. We performed a prospective observational study (NCT04666025 at ClinicalTrials.gov) to longitudinally monitor the transfer of SARS-CoV-2-specific antiviral immunity from HCT donors, who were either vaccinated or had a history of COVID-19, to their recipients via T-cell replete graft. Levels, function, and quality of SARS-CoV-2-specific immune responses were longitudinally analyzed up to 6 months post-HCT in 14 matched unrelated donor/recipients and four haploidentical donor/recipient pairs. A markedly skewed donor-derived SARS-CoV-2 CD4 T-cell response was measurable in 15 (83%) recipients. It showed a polarized Th1 functional profile, with the prevalence of central memory phenotype subsets. SARS-CoV-2-specific IFN-γ was detectable throughout the observation period, including early post-transplant (day +30). Functionally experienced SARS-CoV-2 Th1-type T cells promptly expanded in two recipients at the time of post-HCT vaccination and in two others who were infected and survived post-transplant COVID-19 infection. Our data suggest that donor-derived SARS-CoV-2 T-cell responses are functional in immunosuppressed recipients and may play a critical role in post-HCT vaccine response and protection from the fatal disease. Clinical trial registration: clinicaltrials.gov, identifier NCT04666025.

Evolution of antiphospholipid antibody syndrome.

Antiphospholipid antibody syndrome is a very important cause of cerebral infarction, myocardial infarction, and repeated pregnancy losses in women. We present an extremely rare case of a 44-year-old man with antiphospholipid syndrome who collapsed and died suddenly. At autopsy, he was found to have both cerebral and myocardial infarction. In all young patients with cerebral infarction, myocardial infarction, pulmonary embolism, recurrent miscarriages, and unexplained low platelet count, one must consider the strong possibility of antiphospholipid antibody syndrome.

Direction decoding of imagined hand movements using subject-specific features from parietal EEG.

Objective.Research on the decoding of brain signals to control external devices is rapidly emerging due to its versatile potential applications, including neuroprosthetic control and neurorehabilitation. Electroencephalogram (EEG)-based non-invasive brain-computer interface (BCI) systems decode brain signals to establish an augmented communication and control pathway between the brain and the computer. The development of an efficient BCI system requires accurate decoding of neural activity underlying the user's intentions. This study investigates the directional tuning of EEG characteristics from the posterior parietal region, associated with bidirectional hand movement imagination or motor imagery (MI) in left and right directions.Approach. The imagined movement directions of the chosen hand were decoded using a combination of envelope and phase features derived from parietal EEGs of both hemispheres. The proposed algorithm uses wavelets for spectral decomposition, and discriminative subject-specific subband levels are identified based on Fisher analysis of envelope and phase features. The selected features from the discriminative subband levels are used to classify left and right MI directions of the hand using a support vector machine classifier. Furthermore, the performance of the proposed algorithm is evaluated by incorporating a maximum-variance-based EEG time bin selection algorithm.Main results.With the time bin selection approach using subject-specific features, the proposed algorithm yielded an average left vs right MI direction decoding accuracy of 73.33% across 15 healthy subjects. In addition, the decoding accuracy offered by the phase features was higher than that of the envelope features, indicating the importance of phase features in MI kinematics decoding.Significance.The results reveal the significance of the parietal EEG in decoding of imagined kinematics and open new possibilities for future BCI research.

Drowsiness detection using portable wireless EEG.

BACKGROUND AND OBJECTIVE: The ever-increasing fatality rate due to traffic and workplace accidents, resulting from drowsiness have been a persistent concern during the past years. An efficient technology capable of monitoring and detecting drowsiness can help to alleviate this concern and has potential applications in driver vigilance monitoring, vigilance monitoring in air traffic control rooms and other safety critical work places. In this paper, we present the feasibility of a wearable light weight wireless consumer grade Electroencephalogram (EEG)-based drowsiness detection. METHODS: A set of informative features were extracted from short daytime nap EEG signals and their applicability in discriminating between alert and drowsy state was studied. We derived an optimal set of EEG features, that give maximum detection rate for the drowsy state. In addition, heart rate was also recorded concurrently with EEG and correlation between heart rate and the EEG features corresponding to drowsiness was also studied. RESULTS: Using the selected features, the EEG data is shown to be capable of classifying alert and drowsy states with an accuracy of 78.3% using Support Vector Machine classifier employing cross subject validation. The feature selection results also revealed that, the EEG features extracted from the temporal electrodes are more significant for drowsiness detection than the features from frontal electrodes. In addition, EEG features extracted from the temporal electrodes yielded higher correlation coefficient with heart rate, which was in concordance with the feature selection results. CONCLUSIONS: The results reveal that using the proposed drowsiness detection algorithm, it is possible to perform drowsiness detection using a single EEG electrode placed behind the ear.

Single-trial detection of EEG error-related potentials in serial visual presentation paradigm.

When the outcome of an event is not the same as expected, the cognitive state that monitors performance elicits a time-locked brain response termed as Error-Related Potential (ErrP).Objective-In the existing work, ErrP is not recorded when there is a disassociation between an object and its description. The objective of this work is to propose a Serial Visual Presentation (SVP) experimental paradigm to record ErrP when an image and its label are disassociated. Additionally, this work aims to propose a novel method for detecting ErrP on a single-trial basis.Method-The method followed in this work includes designing of SVP paradigm in which labeled images from six categories (bike, car, flower, fruit, cat, and dog) are presented serially. In this work, a text (visual) or an audio clip describing the image in one word is presented as the label. Further, the ErrP is detected on a single-trial basis using novel electrode-averaged features.Results -The ErrP data recorded from 11 subjects' have consistent characteristics compared to existing ErrP literature. Detection of ErrP on a single-trial basis is carried out using a novel feature extraction method on two type labeling types separately. The best average classification accuracy achieved is69.09±4.70%and63.33±4.56%for the audio and visual type of labeling the image, respectively. The proposed feature extraction method achieved higher classification accuracy when compared with two existing feature extraction methods.Significance -The significance of this work is that it can be used as a Brain-Computer Interface (BCI) system for quantitative evaluation and treatment of mild cognitive impairment. This work can also find non-clinical BCI applications such as image annotation.

Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma.

Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-XL without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. SIGNIFICANCE: In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant.See related commentary by Larkin and Byrd, p. 1324.This article is highlighted in the In This Issue feature, p. 1307.

Heart transplantation techniques after hybrid single-ventricle palliation.

The Norwood procedure for hypoplastic left heart syndrome (HLHS) aims to provide an unobstructed systemic outflow tract, unrestrictive inter-atrial communication, controlled source of pulmonary blood flow, and reliable source of coronary blood flow. The hybrid palliative strategy of pulmonary artery banding and ductal stenting has emerged as an alternative treatment for neonates with HLHS. Neonates who have undergone a hybrid Norwood but are not candidates for the three-stage single-ventricle pathway may need heart transplantation. Patients who have undergone hybrid Norwood or those with visceral heterotaxy who have undergone ductal stenting and bilateral PA bands represent a technically challenging group of patients for heart transplantation, but it appears to be a favorable approach and we describe our experience with three patients who underwent heart transplant after a hybrid Norwood procedure.

Motor Imagery Hand Movement Direction Decoding Using Brain Computer Interface to Aid Stroke Recovery and Rehabilitation.

Motor Imagery (MI)-based Brain Computer Interface (BCI) system is a potential technology for active neurorehabilitation of stroke patients by complementing the conventional passive rehabilitation methods. Research to date mainly focused on classifying left vs. right hand/foot MI of stroke patients. Though a very few studies have reported decoding imagined hand movement directions using electroencephalogram (EEG)-based BCI, the experiments were conducted on healthy subjects. Our work analyzes MI-based brain cortical activity from EEG signals and decodes the imagined hand movement directions in stroke patients. The decoded direction (left vs. right) of hand movement imagination is used to provide control commands to a motorized arm support on which patient's affected (paralyzed) arm is placed. This enables the patient to move his/her stroke-affected hand towards the intended (imagined) direction that aids neuroplasticity in the brain. The synchronization measure called Phase Locking Value (PLV), extracted from EEG, is the neuronal signature used to decode the directional movement of the MI task. Event-related desynchronization/synchronization (ERD/ERS) analysis on Mu and Beta frequency bands of EEG is done to select the time bin corresponding to the MI task. The dissimilarities between the two directions of MI tasks are identified by selecting the most significant channel pairs that provided maximum difference in PLV features. The training protocol has an initial calibration session followed by a feedback session with 50 trials of MI task in each session. The feedback session extracts PLV features corresponding to most significant channel pairs which are identified in the calibration session and is used to predict the direction of MI task in left/right direction. An average MI direction classification accuracy of 74.44% is obtained in performing the training protocol and 68.63% from the prediction protocol during feedback session on 16 stroke patients.