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Introduction Prioritization and acuity tools have been leveraged to facilitate targeted and efficient clinical pharmacist interventions. However, there is a lack of established pharmacy-specific acuity factors in the ambulatory hematology/oncology setting. Therefore, National Comprehensive Cancer Network's Pharmacy Directors Forum conducted a survey to establish consensus on acuity factors associated with hematology/oncology patients that are high priority for ambulatory clinical pharmacist review. Methods A three-round electronic Delphi survey was conducted. During the first round, respondents were asked an open-ended question to suggest acuity factors based on their expert opinion. Respondents were then asked in the second round to agree or disagree with the compiled acuity factors, in which those with ≥75% agreement were included in the third round. The final consensus was defined as a mean score ≥3.33 on a modified 4-point Likert scale (4 = strongly agree, 1 = strongly disagree) during the third round. Results A total of 124 hematology/oncology clinical pharmacists completed the first round of the Delphi survey (invitation response rate, 36.7%), of which 103 completed the second round (response rate, 83.1%) and 84 the third round (response rate, 67.7%). A final consensus was achieved for 18 acuity factors. Acuity factors were identified in the following themes: antineoplastic regimen characteristics, drug interactions, organ dysfunction, pharmacogenomics, recent discharge, laboratory parameters, and treatment-related toxicities. Conclusions This Delphi panel of 124 clinical pharmacists achieved consensus on 18 acuity factors that would identify a hematology/oncology patient as a high priority for ambulatory clinical pharmacist review. The research team envisions incorporating these acuity factors into a pharmacy-specific electronic scoring tool.

Abstract Background: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10–2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17–3.81; P = 2.2 × 10−13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66–2.95; P = 4.1 × 10−8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10−7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10−4) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.

Abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������

Purpose: The purpose of this study was to describe, compare, and understand speech modulation capabilities of patients with varying motor speech disorders (MSDs) in a paradigm in which patients made highly cued attempts to speak faster or slower. Method: Twenty-nine patients, 12 with apraxia of speech (AOS; four phonetic and eight prosodic subtype), eight with dysarthria (six hypokinetic and two spastic subtype), and nine patients without any neurogenic MSD completed a standard motor speech evaluation where they were asked to repeat words and sentences, which served as their “natural” speaking rate. They were then asked to repeat lower complexity (counting 1–5; repeating “cat” and “catnip” 3 times each) and higher complexity stimuli (repeating “catastrophe” and “stethoscope” 3 times each and “My physician wrote out a prescription” once) as fast/slow as possible. Word durations and interword intervals were measured. Linear mixed-effects models were used to assess differences related to MSD subtype and stimuli complexity on bidirectional rate modulation capacity as indexed by word duration and interword interval. Articulatory accuracy was also judged and compared. Results: Patients with prosodic AOS demonstrated a reduced ability to go faster; while they performed similarly to patients with spastic dysarthria when counting, patients with spastic dysarthria were able to increase rate similar to controls during sentence repetition; patients with prosodic AOS could not and made increased articulatory errors attempting to increase rate. AOS patients made more articulatory errors relative to other groups, regardless of condition; however, their percentage of errors reduced with an intentionally slowed speaking rate. Conclusions: The findings suggest comparative rate modulation abilities in conjunction with their impact on articulatory accuracy may support differential diagnosis between healthy and abnormal speech and among subtypes of MSDs (i.e., type of dysarthria or AOS). Findings need to be validated in a larger, more representative cohort encompassing several types of MSDs. Supplemental Material: https://doi.org/10.23641/asha.22044632

Purpose: Prior studies have shown that communication-related participation restrictions in patients with degenerative disease do not always match clinician judgment or objective indices of symptom severity. Although there is a growing body of literature documenting that discrepancies between patients with dementia and their care partners' perception of participation restrictions exist, it is not known how care partner perceptions of communication participation restrictions specifically match or diverge from the patients' experiences, which may inform the use of care partner proxy in the context of degenerative diseases. Method: Thirty-eight patients with progressive neurologic conditions (progressive supranuclear palsy, corticobasal syndrome, and primary progressive aphasia or apraxia of speech) and, in most instances, focal cognitive-communication disorders were included. The patients and their accompanying care partners independently completed the Communicative Participation Item Bank, short form, a 10-question survey about communication participation restrictions in different contexts. Care partners were instructed to complete the form with their perception of the patient's experience. The difference between patient and care partner total scores were calculated and analyzed relative to clinical and demographic variables of interest. Results: Care partner ratings modestly tracked with patient experience and objective indices of symptom severity but did not exactly match patient ratings. The presence of aphasia increased, but did not fully account for, the likelihood of a discrepancy between care partner and patient ratings. Conclusion: Although careful consideration should be given prior to using care-partner report as a proxy for patient experience, it is worthwhile to include care partner ratings as a means of supporting conversations about differing perceptions, guiding joint intervention planning, and monitoring care-partner perceptions of change along with the implementation of supported conversation strategies.

PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

Abstract Objective Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic‐based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment. Methods Participants ≥18 years of age with overnight polysomnogram‐confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were enrolled from nine sites across North America (8/2018 to 4/2021). Data collection included family/personal history of RBD and standardized assessments of cognitive, motor, sensory, and autonomic function. Results Outcomes are primarily reported based on sex (361 total: n = 295 male, n = 66 female), and secondarily based on history of antidepressant use ( n = 200 with, n = 154 without; with correction for sex differences) and based on extent of synucleinopathy burden ( n = 56 defined as isolated RBD, n = 305 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Overall, these participants commonly demonstrated abnormalities in global cognition (MoCA; 38%), motor function (alternate tap test; 48%), sensory (BSIT; 57%), autonomic function (orthostatic hypotension, 38.8%), and anxiety/depression (BAI and PHQ‐9; 39.3% and 31%, respectively). Interpretation These RBD participants, assessed with extensive history, demographic, cognitive, motor, sensory, and autonomic function demonstrated a lack of sex differences and high frequency of concomitant neurological abnormalities. These participants will be valuable for future longitudinal study and neuroprotective clinical trials.

AbstractAlterations of cerebral glucose metabolism can be detected in patients with isolated rapid eye movement sleep behaviour disorder, a prodromal feature of neurodegenerative diseases with α-synuclein pathology. However, metabolic characteristics that determine clinical progression in isolated rapid eye movement sleep behaviour disorder and their association with other biomarkers need to be elucidated. We investigated the pattern of cerebral glucose metabolism on 18F-fluorodeoxyglucose PET in patients with isolated rapid eye movement sleep behaviour disorder, differentiating between those who clinically progressed and those who remained stable over time. Second, we studied the association between 18F-fluorodeoxyglucose PET and lower dopamine transporter availability in the putamen, another hallmark of synucleinopathies. Patients with isolated rapid eye movement sleep behaviour disorder from the Mayo Clinic Alzheimer’s Disease Research Center and Center for Sleep Medicine (n = 22) and age-and sex-matched clinically unimpaired controls (clinically unimpaired; n = 44) from the Mayo Clinic Study of Aging were included. All participants underwent 18F-fluorodeoxyglucose PET and dopamine transporter imaging with iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane on single-photon emission computerized tomography. A subset of patients with isolated rapid eye movement sleep behaviour disorder with follow-up evaluations (n = 17) was classified as isolated rapid eye movement sleep behaviour disorder progressors (n = 7) if they developed mild cognitive impairment or Parkinson’s disease; or isolated rapid eye movement sleep behaviour disorder stables (n = 10) if they remained with a diagnosis of isolated rapid eye movement sleep behaviour disorder with no cognitive impairment. Glucose metabolic abnormalities in isolated rapid eye movement sleep behaviour disorder were determined by comparing atlas-based regional 18F-fluorodeoxyglucose PET uptake between isolated rapid eye movement sleep behaviour disorder and clinically unimpaired. Associations between 18F-fluorodeoxyglucose PET and dopamine transporter availability in the putamen were analyzed with Pearson’s correlation within the nigrostriatal pathway structures and with voxel-based analysis in the cortex. Patients with isolated rapid eye movement sleep behaviour disorder had lower glucose metabolism in the substantia nigra, retrosplenial cortex, angular cortex, and thalamus, and higher metabolism in the amygdala and entorhinal cortex compared with clinically unimpaired. Patients with isolated rapid eye movement sleep behaviour disorder who clinically progressed over time were characterized by higher glucose metabolism in the amygdala and entorhinal cortex, and lower glucose metabolism in the cerebellum compared with clinically unimpaired. Lower dopamine transporter availability in the putamen was associated with higher glucose metabolism in the pallidum within the nigrostriatal pathway; and with higher 18F-fluorodeoxyglucose uptake in the amygdala, insula, and temporal pole on a voxel-based analysis, although these associations did not survive after correcting for multiple comparisons. Our findings suggest that cerebral glucose metabolism in isolated rapid eye movement sleep behaviour disorder is characterized by hypometabolism in regions frequently affected during the prodromal stage of synucleinopathies, potentially reflecting synaptic dysfunction. Hypermetabolism is also seen in isolated rapid eye movement sleep behaviour disorder, suggesting that synaptic metabolic disruptions may be leading to a lack of inhibition, compensatory mechanisms, or microglial activation, especially in regions associated with nigrostriatal degeneration.

Disease-modifying therapies in both light chain and transthyretin amyloidosis have improved patient functional status and survival. Conceivably, as heart failure may progress despite amyloid therapies, more patients may be considered for heart transplantation. In earlier eras, extra-cardiac amyloid deposits significantly reduced post-heart transplant patient survival and functional status compared to the non-amyloid population. In the modern era, transplant centres have reported improved outcomes in amyloidosis as patient selection has grown more stringent. Importantly, systematic candidate evaluation should assess the degree of extra-cardiac involvement, the effectiveness of disease-modifying therapies and downstream effects on patients’ nutrition and frailty. This review outlines such an overall approach while also considering that organ-specific selection criteria may vary between individual transplant centres. A methodical approach to patient evaluation will promote better understanding of the prevalence and severity of extra-cardiac disease in amyloidosis patients referred for heart transplantation and of any disparities in decision outcomes in this population.

Abstract Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Health’s Alzheimer’s Disease Centers (ADCs). Questions covered infrastructure, funding sources, and data management related to digital pathology. Of the 35 ADCs to which the survey was sent, 33 responded. Most respondents (81%) stated that their ADC had digital slide scanner access, with the most frequent brand being Aperio/Leica (62.9%). Approximately a third of respondents stated there were fees to utilize the scanner. For DP and machine learning (ML) resources, 41% of respondents stated none was supported by their ADC. For scanner purchasing and operations, 50% of respondents stated they received institutional support. Some were unsure of the file size of scanned digital images (37%) and total amount of storage space files occupied (50%). Most (76%) were aware of other departments at their institution working with ML; a similar (76%) percentage were unaware of multiuniversity or industry partnerships. These results demonstrate many ADCs have access to a digital slide scanner; additional investigations are needed to further understand hurdles to implement DP and ML workflows.