Age, Motion, Medical, and Psychiatric Associations With Incidental Findings in Brain MRI.

Importance: Few investigations have evaluated rates of brain-based magnetic resonance imaging (MRI) incidental findings (IFs) in large lifespan samples, their stability over time, or their associations with health outcomes. Objectives: To examine rates of brain-based IFs across the lifespan, their persistence, and their associations with phenotypic indicators of behavior, cognition, and health; to compare quantified motion with radiologist-reported motion and evaluate its associations with IF rates; and to explore IF consistency across multiple visits. Design, Setting, and Participants: This cross-sectional study included participants from the Nathan Kline Institute-Rockland Sample (NKI-RS), a lifespan community-ascertained sample, and the Healthy Brain Network (HBN), a cross-sectional community self-referred pediatric sample focused on mental health and learning disorders. The NKI-RS enrolled participants (ages 6-85 years) between March 2012 and March 2020 and had longitudinal participants followed up for as long as 4 years. The HBN enrolled participants (ages 5-21 years) between August 2015 and October 2021. Clinical neuroradiology MRI reports were coded for radiologist-reported motion as well as presence, type, and clinical urgency (category 1, no abnormal findings; 2, no referral recommended; 3, consider referral; and 4, immediate referral) of IFs. MRI reports were coded from June to October 2021. Data were analyzed from November 2021 to February 2023. Main Outcomes and Measures: Rates and type of IFs by demographic characteristics, health phenotyping, and motion artifacts; longitudinal stability of IFs; and Euler number in projecting radiologist-reported motion. Results: A total of 1300 NKI-RS participants (781 [60.1%] female; mean [SD] age, 38.9 [21.8] years) and 2772 HBN participants (976 [35.2%] female; mean [SD] age, 10.0 [3.5] years) had health phenotyping and neuroradiology-reviewed MRI scans. IFs were common, with 284 of 2956 children (9.6%) and 608 of 1107 adults (54.9%) having IFs, but rarely of clinical concern (category 1: NKI-RS, 619 [47.6%]; HBN, 2561 [92.4%]; category 2: NKI-RS, 647 [49.8%]; HBN, 178 [6.4%]; category 3: NKI-RS, 79 [6.1%]; HBN, 30 [1.1%]; category 4: NKI-RS: 12 [0.9%]; HBN, 6 [0.2%]). Overall, 46 children (1.6%) and 79 adults (7.1%) required referral for their IFs. IF frequency increased with age. Elevated blood pressure and BMI were associated with increased T2 hyperintensities and age-related cortical atrophy. Radiologist-reported motion aligned with Euler-quantified motion, but neither were associated with IF rates. Conclusions and Relevance: In this cross-sectional study, IFs were common, particularly with increasing age, although rarely clinically significant. While T2 hyperintensity and age-related cortical atrophy were associated with BMI and blood pressure, IFs were not associated with other behavioral, cognitive, and health phenotyping. Motion may not limit clinical IF detection.

Tolerability and efficacy of the cancer vaccine UV1 in patients with recurrent or metastatic PD-L1 positive head and neck squamous cell carcinoma planned for first-line treatment with pembrolizumab - the randomized phase 2 FOCUS trial.

Background: Globally, head and neck squamous cell carcinoma (HNSCC) is the seventh most common malignancy. Despite aggressive multimodal treatment approaches, recurrent and/or metastatic (R/M) disease develops in >50% of patients. In this setting, pembrolizumab was approved for patients with PD-L1 expression. However, response rates with checkpoint inhibitor monotherapy remain limited and strategies to strengthen tumor-directed immune responses are needed. Objective: The FOCUS trial is designed to estimate the effectiveness of UV1 vaccination in combination with pembrolizumab versus pembrolizumab as a single agent in patients with R/M HNSCC. Methods and analysis: The FOCUS trial is a two-armed, randomized, multicenter phase II study which was designed to evaluate the efficacy and feasibility of the hTERT-targeted cancer vaccine UV1 as add-on to pembrolizumab in the 1st line treatment of patients with R/M PD-L1 positive (combined positive score ≥1) HNSCC. Secondary objectives are the exploration of patient subgroups most likely deriving benefit from this novel combination and the establishment of liquid biopsy tumor monitoring in HNSCC. Ethics and dissemination: This clinical study was designed and will be conducted in compliance with Good Clinical Practice and in accordance with the Declaration of Helsinki. It is intended to publish the results of this study in peer-reviewed scientific journals and to present its content at academic conferences. Conclusions: A significant number of patients with R/M HNSCC are frail and may not tolerate chemotherapy, these patients may only be suitable for pembrolizumab monotherapy. However, long term disease stabilizations remain the exception and there is a need for the development of efficacious combination regimens for this patient population. The FOCUS study aims to optimize treatment of R/M HNSCC patients with this promising new treatment approach. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT05075122, identifier NCT05075122.

Adipose biopsy techniques for studies in human exercise physiology.

Adipose biopsy techniques are relatively undefined for exercise physiology research in individuals at or near normal weight. The purpose of this study was to compare the influence of two adipose biopsy techniques on tissue quality through measurements of adipocyte cell size, as well as mRNA and protein levels of select pro- and anti-inflammatory cytokines and adipokines. Thirteen participants (9 M, 4 W; 28 ± 4 yr; 27 ± 3 kg·m-2; V̇o2max: 3.3 ± 0.7 L·min-1) underwent subcutaneous adipose biopsies on either side of the umbilicus (incision: ∼8 cm lateral, sampling area: ∼5 cm lateral) using 1) a 6-mm Bergström biopsy needle and 2) a mini-liposuction approach with a 4-mm Mercedes biopsy needle that used prebiopsy tumescent delivery (∼30 mL 0.9% NaCl solution) into the sampling area (i.e., 'wet' technique). Tissue obtained was processed identically for analysis and both techniques returned high-quality tissue for histology (similar % intact adipocytes), mRNA (RNA integrity numbers >7.0), and protein. Adipocyte size was similar (P > 0.05) between both techniques (Bergström: 6,116 ± 1,652 µm2, 554-23,522 µm2; Mercedes: 6,517 ± 952 µm2, 926-21,969 µm2). There were also no differences (P > 0.05) between the two techniques for the measured cytokines (pro- and anti-inflammatory) and adipokines at the mRNA and protein levels. Adipocyte size was positively correlated with body mass index and body fat percentage, and negatively correlated with V̇o2max (P < 0.05). These results suggest both adipose biopsy techniques used in the current investigation are appropriate for histological, transcriptional, and translational level measurements in exercise physiology studies of nonobese women and men.NEW & NOTEWORTHY This study provides investigators with useful information related to adipose biopsy sampling approaches that can be used when planning studies that use measurements of adipose histology, as well as measurements at the mRNA and protein level. Adipose periumbilical sampling with the Bergström biopsy needle and the Mercedes wet mini-liposuction technique are both appropriate options for studies in exercise physiology and in nonobese individuals.

Multitissue responses to exercise: a MoTrPAC feasibility study.

We assessed the feasibility of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) human adult clinical exercise protocols, while also documenting select cardiovascular, metabolic, and molecular responses to these protocols. After phenotyping and familiarization sessions, 20 subjects (25 ± 2 yr, 12 M, 8 W) completed an endurance exercise bout (n = 8, 40 min cycling at 70% V̇o2max), a resistance exercise bout (n = 6, ∼45 min, 3 sets of ∼10 repetition maximum, 8 exercises), or a resting control period (n = 6, 40 min rest). Blood samples were taken before, during, and after (10 min, 2 h, and 3.5 h) exercise or rest for levels of catecholamines, cortisol, glucagon, insulin, glucose, free fatty acids, and lactate. Heart rate was recorded throughout exercise (or rest). Skeletal muscle (vastus lateralis) and adipose (periumbilical) biopsies were taken before and ∼4 h following exercise or rest for mRNA levels of genes related to energy metabolism, growth, angiogenesis, and circadian processes. Coordination of the timing of procedural components (e.g., local anesthetic delivery, biopsy incisions, tumescent delivery, intravenous line flushes, sample collection and processing, exercise transitions, and team dynamics) was reasonable to orchestrate while considering subject burden and scientific objectives. The cardiovascular and metabolic alterations reflected a dynamic and unique response to endurance and resistance exercise, whereas skeletal muscle was transcriptionally more responsive than adipose 4 h postexercise. In summary, the current report provides the first evidence of protocol execution and feasibility of key components of the MoTrPAC human adult clinical exercise protocols. Scientists should consider designing exercise studies in various populations to interface with the MoTrPAC protocols and DataHub.NEW & NOTEWORTHY This study highlights the feasibility of key aspects of the MoTrPAC adult human clinical protocols. This initial preview of what can be expected from acute exercise trial data from MoTrPAC provides an impetus for scientists to design exercise studies to interlace with the rich phenotypic and -omics data that will populate the MoTrPAC DataHub at the completion of the parent protocol.

Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma.

Tumors shed cell-free DNA (cfDNA) into the plasma. "Liquid biopsies" are a diagnostic test to analyze cfDNA in order to detect minimal residual cancer, profile the genomic tumor landscape, and monitor cancers non-invasively over time. This technique may be useful in patients with head and neck squamous cell carcinoma (HNSCC) due to genetic tumor heterogeneity and limitations in imaging sensitivity. However, there are technical challenges that need to be overcome for the widespread use of liquid biopsy in the clinical management of these patients. In this review, we discuss our current understanding of HNSCC genetics and the role of cfDNA genomic analyses as an emerging precision diagnostic tool.

Factors Affecting Turnover of Advanced Practice Providers: A University Teaching Hospital Review.

GOAL: Retention of advanced practice providers (APPs) is an issue of critical importance to healthcare leaders. High APP turnover negatively affects an organization's ability to meet patient needs, maintain quality of care, and control costs. Our goal was to identify any association between intent to leave and specific survey factors; analyze the distribution of scale factors from the survey; and describe differences among the APP roles, specialties, and length of employment. METHODS: This study used a self-administered questionnaire for APPs at a large university medical center to determine job satisfaction rates and intent to resign. The survey used a modified Misener Nurse Practitioner Job Satisfaction Scale and Anticipated Turnover Scale. PRINCIPAL FINDINGS: We received surveys from 102 providers (for a 38.9% response rate). Results were used to determine the correlation between job satisfaction and intent to leave and to identify possible factors involved in APP commitment to the hospital and intent to stay. We found that APPs reported the most satisfaction in benefits, followed by time (i.e., time available for answering messages, reviewing laboratory and other test results, seeing patients, scheduling work). Intrapractice partnership/collegiality received the lowest satisfaction score. Extrinsic factors such as monetary bonuses available in addition to salary, reward distribution, involvement in research, conflict resolution, and opportunity to receive compensation for services performed outside normal duties were common dissatisfiers. PRACTICAL APPLICATIONS: This survey may help hospitals identify in real time the triggers of APP dissatisfaction and intent to resign. In addition, the results may guide possible revisions to hospital policies and practice procedures to improve APP commitment and decrease turnover intent. Additional surveys in similar university teaching hospital systems could confirm comparable intrinsic and extrinsic factors that are relevant to the satisfaction and turnover of APPs.

A longitudinal resource for studying connectome development and its psychiatric associations during childhood.

Most psychiatric disorders are chronic, associated with high levels of disability and distress, and present during pediatric development. Scientific innovation increasingly allows researchers to probe brain-behavior relationships in the developing human. As a result, ambitions to (1) establish normative pediatric brain development trajectories akin to growth curves, (2) characterize reliable metrics for distinguishing illness, and (3) develop clinically useful tools to assist in the diagnosis and management of mental health and learning disorders have gained significant momentum. To this end, the NKI-Rockland Sample initiative was created to probe lifespan development as a large-scale multimodal dataset. The NKI-Rockland Sample Longitudinal Discovery of Brain Development Trajectories substudy (N = 369) is a 24- to 30-month multi-cohort longitudinal pediatric investigation (ages 6.0-17.0 at enrollment) carried out in a community-ascertained sample. Data include psychiatric diagnostic, medical, behavioral, and cognitive phenotyping, as well as multimodal brain imaging (resting fMRI, diffusion MRI, morphometric MRI, arterial spin labeling), genetics, and actigraphy. Herein, we present the rationale, design, and implementation of the Longitudinal Discovery of Brain Development Trajectories protocol.

Clinical Predictors of Neurogenic Lower Urinary Tract Dysfunction in Persons with Multiple Sclerosis.

BACKGROUND: Multiple sclerosis patients often develop neurogenic lower urinary tract dysfunction with a potential risk of upper urinary tract damage. Diagnostic tools are urodynamics, bladder diary, uroflowmetry, and post-void residual, but recommendations for their use are controversial. OBJECTIVE: We aimed to identify clinical parameters indicative of neurogenic lower urinary tract dysfunction in multiple sclerosis patients. METHODS: 207 patients were prospectively assessed independent of the presence of lower urinary tract symptoms. We analyzed Expanded Disability Status Scale scores, uroflowmetry, post-void residual, rate of urinary tract infections, standardized voiding frequency, and voided volume in correlation with urodynamic findings. RESULTS: We found a significant correlation between post-void residual (odds ratio (OR) 4.17, confidence interval (CI) 1.20-22.46), urinary tract infection rate (OR 3.91, CI 1.13-21.0), voided volume (OR 4.53, CI 1.85-11.99), increased standardized voiding frequency (OR 7.40, CI 2.15-39.66), and urodynamic findings indicative of neurogenic lower urinary tract dysfunction. Expanded Disability Status Scale shows no correlation. Those parameters (except post-void residual) are also associated with reduced bladder compliance, as potential risk for kidney damage. CONCLUSION: Therefore, bladder diary and urinary tract infection rate should be routinely assessed to identify patients who require urodynamics.

Occupational burnout among workers in the long-term care sector in relation to their personality traits.

OBJECTIVES: This paper investigates the sense of occupational burnout among people working with older persons in the long-term care sector in relation to their personality traits. The study objective is to examine the correlation between the sense of burnout and personality traits of persons working in the helping professions, the so-called human services. According to researchers, these professionals are susceptible to occupational burnout due to the involvement of their personal emotions in the helping process. MATERIAL AND METHODS: The study encompassed 238 workers employed at care institutions for older people. The authors used a diagnostic survey as the research method, and the following research instruments: the Maslach Burnout Inventory by C. Maslach (to assess an individual's sense of burnout) and the NEO Five-Factor Inventory by P.T. Costa and R.R. McCrae (to assess personality traits). RESULTS: The survey indicates that workers are at risk of occupational burnout, and statistically significant differences have been observed in their sense of burnout depending on their personality traits in all the inventories analyzed: emotional exhaustion, depersonalization, and personal accomplishment. CONCLUSIONS: Since the survey results confirm the differences in the sense of occupational burnout among the respondents with different personality traits, measures should be taken for the prevention and early detection of burnout in workers. For the intervention methods to be effective, workers' personality traits should be taken into account. Int J Occup Med Environ Health. 2021;34(4):491-504.

[Current aspects of neurogenic dysfunctions of the lower urinary tract in multiple sclerosis]. / Aktuelles zu neurogenen Dysfunktionen des unteren Harntraktes bei Multipler Sklerose.

BACKGROUND: In the clinical management of patients with multiple sclerosis (MS), the challenge is to make an early diagnosis and initiate adequate treatment of neurogenic disorders of the lower urinary tract (NLUTD). Various national guidelines provide practical recommendations which are sometimes discordant. OBJECTIVE: To develop a simple evidence-based algorithm for detecting NLUTD in patients with MS that could be taken as a principle for deriving therapeutic consequences. MATERIAL AND METHODS: A prospective multicenter study was initiated as a direct result of two multidisciplinary conferences. The aim was to identify statistically and clinically relevant parameters for the routine diagnosis of NLUTD in patients with MS. Urodynamic abnormalities served as the gold standard. At three subsequent consensus conferences, the results of the study were discussed, a diagnostic algorithm was developed and consensus was reached on a first-line treatment. RESULTS AND DISCUSSION: The proposed algorithm enables the detection of NLUTD in patients with MS with the help of four statistically significant predictors: 1) the residual urine volume, 2) the number of urinary tract infections (UTI) within the last 6 months, 3) the standardized micturition frequency and 4) the presence/absence of urinary incontinence. The newly developed algorithm has proved to be efficient with the following results: approximately 75% of the patients do not need a urodynamic examination for a first-line treatment decision. In 25% of cases, urodynamic examinations are essential for an adequate treatment decision. Routine assessments include the patient medical history, residual urine volume measurement, a micturition diary and a uroflowmetry (optional).

Neurourological assessment in people with multiple sclerosis (MS): a new evaluated algorithm.

BACKGROUND: Neurogenic lower urinary tract dysfunction (NULTD) is common in patients with multiple sclerosis (MS); nevertheless, it is often underestimated, underdiagnosed, and undertreated due to patients' sense of shame, variability of symptoms, as well as lack of communication between neurologists and urologists, despite the availability of several guidelines based on scientific evidence and expert opinion. OBJECTIVE: This study was conducted to develop an easy-to-perform algorithm for diagnosing neurogenic lower urinary tract disease in patients with MS for daily neurological and urological routine, including the identification of red flags. METHODS: In consensus group meetings, interprofessional experts (neurologists, urologists, neurourologists, nurses, nurse practitioners, occupational therapists, physical therapists as well as representatives of national MS centers, self-care groups, social care, residential care, and health-aid-providers) developed a diagnostic algorithm to detect NULTD in patients with MS. Subsequently, the group evaluated the algorithm in 121 patients with MS using micturition diary, post-void residual volume, uroflowmetry, and urodynamic studies. Statistical analysis was conducted on the basis of logistic regression models to compare patients with normal and abnormal urodynamic examinations. Differentiation was performed using selected diagnostic parameters as well as standard performance measures for binary classifiers to assess prognostic quality. RESULTS: The following four parameters allowed to diagnose NLUTD in patients with MS: post-void residual urine volume, rate of urinary tract infections during the past 6 months, micturition frequency, and incontinence. According to statistical analysis, the following thresholds could be defined: post-void residual volume (PVR) ≥70 mL (Odds Ratio (OR) = 1.24; 95% CI:[1.07,1.62]), urinary tract infection (UTI) rate - none in 6 months (OR = 2.03; 95% CI:[1.04,6.68]), and micturition frequency >13/day, standardized on 2000 mL urine excretion (OR = 1.24; 95% CI:[1.07,1.49]). Uroflowmetry served as a further predictor of urodynamically measurable urinary bladder dysfunction (OR = 4.80; 95% CI: [1.41, 19.21]). Interestingly, patients without any complaints of NLUTD had an abnormal urodynamic examination in >50% of the cases. The entire algorithm has a sensitivity of 95%. CONCLUSIONS: All patients with MS should undergo a basic examination to detect NLUTDs. Within the algorithm developed in this study, four easy-to-collect parameters may reveal NLUTD in patients with MS.

Extrication Times During Avalanche Companion Rescue: A Randomized Single-Blinded Manikin Study.

Aims: This study aimed to determine the time needed for one or two companion rescuers to access, extricate, and deliver cardiopulmonary resuscitation (CPR) to a fully buried manikin during a simulated avalanche burial scenario. Materials and Methods: In this randomized, single-blinded study, 18 medical students were required to extricate a manikin manually from a simulated avalanche burial of 1 m in depth, either alone or in teams of two. Each participant performed three consecutive tests with the manikin in three different positions in random order. Results: Median time to first manikin contact was 2.5 minutes, median time to airway access 7.2 minutes, and median time to standard position for CPR 10.1 minutes. Overall, the number of rescuers (one compared to two rescuers, 10.5 minutes vs. 9.3 minutes; p = 0.686) and the burial position of the manikin (10.8 minutes vs. 10.6 minutes vs. 8.8 minutes; p = 0.428) had no influence on extrication times. Preexisting training (6.1 minutes vs. 11.0 minutes p = 0.006) and a learning effect obtained during the experiments (12.4 minutes the first test vs. 9.3 in the third test; p = 0.017) improved all extrication times. Conclusion: It takes an average of 7 minutes after location of a simulated avalanche victim, buried at a depth of 1 m, to free the airway, plus a further 3 minutes to initiate CPR in standard supine position. This is more than two-thirds of the 15 minutes considered necessary for successful companion avalanche rescue. Even minimal training significantly reduced extrication times. These findings emphasize the importance of regular practice in specific extrication techniques that should be part of any training in avalanche companion rescue.

Effect of aerobic exercise on cognition in younger adults: A randomized clinical trial.

OBJECTIVE: To determine efficacy of aerobic exercise for cognitive function in younger healthy adults. METHODS: In a randomized, parallel-group, observer-masked, community-based clinical trial, 132 cognitively normal individuals aged 20-67 with below median aerobic capacity were randomly assigned to one of two 6-month, 4-times-weekly conditions: aerobic exercise and stretching/toning. Efficacy measures included aerobic capacity; cognitive function in several domains (executive function, episodic memory, processing speed, language, and attention), everyday function, body mass index (BMI), and cortical thickness. RESULTS: Aerobic capacity increased significantly (ß = 2.718; p = 0.003), and BMI decreased significantly (ß = -0.596; p = 0.013) in the aerobic exercise but not in the stretching/toning condition. Executive function improved significantly in the aerobic exercise condition; this effect was moderated by age (ß = 0.018 SD/y; p = 0.028). At age 40, the executive function measure increased by 0.228 SD (95% confidence interval [CI] 0.007-0.448), and by 0.596 SD (95% CI 0.219-0.973) at age 60. Cortical thickness increased significantly in the aerobic exercise group in a left frontal region and did not interact with age. Controlling for age and baseline performance, individuals with at least one APOE ε4 allele showed less improvement in executive function with aerobic exercise (ß = 0.5129, 95% CI 0.0381-0.988; p = 0.0346). CONCLUSIONS: This randomized clinical trial demonstrates the efficacy of aerobic exercise for cognition in adults age 20-67. The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines. Increased cortical thickness suggests that aerobic exercise contributes to brain health in individuals as young as age 20. CLINICALTRIALSGOV IDENTIFIER: NCT01179958. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for adults age 20-67 with below median aerobic capacity, aerobic exercise significantly improves executive function but not other measures of cognitive function.

A significant proportion of patients with primary central nervous system lymphoma harbor clonal bone marrow B-cells.

Clonal bone marrow (BM) B-cell populations are a common finding in patients with suspected primary central nervous system lymphoma (PCNSL). To assess their clinical significance, benign monoclonal B-cell lymphocytosis (MBL) needs to be differentiated from concomitant BM involvement, since patients with secondary central nervous system lymphoma (SCNSL) generally require more intensive treatment directed also at the component outside the central nervous system (CNS). Here, we retrospectively analyzed BM samplings in 51 patients with suspected PCNSL. We found clonal B cell populations in 8 of 51 cases (16%) by flow cytometry. None of these eight cases had BM involvement by high-grade lymphoma. No lymphoma relapses outside the CNS were recorded. Together, our data points at a significant percentage of patients with suspected PCNSL harboring clonal BM B-cells, which in this patient group always represented benign MBL. Failure to differentiate these populations from systemic lymphoma involvement may result in overtreatment of patients.

Effects of silymarin on angiogenesis and oxidative stress in streptozotocin-induced diabetes in mice.

The present study evaluated the effects of acute treatment with silymarin, an extract that is obtained from Silybum marianum, on angiogenesis, oxidative stress, and inflammation in normoglycemic and diabetic mice. Diabetes was induced by streptozotocin (80 mg/kg, intraperitoneal) in male Swiss mice, 6 weeks of age. A polyether-polyurethane sponge was surgically implanted in the back of the mice as a model of healing in both diabetic and normoglycemic animals that were treated with oral silymarin or water for 10 days. The pancreas, liver, kidneys, blood, and sponges were collected and analyzed. Diabetes led to impairments of antioxidant defenses, reflected by a reduction of pancreatic superoxide dismutase and hepatic and renal catalase and an increase in pancreatic lipoperoxidation. An inflammatory process was observed in diabetic mice, reflected by an increase in pancreatic tumor necrosis factor α (TNF-α) and the infiltration of inflammatory cells in islets. The number of vessels was lower in the implanted sponges in diabetic mice. Silymarin treatment attenuated this damage, restoring antioxidant enzymes and reducing pancreatic TNF-α and inflammatory infiltration. However, silymarin treatment did not restore angiogenesis or glycemia. In conclusion, treatment with silymarin red uced oxidative stress and inflammation that were induced in the model of streptozotocin-induced diabetes in several organs, without apparent toxicity. Silymarin may be a promising drug for controlling diabetic complications.

Mood and Personality Characteristics are Associated with Metamemory Knowledge Accuracy in a Community-Based Cohort of Older Adults.

OBJECTIVES: Emerging work reveals the neuroanatomic changes that compromise metacognition; however, little is known about the impact of premorbid factors. Research suggests that psychological variables influence the perception of cognition, but whether they influence the accuracy of those perceptions (i.e., metacognition) has not been directly examined. PARTICIPANTS AND METHODS: Using Latent Class Analysis (LCA), we tested for discrete personality (NEOFFI) and mood (STAI, BDI-II, and GDS) classes among a community-based cohort of 151 older adults, enrolled in the NKI-Rockland study. Metamemory was calculated by comparing subjective memory ratings (modified Cognitive Failures Questionnaire) to objective memory (Rey Auditory Verbal Learning Test) to determine the degree to which individuals were overconfident, underconfident, or accurate in their self-assessment. A generalized linear model was used to examine whether metamemory differed across the emergent classes. A one sample t test was used to determine whether the metamemory scores of the emergent classes were statistically significantly different from zero, that is, over or under confident. RESULTS: Two discrete classes emerged in the LCA: Class 1 was characterized predominantly by high extraversion and conscientiousness and low neuroticism and anxiety; Class 2 was characterized predominantly by low extraversion and conscientiousness and high neuroticism and anxiety. Metamemory differed significantly as a function of Class Membership (F(4,151)=5.42; p<.001), with Class 1 demonstrating accurate metamemory (M=0.21; SD=1.31) and Class 2 demonstrating under-confidence (M=-0.59; SD=1.39) in their memory. CONCLUSIONS: The significant association between psychological factors and metamemory knowledge accuracy suggests that such characteristics may be important to consider in the conceptualization, assessment, and treatment of metacognitive disturbances. (JINS, 2018, 24, 498-510).

Age-Based Differences in Task Switching Are Moderated by Executive Control Demands.

Objectives: Recent work has identified different aspects of executive function that may underlie cognitive changes associated with age. The current study used a multifactorial design to investigate age sensitivity in the ability to shift between different task sets and the interaction of this ability with several specific aspects of executive control. Method: A large, well-characterized sample of younger (n = 40) and clinically healthy older (n = 51) adults completed a task switching paradigm in which 3 aspects of executive control were manipulated between subjects: a) sensorimotor demand (the number of distinct stimulus-response options); b) stimulus-level interference (i.e., flanker effects); and c) updating/monitoring (the frequency of task switches). Results: Unique age-related deficits were observed for different aspects of local task switching performance costs and updating/monitoring, but not for interference. Sensorimotor demand was also an important additional factor that interacted with task switching performance. Discussion: Our findings suggest that task switching, coupled with infrequent and unexpected transitions from one task set to another, in the context of high motoric demands, is particularly difficult for older adults.

Monitoring multiple myeloma by next-generation sequencing of V(D)J rearrangements from circulating myeloma cells and cell-free myeloma DNA.

Recent studies suggest that circulating tumor cells and cell-free DNA may represent powerful non-invasive tools for monitoring disease in patients with solid and hematologic malignancies. Here, we conducted a pilot study in 27 myeloma patients to explore the clonotypic V(D)J rearrangement for monitoring circulating myeloma cells and cell-free myeloma DNA. Next-generation sequencing was used to define the myeloma V(D)J rearrangement and for subsequent peripheral blood tracking after treatment initiation. Positivity for circulating myeloma cells/cell-free myeloma was associated with conventional remission status (P<0.001) and 91% of non-responders/progressors versus 41% of responders had evidence of persistent circulating myeloma cells/cell-free myeloma DNA (P<0.001). About half of the partial responders showed complete clearance of circulating myeloma cells/cell-free myeloma DNA despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover and, therefore, decline more rapidly after initiation of effective treatment. Positivity for circulating myeloma cells and for cell-free myeloma DNA were associated with each other (P=0.042), but discordant in 30% of cases. This indicates that cell-free myeloma DNA may not be generated entirely by circulating myeloma cells and may reflect overall tumor burden. Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma.

T-cell diversification reflects antigen selection in the blood of patients on immune checkpoint inhibition and may be exploited as liquid biopsy biomarker.

Cancer immunotherapy with antibodies targeting immune checkpoints, such as programmed cell death protein 1 (PD-1), shows encouraging results, but reliable biomarkers predicting response to this costly and potentially toxic treatment approach are still lacking. To explore an immune signature predictive for response, we performed liquid biopsy immunoprofiling in 18 cancer patients undergoing PD-1 inhibition before and shortly after initiation of treatment by multicolor flow cytometry and next-generation T- and B-cell immunosequencing (TCRß/IGH). Findings were correlated with clinical outcomes. We found almost complete saturation of surface PD-1 on all T-cell subsets after the first dose of the antibody. Both T- and B-cell compartments quantitatively expanded during treatment. These expansions were mainly driven by an increase in the activated T-cell compartments, as well as of naïve B- and plasma cells. Deep immunosequencing revealed a clear diversification pattern of the clonal T-cell space indicative of antigenic selection in 47% of patients, while the remaining patients showed stable repertoires. 43% of the patients with a diversification pattern showed disease control in response to the PD-1 inhibitor. No disease stabilizations were observed without clonal T-cell space diversification. Our data show for the first time a clear impact of PD-1 targeting not only on circulating T-cells, but also on B-lineage cells, shedding light on the complexity of the anti-tumor immune response. Liquid biopsy T-cell next-generation immunosequencing should be prospectively evaluated as part of a composite response prediction biomarker panel in the context of clinical studies.