7T MRI Versus 3T MRI of the Brain in Professional Fighters and Patients With Head Trauma.

Many studies have investigated the imaging sequelae of repetitive head trauma with mixed results, particularly with regard to the detection of intracranial white matter changes (WMCs) and cerebral microhemorrhages (CMHs) on ≤3 Tesla (T) field magnetic resonance imaging (MRI). 7T MRI, which has recently been approved for clinical use, is more sensitive at detecting lesions associated with multiple neurological diagnoses. In this study, we sought to determine whether 7T MRI would detect more WMCs and CMHs than 3T MRI in 19 professional fighters, 16 patients with single TBI, versus 82 normal healthy controls (NHCs). Fighters and patients with TBI underwent both 3T and 7T MRI; NHCs underwent either 3T (n = 61) or 7T (n = 21) MRI. Readers agreed on the presence/absence of WMCs in 88% (84 of 95) of 3T MRI studies (Cohen's kappa, 0.76) and in 93% (51 of 55) of 7T MRI studies (Cohen's kappa, 0.79). Readers agreed on the presence/absence of CMHs in 96% (91 of 95) of 3T MRI studies (Cohen's kappa, 0.76) and in 96% (54 of 56) of 7T MRI studies (Cohen's kappa, 0.88). The number of WMCs detected was greater in fighters and patients with TBI than NHCs at both 3T and 7T. Moreover, the number of WMCs was greater at 7T than at 3T for fighters, patients with TBI, and NHCs. There was no difference in the number of CMHs detected with 7T MRI versus 3T MRI or in the number of CMHs observed in fighters/patients with TBI versus NHCs. These initial findings suggest that fighters and patients with TBI may have more WMCs than NHCs and that the improved voxel size and signal-to-noise ratio at 7T may help to detect these changes. As 7T MRI becomes more prevalent clinically, larger patient populations should be studied to determine the cause of these WMCs.

Polymeric particle-based therapies for acute inflammatory diseases.

Acute inflammation is essential for initiating and coordinating the body's response to injuries and infections. However, in acute inflammatory diseases, inflammation is not resolved but propagates further, which can ultimately lead to tissue damage such as in sepsis, acute respiratory distress syndrome and deep vein thrombosis. Currently, clinical protocols are limited to systemic steroidal treatments, fluids and antibiotics that focus on eradicating inflammation rather than modulating it. Strategies based on stem cell therapeutics and selective blocking of inflammatory molecules, despite showing great promise, still lack the scalability and specificity required to treat acute inflammation. By contrast, polymeric particle systems benefit from uniform manufacturing at large scales while preserving biocompatibility and versatility, thus providing an ideal platform for immune modulation. Here, we outline design aspects of polymeric particles including material, size, shape, deformability and surface modifications, providing a strategy for optimizing the targeting of acute inflammation.

Implementing Just Culture to Improve Patient Safety.

INTRODUCTION: The number of deaths in the United States related to medical errors remains unacceptably high. Further complicating this situation is the problem of underreporting due to the fear of the consequences. In fact, the most commonly reported cause of underreporting worldwide is the fear of the negative consequences associated with reporting. As health care organizations along the journey to high-reliability strive to improve patient safety, a concerted effort needs to be focused on changing how medical errors are addressed. A paradigm shift is needed from immediately assigning blame and punishing individuals to one that is trusting and just. Staff must trust that when errors occur, organizations will respond in a manner that is fair and appropriate. MATERIALS AND METHODS: An extensive review of the literature from 2017 until January 2022 was conducted for the most current evidence describing the principles and practices of "just culture" in health care organizations. Additionally, recommendations were sought on how health care organizations can go about implementing "just culture" principles. RESULTS: Twenty sources of evidence on "just culture' were retrieved and reviewed. The evidence was used to describe the concept and principles of "just culture" in health care organizations. Furthermore, five strategies for implementing "just culture" principles were identified. CONCLUSIONS: Improving patient safety requires that high-reliability organizations strive to ensure that the culture of the organization is trusting and just. In a trusting and just culture, adverse events are recognized as valuable opportunities to understand contributing factors and learn rather than immediately assign blame. Moving away from a blame culture is a paradigm shift for many health care organizations yet critically important for improving patient safety.

Structured Reporting in Multiple Sclerosis Reduces Interpretation Time.

RATIONALE AND OBJECTIVES: Previous studies have reported mixed results regarding whether the use of structured reporting (SR) leads to a change in interpretation times. The objective of this study was to quantify any change in interpretation times after the implementation of SR for multiple sclerosis (MS) follow-up magnetic resonance imaging (MRI) of the brain. MATERIALS AND METHODS: Interpretation times before and after the transition to MS MRI SR were compared over a 5-year period. To control for changing practice patterns, a control group of non-MS (intracranial masses) reports not using SR was also assessed. In a secondary analysis, interpretation times for 2D and 3D MRI MS protocols after the initiation of SR were compared to determine whether increased image number with the 3D protocol affected interpretation times. RESULTS: Mean and median interpretation times before the initiation of SR for MS MRI were 11.0 and 8.0 minutes versus 8.5 and 6.0 minutes after the implementation of SR (p < 0.001). Although non-MS MRI interpretation times also decreased, an interaction analysis demonstrated that the decrease in MS interpretation times was significantly higher (p < 0.001). Mean and median interpretation times using 3D protocols were slighter increased compared to interpretation times with 2D protocols (p = 0.036). CONCLUSION: After the implementation of SR for MS follow-up MRI at our institution, interpretation times significantly decreased despite the increased number of images with some of the examinations due to the adoption of 3D protocols. The adoption of SR for MS MRI follow-up scans may improve radiologist efficiency.

Association of Cavum Septum Pellucidum and Cavum Vergae With Cognition, Mood, and Brain Volumes in Professional Fighters.

Importance: Many studies have investigated the imaging findings showing sequelae of repetitive head trauma, with mixed results. Objective: To determine whether fighters (boxers and mixed martial arts fighters) with cavum septum pellucidum (CSP) and cavum vergae (CV) have reduced volumes in various brain structures or worse clinical outcomes on cognitive and mood testing. Design, Setting, and Participants: This cohort study assessed participants from the Professional Fighters Brain Health Study. Data were collected from April 14, 2011, to January 17, 2018, and were analyzed from September 1, 2018, to May 23, 2019. This study involved a referred sample of 476 active and retired professional fighters. Eligible participants were at least 18 years of age and had at least a fourth-grade reading level. Healthy age-matched controls with no history of trauma were also enrolled. Exposures: Presence of CSP, CV, and their total (additive) length (CSPV length). Main Outcomes and Measures: Information regarding depression, impulsivity, and sleepiness among study participants was obtained using the Patient Health Questionnaire depression scale, Barrett Impulsiveness Scale, and the Epworth Sleepiness Scale. Cognition was assessed using raw scores from CNS Vital Signs. Volumes of various brain structures were measured via magnetic resonance imaging. Results: A total of 476 fighters (440 men, 36 women; mean [SD] age, 30.0 [8.2] years [range, 18-72 years]) and 63 control participants (57 men, 6 women; mean [SD] age, 30.8 [9.6] years [range, 18-58 years]) were enrolled in the study. Compared with fighters without CV, fighters with CV had significantly lower mean psychomotor speed (estimated difference, -11.3; 95% CI, -17.4 to -5.2; P = .004) and lower mean volumes in the supratentorium (estimated difference, -31 191 mm3; 95% CI, -61 903 to -479 mm3; P = .05) and other structures. Longer CSPV length was associated with lower processing speed (slope, -0.39; 95% CI, -0.49 to -0.28; P < .001), psychomotor speed (slope, -0.43; 95% CI, -0.53 to -0.32; P < .001), and lower brain volumes in the supratentorium (slope, -1072 mm3 for every 1-mm increase in CSPV length; 95% CI, -1655 to -489 mm3; P < .001) and other structures. Conclusions and Relevance: This study suggests that the presence of CSP and CV is associated with lower regional brain volumes and cognitive performance in a cohort exposed to repetitive head trauma.

Different culture media modulate growth, heterogeneity, and senescence in human mammary epithelial cell cultures.

The ability to culture normal human mammary epithelial cells (HMEC) greatly facilitates experiments that seek to understand both normal mammary cell biology and the many differences between normal and abnormal human mammary epithelia. To maximize in vivo relevance, the primary cell culture conditions should maintain cells in states that resemble in vivo as much as possible. Towards this goal, we compared the properties of HMEC strains from two different reduction mammoplasty tissues that were grown in parallel using different media and culture conditions. Epithelial organoids were initiated into three different media: two commonly used serum-free-media, MCDB 170-type (e.g. MEGM) and WIT-P, and a low stress media, M87A. Growth, lineage heterogeneity, p16 protein expression, and population doublings to senescence were measured for each culture condition. MCDB 170 caused rapid senescence and loss of heterogeneity within 2 to 3 passages, but some cultures went through the 1 to 2 month process of selection to generate clonal finite post-selection post-stasis cells. WIT-P caused impressive expansion of luminal cells in 2nd passage followed by their near complete disappearance by passage 4 and senescence shortly thereafter. M87A supported as much as twice the number of population doublings compared to either serum-free medium, and luminal and myoepithelial cells were present for as many as 8 passages. Thus, of the three media compared, WIT-P and MCDB 170 imposed rapid senescence and loss of lineage heterogeneity, phenotypes consistent with cells maintained in high-stress conditions, while M87A supported cultures that maintained multiple lineages and robust growth for up to 60 population doublings. In conjunction with previous studies examining the molecular properties of cultures grown in these media, we conclude that M87A medium is most able to support long-term culture of multiple lineages similar to in vivo conditions, thereby facilitating investigations of normal HMEC biology relevant to the mammary gland in situ.

High-Dimensional Phenotyping Identifies Age-Emergent Cells in Human Mammary Epithelia.

Aging is associated with tissue-level changes in cellular composition that are correlated with increased susceptibility to disease. Aging human mammary tissue shows skewed progenitor cell potency, resulting in diminished tumor-suppressive cell types and the accumulation of defective epithelial progenitors. Quantitative characterization of these age-emergent human cell subpopulations is lacking, impeding our understanding of the relationship between age and cancer susceptibility. We conducted single-cell resolution proteomic phenotyping of healthy breast epithelia from 57 women, aged 16-91 years, using mass cytometry. Remarkable heterogeneity was quantified within the two mammary epithelial lineages. Population partitioning identified a subset of aberrant basal-like luminal cells that accumulate with age and originate from age-altered progenitors. Quantification of age-emergent phenotypes enabled robust classification of breast tissues by age in healthy women. This high-resolution mapping highlighted specific epithelial subpopulations that change with age in a manner consistent with increased susceptibility to breast cancer.

Biomimetic Accommodating Intraocular Lens Using a Valved Deformable Liquid Balloon.

OBJECTIVE: Presbyopia is a common age-related condition that prevents people from focusing on near objects. The etiology of presbyopia continues to be debated, but the end effect of all postulated mechanisms is the lack of deformation of the human lens. Using our understanding of the biomechanical properties of the natural human lens, we created a unique accommodating intraocular lens. Although this lens can be used for lenticular disease such as myopia and hyperoperopia, this study addresses the needs of cataract patients with presbyopia. METHODS: The lens was implanted into presbyopic human cadaver eyes. Focal length of the lens was measured with simulated muscle contraction. Lens dimensions were measured using artificial tissue and a finite-element analysis (FEA) to simulate accommodation. Lens power was measured at various fill volumes. Accelerated soak testing for an equivalent of 7.4 years was performed and lens weight and optical transmittance were measured. RESULTS: Previously presbyopic human eyes were able to accommodate between 2.0 and 7.4 diopters after lens implantation. FEA and lens measurements demonstrated a change in curvature of the anterior and posterior portions of the lens during accommodation. After accelerated aging, lens weight remained unchanged and optical transmission was 96%. Lens power increased with fill volume. CONCLUSION: A deformable liquid lens reversed presbyopia, can be individualized by optically adjusting for each patient, is stable for long periods of time, and is compatible with minimally invasive surgical techniques. SIGNIFICANCE: A deformable liquid-filled lens can significantly improve accommodation over the presbyopic natural lens.

Age and the means of bypassing stasis influence the intrinsic subtype of immortalized human mammary epithelial cells.

Based on molecular features, breast cancers are grouped into intrinsic subtypes that have different prognoses and therapeutic response profiles. With increasing age, breast cancer incidence increases, with hormone receptor-positive and other luminal-like subtype tumors comprising a majority of cases. It is not known at what stage of tumor progression subtype specification occurs, nor how the process of aging affects the intrinsic subtype. We examined subtype markers in immortalized human mammary epithelial cell lines established following exposure of primary cultured cell strains to a two-step immortalization protocol that targets the two main barriers to immortality: stasis (stress-associated senescence) and replicative senescence. Cell lines derived from epithelial cells obtained from non-tumorous pre- and post-menopausal breast surgery tissues were compared. Additionally, comparisons were made between lines generated using two different genetic interventions to bypass stasis: transduction of either an shRNA that down-regulated p16(INK4A), or overexpressed constitutive active cyclin D1/CDK2. In all cases, the replicative senescence barrier was bypassed by transduction of c-Myc. Cells from all resulting immortal lines exhibited normal karyotypes. Immunofluorescence, flow cytometry, and gene expression analyses of lineage-specific markers were used to categorize the intrinsic subtypes of the immortalized lines. Bypassing stasis with p16 shRNA in young strains generated cell lines that were invariably basal-like, but the lines examined from older strains exhibited some luminal features such as keratin 19 and estrogen receptor expression. Overexpression of cyclin D1/CDK2 resulted in keratin 19 positive, luminal-like cell lines from both young and old strains, and the lines examined from older strains exhibited estrogen receptor expression. Thus age and the method of bypassing stasis independently influence the subtype of immortalized human mammary epithelial cells.

Investigating cognitive flexibility as a potential mechanism of mindfulness in Generalized Anxiety Disorder.

BACKGROUND AND OBJECTIVES: Research suggests mindfulness-based treatments may enhance efficacy of CBT for Generalized Anxiety Disorder (GAD). One hypothesized mechanism of mindfulness is cognitive flexibility; however, research findings to date are mixed as to a) whether cognitive inflexibility represents a characteristic of GAD, and b) whether mindfulness impacts cognitive flexibility. It is proposed that limitations in study methodology may partially account for these mixed findings. The present study investigated cognitive flexibility as a potential mechanism of mindfulness in a sample with elevated GAD symptoms using a modified emotional Stroop switching task while attempting to control for limitations of previous research. The purpose of the study was: 1) to explore cognitive inflexibility as a potential characteristic of GAD, and 2) to examine whether a brief mindfulness induction has measurable impact on cognitive flexibility. METHODS: A total of 66 participants (53 with elevated GAD symptoms, and 13 non-anxious) were randomized to a mindful-breathing, music-assisted relaxation, or thought wandering condition prior to completing an emotional Stroop and emotional Stroop switching task. RESULTS: Results suggest that GAD may be characterized by an inflexible style of responding, and exposure to mindfulness and relaxation result in partial improvements in cognitive flexibility. LIMITATIONS: Limitations of this study include small sample size, brief induction period, and use of an analog sample. CONCLUSIONS: The present findings suggest that mindfulness may be associated with partial improvement in cognitive flexibility.

Convergence and divergence of neuroanatomic correlates and executive task performance in healthy controls and psychiatric participants.

The associations between brain matter volume in the cerebral cortex and set shifting and attentional control as operationalized by the Wisconsin Card Sort Test (WCST) and Condition Three of the Delis-Kaplan version of the Color Word Interference Test (CWIT) were investigated in 15 healthy controls and 16 heterogeneously diagnosed psychiatric patients with self-control problems using voxel based morphometry. Both groups underwent standardized magnetic resonance imaging and neuropsychological assessment. WCST and CWIT variables, and a composite, were regressed across the whole brain. Although CWIT performance levels were the same in both groups, neuroanatomic correlates for the psychiatric participants invoked the left hemisphere language system, but the bilateral dorsal attention system in the healthy controls. On its own, no neuroanatomic correlates were observed for the WCST. But when part of a composite with CWIT, neuroanatomic correlates in the dorsal attention system emerged for the psychiatric participants. Psychometric combinations of manifest executive task variables may best represent higher level latent neuro-cognitive control systems. Factor analytic studies of neuropsychological test performances suggest the constructs being measured are the same across psychiatric and non-diagnosed participants, however, imaging modalities indicate the relevant neural architecture can vary by group.

Using Mindfulness- and Acceptance-Based Treatments With Clients From Nondominant Cultural and/or Marginalized Backgrounds: Clinical Considerations, Meta-Analysis Findings, and Introduction to the Special Series.

A growing body of research suggests that mindfulness- and acceptance-based principles can increase efforts aimed at reducing human suffering and increasing quality of life. A critical step in the development and evaluation of these new approaches to treatment is to determine the acceptability and efficacy of these treatments for clients from nondominant cultural and/or marginalized backgrounds. This special series brings together the wisdom of clinicians and researchers who are currently engaged in clinical practice and treatment research with populations who are historically underrepresented in the treatment literature. As an introduction to the series, this paper presents a theoretical background and research context for the papers in the series, highlights the elements of mindfulness- and acceptance-based treatments that may be congruent with culturally responsive treatment, and briefly outlines the general principles of cultural competence and responsive treatment. Additionally, the results of a meta-analysis of mindfulness- and acceptance-based treatments with clients from nondominant cultural and/or marginalized backgrounds are presented. Our search yielded 32 studies totaling 2,198 clients. Results suggest small (Hedges' g=.38, 95% CI=.11 - .64) to large (Hedges' g=1.32, 95% CI=.61 - 2.02) effect sizes for mindfulness- and acceptance-based treatments, which varied by study design.

Fabrication and use of microenvironment microarrays (MEArrays).

The interactions between cells and their surrounding microenvironment have functional consequences for cellular behaviour. On the single cell level, distinct microenvironments can impose differentiation, migration, and proliferation phenotypes, and on the tissue level the microenvironment processes as complex as morphogenesis and tumorigenesis(1). Not only do the cell and molecular contents of microenvironments impact the cells within, but so do the elasticity(2) and geometry(3) of the tissue. Defined as the sum total of cell-cell, -ECM, and -soluble factor interactions, in addition to physical characteristics, the microenvironment is complex. The phenotypes of cells within a tissue are partially due to their genomic content and partially due to the combinatorial interactions with the microenviroment. A major challenge is to link specific combinations of microenvironmental components with distinctive behaviours. Here, we present the microenvironment microarray (MEArray) platform for cell-based functional screening of interactions with combinatorial microenvironments(4). The method allows for simultaneous control of the molecular composition and the elastic modulus, and combines the use of widely available microarray and micropatterning technologies. MEArray screens require as few as 10,000 cells per array, which facilitates functional studies of rare cell types such as adult progenitor cells. A limitation of the technology is that entire tissue microenvironments cannot be completely recapitulated on MEArrays. However, comparison of responses in the same cell type to numerous related microenvironments, for instance pairwise combinations of ECM proteins that characterize a given tissue, will provide insights into how microenvironmental components elicit tissue-specific functional phenotypes. MEArrays can be printed using a wide variety of recombinant growth factors, cytokines, and purified ECM proteins, and combinations thereof. The platform is limited only by the availability of specific reagents. MEArrays are amenable to time-lapsed analysis, but most often are used for end point analyses of cellular functions that are measureable with fluorescent probes. For instance, DNA synthesis, apoptosis, acquisition of differentiated states, or production of specific gene products are commonly measured. Briefly, the basic flow of an MEArray experiment is to prepare slides coated with printing substrata and to prepare the master plate of proteins that are to be printed. Then the arrays are printed with a microarray robot, cells are allowed to attach, grow in culture, and then are chemically fixed upon reaching the experimental endpoint. Fluorescent or colorimetric assays, imaged with traditional microscopes or microarray scanners, are used to reveal relevant molecular and cellular phenotypes (Figure 1).

A Fresh Look at Potential Mechanisms of Change in Applied Relaxation for Generalized Anxiety Disorder: A Case Series.

Applied Relaxation (AR), which involves noticing early signs of anxiety and responding with a relaxation response, is an empirically supported treatment for Generalized Anxiety Disorder (GAD). However, research on hypothesized mechanisms of AR (e.g., reduced muscle tension) has been mixed, making it likely that additional mechanisms are contributing to the efficacy of AR. Stemming from more recent conceptualizations of GAD, it is hypothesized that mindfulness, decentering, and acceptance may be potential mechanisms of change in AR. Outcome, mechanism data, and case descriptions from three individuals diagnosed with GAD who received 16 weeks of AR as part of a larger randomized controlled trial are presented to demonstrate the ways that AR may lead to clinical improvement through mindfulness, decentering, and acceptance.

The development of a brief acceptance and mindfulness-based program aimed at reducing sexual revictimization among college women with a history of childhood sexual abuse.

Women with a history of childhood sexual assault (CSA) are more likely to be revictimized; however, most existing programs aimed at reducing sexual victimization do not expressly address the issue of revictimization. The present study examined the efficacy of a brief mindfulness-based program in reducing rates of sexual assault and revictimization in college women over the course of an academic semester. Although the results were not statistically significant, a large-magnitude effect was noted, whereby women with a history of CSA who participated in the program were less likely to be sexually assaulted and raped at 2-month follow-up.

The role of values-consistent behavior in generalized anxiety disorder.

BACKGROUND: Theory and research suggest that generalized anxiety disorder (GAD) is associated with diminished quality of life and restriction in valued action. The purpose of this study was to examine the relevance of values-consistent behavior (valued action) in understanding the impairment in quality of life in GAD. METHOD: Treatment-seeking clients with a principal diagnosis of GAD (n = 30) were compared with demographically matched nonanxious controls (n = 30) using self-report measures. RESULTS: Participants with GAD reported significantly less valued action compared with controls, and within the GAD group, diminished valued action was not fully explained by depression comorbidity. Valued action was significantly correlated with measures of experiential avoidance, distress about emotions, and quality of life. Further, consistent with a theoretical model of GAD, restrictions in valued action contributed unique variance to diminished quality of life over and above the contributions of gender, GAD severity, experiential avoidance, distress about emotions, and depression comorbidity. Finally, an acceptance-based behavioral therapy significantly improved self-reports of valued action for GAD clients with 40% achieving clinically significant change in this domain. CONCLUSION: The findings provide preliminary support for the relevance of valued action in understanding the functional impairment associated with GAD, and the beneficial effects of an acceptance-based behavior therapy in increasing valued action.

Distress and avoidance in generalized anxiety disorder: exploring the relationships with intolerance of uncertainty and worry.

Theory and research suggest that treatments targeting experiential avoidance may enhance outcomes for patients with generalized anxiety disorder (GAD). The present study examined the role of experiential avoidance and distress about emotions in a treatment-seeking sample with a principal diagnosis of GAD compared with demographically matched nonanxious controls and sought to explore their shared relationship with two putative psychopathological processes in GAD: intolerance of uncertainty and worry. Patients with GAD reported significantly higher levels of experiential avoidance and distress about emotions compared with nonclinical controls while controlling for depressive symptoms, and measures of these constructs significantly predicted GAD status. Additionally, experiential avoidance and distress about anxious, positive, and angry emotions shared unique variance with intolerance of uncertainty when negative affect was partialed out, whereas only experiential avoidance and distress about anxious emotions shared unique variance with worry. Discussion focuses on implications for treatment as well as future directions for research.

Mindfulness and emotion regulation difficulties in generalized anxiety disorder: preliminary evidence for independent and overlapping contributions.

Diminished levels of mindfulness (awareness and acceptance/nonjudgment) and difficulties in emotion regulation have both been proposed to play a role in symptoms of generalized anxiety disorder (GAD); the current studies investigated these relationships in nonclinical and clinical samples. In the first study, among a sample of 395 individuals at an urban commuter campus, self-reports of both emotion regulation difficulties and aspects of mindfulness accounted for unique variance in GAD symptom severity, above and beyond variance shared with depressive and anxious symptoms, as well as variance shared with one another. In the second study, individuals with GAD (n=16) reported significantly lower levels of mindfulness and significantly higher levels of difficulties in emotion regulation than individuals in a nonanxious control group (n=16). Results are discussed in terms of directions for future research and potential implications for treatment development.