Prevalence of Cardiovascular Disease and Risk Factors Among Former National Football League Players.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide, but prevalence estimates in former professional athletes are limited. OBJECTIVES: HUDDLE (Heart Health: Understanding and Diagnosing Disease by Leveraging Echocardiograms) aimed to raise awareness and estimate the prevalence of CVD and associated risk factors among members of the National Football League (NFL) Alumni Association and their families through education and screening events. METHODS: HUDDLE was a multicity, cross-sectional study of NFL alumni and family members aged 50 years and older. Subjects reported their health history and participated in CVD education and screening (blood pressure, electrocardiogram, and transthoracic echocardiogram [TTE] assessments). Phone follow-up by investigators occurred 30 days postscreening to review results and recommendations. This analysis focuses on former NFL athletes. RESULTS: Of 498 participants screened, 57.2% (N = 285) were former NFL players, the majority of whom were African American (67.6%). The prevalence of hypertension among NFL alumni was estimated to be 89.8%, though only 37.5% reported a history of hypertension. Of 285 evaluable participants, 61.8% had structural cardiac abnormalities by TTE. Multivariable analysis showed that hypertension was a significant predictor of clinically relevant structural abnormalities on TTE. CONCLUSIONS: HUDDLE identified a large discrepancy between participant self-awareness and actual prevalence of CVD and risk factors, highlighting a significant opportunity for population health interventions. Structural cardiac abnormalities were observed in most participants and were independently predicted by hypertension, affirming the role of TTE for CVD screening in this population aged older than 50 years. (Heart Health: Understanding and Diagnosing Disease by Leveraging Echocardiograms [HUDDLE]; NCT05009589).

Virtual focus groups among individuals with use disorders: assessing feasibility and acceptability in an underserved clinical population.

Objective: There are substantial barriers to conducting research among individuals with stigmatized and complicated health conditions like substance use disorders. These barriers slow progress when developing, refining, and assessing interventions to better treat underserved populations. Virtual focus groups are an innovative method for collecting data from individuals via a discreet and accessible platform which can inform novel as well as existing treatment approaches. This article reports on the feasibility and acceptability of virtual focus groups as a mechanism to recruit and engage geographically and demographically diverse samples of participants with substance use disorders that are otherwise logistically difficult to assess. Method: Participants were assessed for eligibility for a virtual focus group study based on demographic features, drug use history, and psychiatric history via a remote, interview-based screening. Focus groups were completed anonymously without video or name-sharing. Discussion contributions, quantified with number of times speaking and total number of words spoken, were compared across gender, and treatment status. Participants provided quantitative and qualitative feedback on the focus group experience in a follow-up survey. Results: Focus groups (N=26) based in geographical areas throughout the United States were conducted with 88 individuals with opioid use disorder or stimulant use disorder. Discussion contributions were comparable between genders and among individuals in treatment versus those seeking treatment. A follow-up survey (n=50, 57% of focus group participants) reflected high levels of enjoyment, comfort, and honesty during focus group discussions. Discussion: Findings suggest virtual focus groups can be an effective and efficient tool for substance use research.

Integrator-mediated clustering of poised RNA polymerase II synchronizes histone transcription.

Numerous components of the transcription machinery, including RNA polymerase II (Pol II), accumulate in regions of high local concentration known as clusters, which are thought to facilitate transcription. Using the histone locus of Drosophila nurse cells as a model, we find that Pol II forms long-lived, transcriptionally poised clusters distinct from liquid droplets, which contain unbound and paused Pol II. Depletion of the Integrator complex endonuclease module, but not its phosphatase module or Pol II pausing factors disperses these Pol II clusters. Consequently, histone transcription fails to reach peak levels during S-phase and aberrantly continues throughout the cell cycle. We propose that Pol II clustering is a regulatory step occurring near promoters that limits rapid gene activation to defined times. One Sentence Summary: Using the Drosophila histone locus as a model, we show that clustered RNA polymerase II is poised for synchronous activation.

Transient TKI-resistant CD44+pBAD+ blasts undergo intrinsic homeostatic adaptation to promote the survival of acute myeloid leukemia in vitro.

Acute myeloid leukemia (AML) patients have frequent mutations in FMS-like receptor tyrosine kinase 3 (FLT3-mut AML), who respond poorly to salvage chemotherapies and targeted therapies such as tyrosine kinase inhibitors (TKIs). Disease relapse is a common reason of treatment failures in FLT3-mut AML patients, but its intracellular refractory mechanism remains to be discovered. In this study, we designed serial in vitro time-course studies to investigate the biomarkers of TKI-resistant blasts and their survival mechanism. First, we found that a group of transient TKI-resistant blasts were CD44+Phosphorylated-BAD (pBAD)+ and that they could initiate the regrowth of blast clusters in vitro. Notably, TKI-treatments upregulated the compensation pathways to promote PIM2/3-mediated phosphorylation of BAD to initiate the blast survival. Next, we discovered a novel process of intracellular adaptive responses in these transient TKI-resistant blasts, including upregulated JAK/STAT signaling pathways for PIM2/3 expressions and activated SOCS1/SOCS3/PIAS2 inhibitory pathways to down-regulate redundant signal transduction and kinase phosphorylation to regain intracellular homeostasis. Finally, we found that the combination of TKIs with TYK2/STAT4 pathways-driven inhibitors could effectively treat FLT3-mut AML in vitro. In summary, our findings reveal that TKI-treatment can activate a JAK/STAT-PIM2/3 axis-mediated signaling pathways to promote the survival of CD44+pBAD+blasts in vitro. Disrupting these TKIs-activated redundant pathways and blast homeostasis could be a novel therapeutic strategy to treat FLT3-mut AML and prevent disease relapse in vivo.

Optimization of specific RNA knockdown in mammalian cells with CRISPR-Cas13.

Prokaryotic adaptive immune systems use Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) and CRISPR Associated (Cas) proteins to target and cleave foreign genetic elements in an RNA-guided manner [1-3]. Type VI CRISPR-Cas systems contain a single effector ribonuclease, Cas13, that binds and processes a CRISPR-RNA (crRNA; also known as a guide-RNA), forming an RNA-guided RNA-targeting effector complex [4,5]. Previous studies have shown that Cas13 can be engineered to target and modulate RNA processes in human cells, illustrating the versatility and specificity of Cas13 as an RNA knockdown (KD), splicing, editing, or imaging tool [6-8]. While Cas13 has been successfully used by several groups, our lab has observed significant variability in Cas13 KD ability depending which protocol is being followed [9-12]. To further understand this variability and generate a robust Cas13 KD protocol we thoroughly tested which Cas13 ortholog to use, the duration of KD experiments, the amount of plasmid DNA transfected, methods for analyzing KD efficiency, and report an optimized method for carrying out and analyzing Cas13 mediated RNA KD experiments. The method outlined in this paper illustrates a faster and more reliable protocol to iteratively test gRNA performance and target gene KD.

Neuropsychological and behavioral measures of attention assess different constructs in children with traumatic brain injury.

Neuropsychological and behavioral measures are used to assess attention, but little convergence has been found between these two assessment methods. However, many prior studies have not considered attention as a multicomponent system, which may contribute to this lack of agreement between neuropsychological and behavioral measures. To address this the current study examined the relationship between the neuropsychological measures that comprise a four-component model of attention and parent-report behavioral ratings of attention problems and hyperactivity. A total of 65 children and adolescents who had sustained a traumatic brain injury (TBI) were included in the study. Principal components analysis identified the four attention components in this sample, which accounted for 80.9% of the variance. However, correlations between the neuropsychological measures of attention and behavioral ratings of attention and hyperactivity were low and non-significant. This minimal correspondence suggests that neuropsychological and behavioral measures assess different aspects of attentional disturbances in children with TBI.

Attention processing abnormalities in children with traumatic brain injury and attention-deficit/hyperactivity disorder: differential impairment of component processes.

Individuals with acquired and neurodevelopmental brain disorders often exhibit deficits in attention. Recent models of attention have conceptualized it as a multicomponent system. One influential model proposed by Mirsky et al. (1991) consists of factors that include focus, sustain, shift, and encode components. This model has been used to examine the structure of attention in a variety of clinical populations although few studies have contrasted performance of various clinical groups in order to determine whether these components are differentially affected. To address this issue, the current study investigated the differential sensitivity of these attention components in 90 children: 30 who had sustained traumatic brain injury (TBI), 30 who were diagnosed with attention-deficit/hyperactivity disorder (ADHD), and 30 normal controls. Results demonstrated that the TBI group had significantly lower focus factor scores, the ADHD group had significantly lower sustain scores, and that both clinical groups had lower encode factor scores than controls. Stepwise discriminant function analysis (DFA) retained the focus and encode factors in predicting clinical groups from controls with 75.6% accuracy. A second DFA retained the focus factor in differentiating the two clinical groups with 70.0% accuracy. These findings provide evidence of differential attention deficits resulting from TBI and ADHD.

Structure of attention in children with traumatic brain injury.

Traumatic brain injury (TBI) is a common cause of disability among children in the United States, and attention deficits are frequently observed in both the acute and chronic phases of injury. The current study investigated models of attention in children with TBI and examined differential sensitivity of various components of these attention models to the severity of the brain injury. Participants included 151 children and adolescents (mean age 12.9 years, SD=2.6) who had suffered TBI, and 50 normal controls (mean age 12.5 years old, SD=2.2). All children were administered neuropsychological tests of attention as part of a comprehensive neuropsychological battery for brain injury (TBI group) or for the purposes of the current investigation (normal controls). Confirmatory factor analysis (CFA) of the attention tests indicated that a four-factor model of attention composed of Shift, Focus, Encode, and Sustain factors provided the best fit of the TBI group data. Factor scores were subsequently created and used to predict the severity of brain injury. All four factors were sensitive to TBI in that those with TBI performed significantly worse than the controls, but regression analysis indicated that only the Shift and Focus factors were significant predictors of TBI severity. These findings support the utility of a multicomponent model of attention to understand attention deficits resulting from TBI, and may be useful in determining those aspects of attention that are differentially impacted by TBI, in order to assist in assessment and rehabilitation planning.

Acetabular cartilage delamination in femoroacetabular impingement. Risk factors and magnetic resonance imaging diagnosis.

BACKGROUND: Delamination of acetabular articular cartilage is a common abnormality in hips with femoroacetabular impingement. The purpose of the present study was to identify clinical and radiographic factors predisposing to delamination and to assess the diagnostic accuracy of magnetic resonance arthrography for the detection of these lesions. METHODS: Following a retrospective review of records, we determined that acetabular cartilage delamination had been present in twenty-eight of sixty-four hips that had undergone a surgical dislocation procedure for the treatment of femoroacetabular impingement. Multivariable logistic regression was performed to assess the correlation of radiographic findings (i.e., magnetic resonance imaging and computerized tomography findings) with the status of delamination. The preoperative interpretations of the magnetic resonance arthrograms for twenty-seven hips that underwent surgical dislocation were reviewed to assess the accuracy of detecting delamination. At the time of surgery, nine of these twenty-seven hips were found to have delamination. Magnetic resonance arthrography interpretations that did not correlate with operative findings were subjected to conspicuity assessment and error analysis. RESULTS: The rate of delamination of the acetabular cartilage as noted at the time of surgical dislocation was 44% (twenty-eight of sixty-four). Delamination was strongly associated with male sex and femoral sided signs of impingement; however, it was not associated with acetabular overcoverage (center-edge angle, >40 degrees) (odds ratio = 0.16; p < 0.05). While there was no significant difference in the prevalence of labral lesions between groups, whenever labral and delamination lesions were found in the same hip, they were directly adjacent to one another. Preoperative magnetic resonance arthrography had a low sensitivity for delamination (22%) but had a high specificity (100%). Two-thirds of the delamination lesions were visible on retrospective review of these images when the reader was unblinded to the surgical findings. Delamination could most often be identified on the sagittal T1-weighted image and on the proton-density sequences with fat saturation. DISCUSSION: There should be a high level of suspicion for articular cartilage delamination in men and in patients with primarily cam-type femoroacetabular impingement. Acetabular overcoverage may be protective against delamination. Preoperative high-quality magnetic resonance arthrograms should be carefully analyzed for evidence of delamination in this patient population.

Factor V Leiden and venous thromboembolism: risk associated with hormone replacement therapy.

PURPOSE: To determine the risk-benefit ratio of hormone replacement therapy (HRT) and the cost-effectiveness of screening in perimenopausal and postmenopausal women who are carriers of factor V Leiden, as well as to provide evidence-based clinical recommendations for the primary care provider. DATA SOURCES: Databases searched included EMBASE, BIOSIS, MEDLINE, CINAHL, PubMed, SciSearch, and the Cochrane Database. Two reviewers extracted, reviewed, and concurred upon relevant evidence identified in the data-bases. RESULTS: Results confirmed that all women have a higher risk for the development of venous thrombosis while on HRT. The presence of a genetic mutation, such as factor V Leiden, in combination with HRT dramatically increased an individual's chance for developing venous thrombi. CONCLUSION/IMPLICATIONS: Based on the findings of the studies reviewed, it is recommended that women wishing to initiate HRT be thoroughly screened for known risk factors of thrombosis. If risk factors are identified, genetic testing for factor V Leiden may be warranted.