Race differences in pain and pain-related risk factors among former professional American-style football players.

ABSTRACT: The burden of pain is unequal across demographic groups, with broad and persisting race differences in pain-related outcomes in the United States. Members of racial and ethnic minorities frequently report more pervasive and severe pain compared with those in the majority, with at least some disparity attributable to differences in socioeconomic status. Whether race disparities in pain-related health outcomes exist among former professional football players is unknown. We examined the association of race with pain outcomes among 3995 former professional American-style football players who self-identified as either Black or White. Black players reported more intense pain and higher levels of pain interference relative to White players, even after controlling for age, football history, comorbidities, and psychosocial factors. Race moderated associations between several biopsychosocial factors and pain; higher body mass index was associated with more pain among White but not among Black players. Fatigue and psychosocial factors were more strongly related to pain among Black players relative to White players. Collectively, the substantial social and economic advantages of working as a professional athlete did not seem to erase race-related disparities in pain. We highlight an increased burden of pain among elite Black professional football players and identify race-specific patterns of association between pain and biopsychosocial pain risk factors. These findings illuminate potential future targets of interventions that may serve to reduce persistent disparities in the experience and impact of pain.

Oncogenic YAP mediates changes in chromatin accessibility and activity that drive cell cycle gene expression and cell migration.

YAP, the key protein effector of the Hippo pathway, is a transcriptional co-activator that controls the expression of cell cycle genes, promotes cell growth and proliferation and regulates organ size. YAP modulates gene transcription by binding to distal enhancers, but the mechanisms of gene regulation by YAP-bound enhancers remain poorly understood. Here we show that constitutive active YAP5SA leads to widespread changes in chromatin accessibility in untransformed MCF10A cells. Newly accessible regions include YAP-bound enhancers that mediate activation of cycle genes regulated by the Myb-MuvB (MMB) complex. By CRISPR-interference we identify a role for YAP-bound enhancers in phosphorylation of Pol II at Ser5 at MMB-regulated promoters, extending previously published studies that suggested YAP primarily regulates the pause-release step and transcriptional elongation. YAP5SA also leads to less accessible 'closed' chromatin regions, which are not directly YAP-bound but which contain binding motifs for the p53 family of transcription factors. Diminished accessibility at these regions is, at least in part, a consequence of reduced expression and chromatin-binding of the p53 family member ΔNp63 resulting in downregulation of ΔNp63-target genes and promoting YAP-mediated cell migration. In summary, our studies uncover changes in chromatin accessibility and activity that contribute to the oncogenic activities of YAP.

Dysregulation of miR-155 Expression in Professional Mixed Martial Arts (MMA) Fighters.

Psychological and physical stress can induce dysregulation of gene expression via changes in DNA methylation and microRNA (miRNA) expression. Such epigenetic modifications are yet to be investigated in professional Mixed Martial Arts (MMA) fighters subject to highly stressful training involving repetitive head impacts. This study examined differences in DNA methylation and miRNA expression in elite MMA fighters compared to active controls. Global methylation differences between groups were assessed via a LINE-1 assay. At the same time, PCR arrays were used to estimate differential expression in samples of 21 fighters and 15 controls for 192 different miRNAs associated with inflammatory diseases. An Independent-Samples t-Test found no significant difference in LINE-1 methylation between groups. However, an Independent-Samples Mann-Whitney U Test revealed a significant upregulation in the expression of miR-155 in MMA fighter plasma. Since miR-155 has been recognized as an important regulator of neuroinflammation, this dysregulation suggests a possible epigenetic mechanism responsible for chronic inflammation associated with professional-level MMA training. Consistent with other published works, this study highlights the potential of miR-155 not only as a biomarker for monitoring long-term health risks linked to head trauma but also as a target to remediate the impact of chronic neuroinflammation.

Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA.

Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation1,2. A long appreciated, yet undefined relationship exists between the lytic-latent switch and viral non-coding RNAs3,4. Here we identify viral microRNA (miRNA)-mediated inhibition of host miRNA processing as a cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defences and drive the switch from latent to lytic virus infection. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective primary (pri)-miRNA hairpin loops. Subsequent loss of miR-30 and activation of the miR-30-p53-DRP1 axis triggers a profound disruption of mitochondrial architecture. This impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 triggered virus reactivation from latency, identifying viral miR-aU14 as a readily druggable master regulator of the herpesvirus lytic-latent switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 will provide new therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.

The "Warrior" COMT Val/Met Genotype Occurs in Greater Frequencies in Mixed Martial Arts Fighters Relative to Controls.

A functional single-nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene (rs4680) is a gene variant that has been shown to predict the ability to maintain cognitive agility during combat and competition. Critically, COMT Met (low-activity; high dopamine) allele carriers outperform Val (high-activity; low dopamine) homozygotes on a variety of cognitive tasks. However, the relationship between genotype and cognitive performance appears to reverse under stressful conditions. Stress increases pre-frontal cortex dopamine (PFC DA) levels, and Met allele carriers (with higher DA) show performance deficits relative to Val allele carriers. This pattern reflects the inverted U-shaped function of DA activity where too little (Val allele) or too much (Met allele carriers under stress) DA is associated with poor cognitive performance. The Val allele advantage for stress resiliency is referred to as the COMT "warrior/ worrier" model. In line with this model, we predicted that elite level mixed martial arts (MMA) fighters would be more likely than athlete controls to carry the GG (warrior) genotype compared to an athlete group and a non-athlete group. Based on findings in our previous studies, we also assessed the stress biomarkers cortisol and salivary alpha-amylase (sAA). There was an overall significant difference in genotype frequencies between groups (p =0.01) and the MMA group showed a significantly greater GG (warrior) genotype frequency than the non-athlete control group (p = 0.003). There was not a significant group x genotype interaction for the cortisol or sAA; however, the non-athlete GG group had significantly higher cortisol than the A/- group (p = 0.038). Combined, our findings suggest that the "warrior" genotype may play a participation role in combat sports.

Sex Matters: Anxiety and Aggression Predict Cortisol Responsivity in Men but Not Women.

BACKGROUND: Sexual dimorphism in the hypothalamic pituitary adrenal (HPA) axis can influence sex-specific patterns of response to stressors. While a host of findings exist on sex differences in stress-induced activity of the HPA axis and associated mechanisms in rodents, less is known about the intricacies of sex differences in stress responsivity in humans. Accordingly, the overall aim of the present study was to investigate psychological variables that may account for differences in the cortisol stress response between men and women. METHODS: Eighty-six participants filled out self-report measures of anxiety (STA-Y), aggression (BPAQ), and happiness (SHS). We then exposed all participants to a one-minute Cold Pressor Test (CPT) that was maintained between 3-5° C. Cortisol and pain ratings were assessed. We focused on the 20-minute time point for cortisol since that is when cortisol is near its peak post-stress. RESULTS: Women reported higher pain ratings compared to men. Women also showed a positive relationship between pain ratings and cortisol. Aggression was significantly related to cortisol levels in men, but not in women. Similarly, trait anxiety was positively related to cortisol levels in men, but not in women. Happiness was unrelated to cortisol levels in women and men. Follow-up regressions were conducted separately for men and women. A significant model was found for cortisol in men only with trait anxiety, aggression, and the interaction between trait anxiety and aggression. CONCLUSIONS: The current study builds on previous reports by showing that aggression and anxiety differentially influence the cortisol response to an acute stress in men and women.

Blood Transfusion Delay and Outcome in County Hospitals in Kenya.

Severe anemia is a leading indication for blood transfusion and a major cause of hospital admission and mortality in African children. Failure to initiate blood transfusion rapidly enough contributes to anemia deaths in sub-Saharan Africa. This article examines delays in accessing blood and outcomes in transfused children in Kenyan hospitals. Children admitted with nonsurgical conditions in 10 Kenyan county hospitals participating in the Clinical Information Network who had blood transfusion ordered from September 2013 to March 2016 were studied. The delay in blood transfusion was calculated from the date when blood transfusion was prescribed to date of actual transfusion. Five percent (2,875/53,174) of admissions had blood transfusion ordered. Approximately half (45%, 1,295/2,875) of children who had blood transfusion ordered at admission had a documented hemoglobin < 5 g/dl and 36% (2,232/6,198) of all children admitted with a diagnosis of anemia were reported to have hemoglobin < 5 g/dL. Of all the ordered transfusions, 82% were administered and documented in clinical records, and three-quarters of these (75%, 1,760/2,352) were given on the same day as ordered but these proportions varied from 71% to 100% across the 10 hospitals. Children who had a transfusion ordered but did not receive the prescribed transfusion had a mortality of 20%, compared with 12% among those transfused. Malaria-associated anemia remains the leading indication for blood transfusion in acute childhood illness admissions. Delays in transfusion are common and associated with poor outcomes. Variance in delay across hospitals may be a useful indicator of health system performance.

Fecal microbiota transplantation: A 'How-To' guide for nurses.

Fecal microbiota transplantation is emerging as one of the most exciting treatments of this century. Rarely has one treatment provided the opportunity to treat a myriad of diseases, not only within the gastrointestinal tract but also in extra-intestinal organs; such is the power of the gastrointestinal microbiota to modulate the immune system and eradicate infections, even where antibiotics have previously failed. The demand for this therapy, both among patients and physicians, is increasing, and a search of the literature reveals numerous reviews, case reports and discussion on the topic. However, to date, much of the literature addresses the procedure from a physician's point of view, and can therefore be lacking in practical detail. As nurses are often the 'unsung heroes' of the procedure, it is timely to address the subject from a nursing perspective.

Fecal microbiota transplantation: techniques, applications, and issues.

Fecal microbiota transplantation (FMT) has gained widespread recognition in light of the recent Clostridium difficile infection (CDI) epidemic, responsible for almost 110,000 deaths per year. The procedure's success rate has caused experts to reflect on what other conditions may benefit. This article provides an overview of (1) description and history of FMT, (2) FMT publications in CDI, (3) the concept of the gut microbiota as a virtual organ, (4) rationale for FMT use, (5) FMT use in inflammatory bowel disease, (6) emerging FMT applications, (7) how FMT is currently performed, and (8) how FMT may be performed in the future.

Mycobacterium avium ss paratuberculosis-associated diseases: piecing the Crohn's puzzle together.

The relation of Mycobacterium avium ss paratuberculosis (MAP) to Crohn's Disease (CD) and other MAP-associated conditions remains controversial. New data, coupled with the analogous Helicobacter pylori (H. pylori) story, has permitted us to piece together the MAP puzzle and move forward with a more scientific way of treating inflammatory bowel disease, particularly CD. As infection moves centre stage in inflammatory bowel disease, the dated "aberrant reaction" etiology has lost scientific credibility. Now, our growing understanding of MAP-associated diseases demands review and articulation. We focus here on (1) the concept of MAP-associated diseases; (2) causality, Johne Disease, the "aberrant reaction" hypothesis; and (3) responses to published misconceptions questioning MAP as a pathogen in CD.

Durable alteration of the colonic microbiota by the administration of donor fecal flora.

GOALS: To determine whether fecal bacteriotherapy results in a durable beneficial change in the colonic microbiota of patients with flora-related disorders. BACKGROUND: Earlier studies have implicated the colonic microbiota in a number of conditions. Administration of a fecal suspension from a healthy individual to an ill individual (fecal bacteriotherapy) can cure Clostridium difficile infection and potentially other diseases. Oral probiotics do not work in this condition, yet there has been no study to determine whether fecal bacteriotherapy results in prolonged implantation. STUDY: Fecal samples were collected from 10 patients undergoing fecal bacteriotherapy. Patients completed an antibiotic schedule and bowel lavage before the infusion of healthy donor feces. Using a molecular approach, the bacterial populations in patient fecal samples were followed from pretreatment to 24 weeks post-initial infusion and compared with the initial infused donor fecal suspension. RESULTS: At intervals of 4, 8, and 24 weeks after the procedure, the bacterial populations in the patients' fecal samples consisted predominantly of bacteria derived from the healthy donor samples. Comparisons of similarity at 4, 8, and 24 week samples to the donor-infused sample were made and each recipient's baseline sample was statistically significant with Friedman test. CONCLUSIONS: This study demonstrates a durable beneficial change in the patients' bacterial populations of the colon to represent those of the healthy donor's microbiota. Manipulation of the colonic microbiota to improve its protective and beneficial role represents a promising field of new therapeutic strategies for the treatment of gastrointestinal conditions.