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Identifying the principal determinants of life satisfaction following mild TBI (mTBI) may inform efforts to improve subjective well-being in this population. We examined life satisfaction among participants in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study who presented with mTBI (Glasgow Coma Scale [GCS] score = 13–15; n = 1152). An L1-regularization path algorithm was used to select optimal sets of baseline and concurrent symptom measures for prediction of scores on the Satisfaction with Life Scale (SWLS) at 2 weeks and 3, 6, and 12 months post-injury. Multi-variable linear regression models (all n = 744–894) were then fit to evaluate associations between the empirically selected predictors and SWLS scores at each follow-up visit. Results indicated that emotional post-TBI symptoms (all b = −1.27 to −0.77, all p more...

G-quadruplexes (or G4s) are structures formed by guanine-rich nucleic acid sequences. G4s must be promptly unfolded in cells; otherwise, they can interfere with DNA replication, RNA transcription, and other essential processes. Guanines bases are susceptible to oxidative stress forming 8-oxoguanines (8oxoG). Although 8oxoG-modified DNA sequences can still fold into stable G4s, it is not known how 8oxoG4s are repaired in human cells. In our previous study, we have shown that the FANCJ DNA helicase targets G4s using an AKKQ amino acid motif. Here, we have examined the interactions of FANCJ with various 8oxoG4s using biolayer interferometry and fluorescence spectroscopy. We show that a FANCJ AKKQ peptide alone can recognize G4s with an affinity of 3.7uM. Moreover, this motif binds to 8oxoG4s with greater affinities of 1.3 to 2.3uM. A detailed description of the mechanisms by which 8oxoG4s are repaired is essential for understanding how human hearts respond to oxidative stress. To test the importance of FANCJ AKKQ-G4 interactions in cells, we measured the total extent of oxidative DNA damage in human cardiac cells by single-cell electrophoresis. Cells that overexpress FANCJ can readily overcome the chemical stress induced by hydrogen peroxide treatment and the G4-stabilizing compound telomestatin. On the contrary, cells that produce a FANCJ AAAQ mutant, which cannot interact with G4s, resulted in an accumulation of 8oxoG4s. Based on this evidence, FANCJ plays an important role to alleviate the damage caused by oxidative stress. In future experiments, we plan to further examine the cardiovascular risks of DNA damage caused by FANCJ malfunctions. more...

Since 2015 in the United States (US), the US Neisseria meningitidis urethritis clade (US_NmUC) has caused a large multistate outbreak of urethritis among heterosexual males. Its ‘parent’ strain caused numerous outbreaks of invasive meningococcal disease among men who have sex with men in Europe and North America. We highlight the arrival and dissemination of US_NmUC in the United Kingdom and the emergence of multiple antibiotic resistance. Surveillance systems should be developed that include anogenital meningococci. more...

Nonhealing wounds are a major area of unmet clinical need remaining problematic to treat. Improved understanding of prohealing mechanisms is invaluable. The enzyme arginase1 (ARG1) is involved in prohealing responses, with its role in macrophages best characterized. ARG1 is also expressed by keratinocytes; however, ARG1 function in these critical wound repair cells is not understood. We characterized ARG1 expression in keratinocytes during normal cutaneous repair and reveal de novo temporal and spatial expression at the epidermal wound edge. Interestingly, epidermal ARG1 expression was decreased in both human and murine delayed healing wounds. We therefore generated a keratinocyte-specific ARG1-null mouse model (K14-cre;Arg1fl/fl) to explore arginase function. Wound repair, linked to changes in keratinocyte proliferation, migration, and differentiation, was significantly delayed in K14-cre;Arg1fl/fl mice. Similarly, using the arginase inhibitor N(omega)-hydroxy-nor-L-arginine, human in vitro and ex vivo models further confirmed this finding, revealing the importance of the downstream polyamine pathway in repair. Indeed, restoring the balance in ARG1 activity through the addition of putrescine proved beneficial in wound closure. In summary, we show that epidermal ARG1 plays, to our knowledge, a previously unreported intrinsic role in cutaneous healing, highlighting epidermal ARG1 and the downstream mediators as potential targets for the therapeutic modulation of wound repair. more...

OBJECTIVE Understanding suicide risk is a priority for the US military. We aimed to estimate associations of childhood maltreatment with pre-enlistment suicidal behaviors in new Army soldiers. METHODS Cross-sectional survey data from 38,237 soldiers reporting for basic training from April 2011 through November 2012 were analyzed. Scales assessing retrospectively reported childhood abuse and neglect were derived and subjected to latent class analysis, which yielded 5 profiles: No Maltreatment, Episodic Emotional Maltreatment, Frequent Emotional/Physical Maltreatment, Episodic Emotional/Sexual Abuse, and Frequent Emotional/Physical/Sexual Maltreatment. Discrete-time survival analysis was used to estimate associations of maltreatment profiles with suicidal behaviors (assessed with a modified Columbia-Suicide Severity Rating Scale), adjusting for sociodemographics and mental disorders. RESULTS Nearly 1 in 5 new soldiers was classified as experiencing childhood maltreatment. Relative to No Maltreatment, all multivariate maltreatment profiles were associated (P values < .001) with elevated odds of lifetime suicidal ideation (adjusted odds ratios [AORs] = 3.10-4.93), plan (AORs = 3.75-10.77), attempt (AORs = 3.60-15.95), and onset of plan among those with ideation (AORs = 1.40-3.10). Several profiles also predicted attempts among those with plans (AORs = 2.01-2.47), and Frequent Emotional/Physical/Sexual Maltreatment predicted unplanned attempts among ideators (AOR = 5.32). Adjustment for mental disorders attenuated but did not eliminate these associations. CONCLUSIONS Childhood maltreatment is strongly associated with suicidal behavior among new soldiers, even after adjusting for intervening mental disorders. Among soldiers with lifetime ideation, certain maltreatment profiles are associated with elevated odds of subsequently planning and/or attempting suicide. Focus on childhood maltreatment might reveal avenues for risk reduction among new soldiers. more...

BACKGROUND: The annual National Conference on Health Disparities (NCHD) was launched in 2000. It unites health professionals, researchers, community leaders, and government officials, and is a catalyzing force in developing policies, research interventions, and programs that address prevention, social determinants, health disparities, and health equity. The NCHD Student Research Forum (SRF) was established in 2011 at the Medical University of South Carolina to build high-quality biomedical research presentation capacity in primarily underrepresented undergraduate and graduate/professional students. PURPOSE: This paper describes the unique research training and professional development aspects of the NCHD SRF. These include guidance in abstract development, a webinar on presentation techniques and methods, a vibrant student-centric conference, and professional development workshops on finding a mentor and locating scholarship/fellowship funding, networking, and strategies for handling ethical issues in research with mentors. RESULTS: Between 2011 and 2018, 400 undergraduate and graduate/professional students participated in the SRF. The students represented 84 different academic institutions and 27 US states/commonwealths, as well as Germany and the UK. Most students were women (80.5%). Approximately half were African American or Black (52.3%), 18.0% were white, and 21.3% were of Hispanic/Latinx ethnicity. CONCLUSIONS: The NCHD SRF is unique in several ways. First, it provides detailed instructions on developing a scientific abstract, including content area examples. Second, it establishes a mandatory pre-conference training webinar demonstrating how to prepare a scientific poster. Third, it works with the research mentors, faculty advisors, department chairs, and deans to help identify potential sources of travel funding for students with accepted abstracts. These features make the NCHD SRF different from many other conferences focused on students' scientific presentations. Citation Format: Marvella E. Ford, Angela M. Malek, Latecia Abraham-Hilaire, Oluwole Ariyo, Dana Burshell, Gloria Callwood, Laura Campbell, Kimberly Cannady, Courtney Chavis, Brittney Crawford, Andie Edwards, Victoria J. Findlay, Rita Finley, Chamiere Greenaway, Tonya R. Hazelton, Monique Hill, Marion Howard, Kendrea D. Knight, Vanessa Lopez-Littleton, Lloyd Moore, Diandra Randle, David E. Rivers, Judith D. Salley, Terry Seabrook, Sabra Slaughter, James B. Stukes, Roland J. Thorpe, LaVerne Ragster. The National Conference on Health Disparities Student Research Forum [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-057. more...

Background: Platelets, derived from megakaryocytes primarily play a central role in thrombosis and hemostasis, however, they extend beyond this role as immune cells that initiate and accelerate various vascular inflammatory conditions. Upon activation, platelets release TREM-Like Transcript-1 (TLT-1) from their a-granules onto their surface. Early studies by amino link columns preloaded with soluble TLT-1 followed by mass spectrometry and immunoblotting identified fibrinogen as a ligand for TLT-1. Fibrinogen is a plasma protein that is essential for clot formation, during inflammation and hypercoagulable states tissue deposition and plasma concentration of fibrinogen are increased, demonstrating a role of fibrinogen in both thrombosis and inflammation. TLT-1 binding fibrinogen was a surprising discovery since αIIbβ3, the most abundant platelet receptor, also binds fibrinogen and facilitates platelet aggregation. It is difficult to understand why there are two platelet specific receptors that have the same ligand, drawing us to question what the difference in function between the two is? Our studies suggest that although TLT-1 may assist in clot formation and hemostasis to arrest bleeding in a non-inflammatory setting like αIIbβ3, TLT-1's main association is with regulating inflammatory-derived bleeding. Very little is known about the TLT-1-Fibrinogen interaction, further studies would set the stage for a better understanding as to why two fibrinogen ligands exist on platelets and potentially outline a novel platelet therapeutic target during hypercoagulable and/or hyperinflammatory states. We set out to determine the binding affinity and localize the binding sites for the TLT-1 fibrinogen molecular interaction. Aims: Delineate the TLT-1 fibrinogen molecular interaction and elucidate the mechanism by which this interaction drives inflammation and thrombosis-hemostasis. Methods: To confirm the TLT-1 fibrinogen ligand interaction we carried out a kinetics assay using an Octet Qk e Bio-layer Interferometry (BLI) that measures biomolecular complex formation in real time. The TLT-1 Chimera was captured onto an Anti-Human Fc Capture (AHC) Biosensor, washed in kinetics buffer to limit nonspecific binding and submerged in a 96 well plate containing varying concentrations of Fibrinogen. To localize the exact binding sites for this molecular interaction, we digested fibrinogen using trypsin and carried out an immunoprecipitation (IP) followed by Liquid Chromatography-Mass Spectrometry (LC-MS/MS). Results: The curve (Figure 1) shows that the TLT-1 fibrinogen interaction has increasing bimolecular complex formation with increases in concentration of Fibrinogen (15.625nM - 250nM), with a concentration of 250nM showing the best bicomplex formation. In the control well with HIV01 4E10 capture, reference and sensor well, no bicomplex formation is shown, highlighting the specificity of the TLT-1 fibrinogen interaction. The curve illustrates a strong association with no dissociation, suggesting a strong interaction between the proteins. We isolated and identified four potential peptides (Alpha chain: GGSTSYGTGSETESPR, GSESGIFTNTK, Beta chain: QDGSVDFGR , QGFGNVATNTDGK) that bind TLT-1. We are currently performing BLI Competitive kinetics assays using biotinylated constructs of the peptides isolated from the Immunoprecipitation/ LC-MS/MS. The BLI competitive assays using the four peptides are suggestive of an interaction between TLT-1 and the four peptides as illustrated by increasing bimolecular complex formation with increasing concentration of soluble TLT-1 for all four peptides(data not shown). Conclusions: We obtained an equilibrium dissociation constant (KD) of 3.02 ± 0.20 nM for the TLT-1 fibrinogen interaction, suggesting a high affinity interaction between TLT-1 and fibrinogen. In our preliminary results from the BLI Competitive kinetics assays we obtained KD values within the nanomolar concentration range and are currently conducting experiments to optimize conditions to obtain our final bicomplex binding curve and KD values. We are currently assessing the identified peptides for potential of mediating the molecular interaction between TLT-1 and fibrinogen. Our poster will report the current state of these studies . Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. more...

Background Self-assessment of resilience could prove valuable to military and other organizations whose personnel confront foreseen stressors. We evaluated the validity of self-assessed resilience among U.S. Army soldiers, including whether predeployment perceived resilience predicted postdeployment emotional disorder. Methods Resilience was assessed via self-administered questionnaire among new soldiers reporting for basic training (N = 35,807) and experienced soldiers preparing to deploy to Afghanistan (N = 8,558). Concurrent validity of self-assessed resilience was evaluated among recruits by estimating its association with past-month emotional disorder. Predictive validity was examined among 3,526 experienced soldiers with no lifetime emotional disorder predeployment. Predictive models estimated associations of predeployment resilience with incidence of emotional disorder through 9 months postdeployment and with marked improvement in coping at 3 months postdeployment. Weights-adjusted regression models incorporated stringent controls for risk factors. Results Soldiers characterized themselves as very resilient on average [M = 14.34, SD = 4.20 (recruits); M = 14.75, SD = 4.31 (experienced soldiers); theoretical range = 0–20]. Demographic characteristics exhibited only modest associations with resilience, while severity of childhood maltreatment was negatively associated with resilience in both samples. Among recruits, resilience was inversely associated with past-month emotional disorder [adjusted odds ratio (AOR) = 0.65, 95% CI = 0.62–0.68, P < .0005 (per standard score increase)]. Among deployed soldiers, greater predeployment resilience was associated with decreased incidence of emotional disorder (AOR = 0.91; 95% CI = 0.84–0.98; P = .016) and increased odds of improved coping (AOR = 1.36; 95% CI = 1.24–1.49; P < .0005) postdeployment. Conclusions Findings supported validity of self-assessed resilience among soldiers, although its predictive effect on incidence of emotional disorder was modest. In conjunction with assessment of known risk factors, measurement of resilience could help predict adaptation to foreseen stressors like deployment. more...

BackgroundThe stress sensitization theory hypothesizes that individuals exposed to childhood adversity will be more vulnerable to mental disorders from proximal stressors. We aimed to test this theory with respect to risk of 30-day major depressive episode (MDE) and generalized anxiety disorder (GAD) among new US Army soldiers.MethodsThe sample consisted of 30 436 new soldier recruits in the Army Study to Assess Risk and Resilience (Army STARRS). Generalized linear models were constructed, and additive interactions between childhood maltreatment profiles and level of 12-month stressful experiences on the risk of 30-day MDE and GAD were analyzed.ResultsStress sensitization was observed in models of past 30-day MDE (χ28 = 17.6, p = 0.025) and GAD (χ28 = 26.8, p = 0.001). This sensitization only occurred at high (3+) levels of reported 12-month stressful experiences. In pairwise comparisons for the risk of 30-day MDE, the risk difference between 3+ stressful experiences and no stressful experiences was significantly greater for all maltreatment profiles relative to No Maltreatment. Similar results were found with the risk for 30-day GAD with the exception of the risk difference for Episodic Emotional and Sexual Abuse, which did not differ statistically from No Maltreatment.ConclusionsNew soldiers are at an increased risk of 30-day MDE or GAD following recent stressful experiences if they were exposed to childhood maltreatment. Particularly in the military with an abundance of unique stressors, attempts to identify this population and improve stress management may be useful in the effort to reduce the risk of mental disorders. more...

Background:Many patients with anxiety disorders remain symptomatic after receiving evidence-based treatment, yet research on treatment-resistant anxiety is limited. We evaluated effects of cognitive behavioral therapy (CBT) on outcomes of patients with medication-resistant anxiety disorders using data from the Coordinated Anxiety Learning and Management (CALM) trial.Methods:Primary care patients who met study entry criteria (including DSM-IV diagnosis of generalized anxiety disorder, panic disorder, posttraumatic stress disorder, or social anxiety disorder) despite ongoing pharmacotherapy of appropriate type, dose, and duration were classified as medication resistant (n = 227). Logistic regression was used to estimate effects of CALM's CBT program (CALM-CBT; chosen by 104 of 117 medication-resistant patients randomized to CALM) versus usual care (UC; n = 110) on response [≥ 50% reduction of 12-item Brief Symptom Inventory (BSI-12) anxiety and somatic symptom score] and remission (BSI-12 < 6) at 6,12, and ... more...

Prior studies raise questions about whether persistent postconcussive symptoms (PCS) are differentiable from mental health sequelae of traumatic brain injury (TBI). To investigate whether PCS represented a distinct symptom domain, we evaluated the structure of post-concussive and psychological symptoms using data from The Army STARRS Pre/Post Deployment Study, a panel survey of three U.S. Army Brigade Combat Teams that deployed to Afghanistan. Data from 1229 participants who sustained probable TBI during deployment completed ratings of past-30-day post-concussive, posttraumatic stress, and depressive symptoms three months after their return. Exploratory factor analysis (EFA; n = 300) and confirmatory factor analysis (CFA; n = 929) of symptom ratings were performed in independent subsamples. EFA suggested a model with 3 correlated factors resembling PCS, posttraumatic stress, and depression. CFA confirmed adequate fit of the 3-factor model (CFI = .964, RMSEA = .073 [.070, .075]), contingent upon allowing theoretically defensible cross-loadings. Bifactor CFA indicated that variance in all symptoms was explained by a general factor (λ = .36-.93), but also provided evidence of domain factors defined by (a) reexperiencing/hyperarousal, (b) cognitive/somatic symptoms, and (c) depressed mood/anhedonia. Soldiers with more severe TBI had higher cognitive/somatic scores, whereas soldiers with more deployment stress had higher general and reexperiencing/hyperarousal scores. Thus, variance in PCS is attributable to both a specific cognitive/somatic symptom factor and a general factor that also explains variance in posttraumatic stress and depression. Measurement of specific domains representing cognitive/somatic symptoms, reexperiencing/hyperarousal, and depressed mood/anhedonia may help clarify the relative severity of PCS, posttraumatic stress, and depression among individuals with recent TBI. (PsycINFO Database Record (c) 2019 APA, all rights reserved). more...

Stakeholder-developed interventions are needed to support pediatric intensive care unit (PICU) communication and decision-making. Few publications delineate methods and outcomes of stakeholder engagement in research. We describe the process and impact of stakeholder engagement on developing a PICU communication and decision-making support intervention. We also describe the resultant intervention. Stakeholders included parents of PICU patients, healthcare team members (HTMs), and research experts. Through a year-long iterative process, we involved 96 stakeholders in 25 meetings and 26 focus groups or interviews. Stakeholders adapted an adult navigator model by identifying core intervention elements and then determining how to operationalize those core elements in pediatrics. The stakeholder input led to PICU-specific refinements, such as supporting transitions after PICU discharge and including ancillary tools. The resultant intervention includes navigator involvement with parents and HTMs and navigator-guided use of ancillary tools. Subsequent research will test the feasibility and efficacy of our intervention. more...

Background Many patients with anxiety disorders remain symptomatic after receiving evidence-based treatment, yet research on treatment-resistant anxiety is limited. We evaluated effects of cognitive behavioral therapy (CBT) on outcomes of patients with medication-resistant anxiety disorders using data from the Coordinated Anxiety Learning and Management (CALM) trial. Methods Primary care patients who met study entry criteria (including DSM-IV diagnosis of generalized anxiety disorder, panic disorder, posttraumatic stress disorder, or social anxiety disorder) despite ongoing pharmacotherapy of appropriate type, dose, and duration were classified as medication resistant (n = 227). Logistic regression was used to estimate effects of CALM's CBT program (CALM-CBT; chosen by 104 of 117 medication-resistant patients randomized to CALM) versus usual care (UC; n = 110) on response [≥ 50% reduction of 12-item Brief Symptom Inventory (BSI-12) anxiety and somatic symptom score] and remission (BSI-12 < 6) at 6, 12, and 18 months. Within-group analyses examined outcomes by treatment choice (CBT vs. CBT plus medication management) and CBT dose. Results Approximately 58% of medication-resistant CALM-CBT patients responded and 46% remitted during the study. Relative to UC, CALM-CBT was associated with greater response at 6 months (AOR = 3.78, 95% CI 2.02-7.07) and 12 months (AOR = 2.49, 95% CI 1.36-4.58) and remission at 6, 12, and 18 months (AORs = 2.44 to 3.18). Patients in CBT plus medication management fared no better than those in CBT only. Some evidence suggested higher CBT dose produced better outcomes. Conclusions CBT can improve outcomes for patients whose anxiety symptoms are resistant to standard pharmacotherapy. more...

Wound infection is a major clinical problem, yet understanding of bacterial host interactions in the skin remains limited. Microbe-derived molecules, known as pathogen-associated molecular patterns, are recognised in barrier tissues by pattern-recognition receptors. In particular, the pathogen-associated molecular pattern, lipopolysaccharide (LPS), a component of microbial cell walls and a specific ligand for Toll-like receptor 4, has been widely used to mimic systemic and local infection across a range of tissues. Here we administered LPS derived from Klebsiella pneumoniae, a species of bacteria that is emerging as a wound-associated pathogen, to full-thickness cutaneous wounds in C57/BL6 mice. Early in healing, LPS-treated wounds displayed increased local apoptosis and reduced proliferation. Subsequent healing progression was delayed with reduced re-epithelialisation, increased proliferation, a heightened inflammatory response and perturbed wound matrix deposition. Our group and others have previously demonstrated the beneficial effects of 17β-estradiol treatment across a range of preclinical wound models. Here we asked whether oestrogen would effectively promote healing in our LPS bacterial infection model. Intriguingly, co-treatment with 17β-estradiol was able to promote re-epithelialisation, dampen inflammation and induce collagen deposition in our LPS-delayed healing model. Collectively, these studies validate K. pneumoniae-derived LPS treatment as a simple yet effective model of bacterial wound infection, while providing the first indication that oestrogen could promote cutaneous healing in the presence of infection, further strengthening the case for its therapeutic use. more...

IMPORTANCE: Traumatic brain injury (TBI) has been associated with adverse mental health outcomes, such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), but little is known about factors that modify risk for these psychiatric sequelae, particularly in the civilian sector. OBJECTIVE: To ascertain prevalence of and risk factors for PTSD and MDD among patients evaluated in the emergency department for mild TBI (mTBI). DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal cohort study (February 2014 to May 2018). Posttraumatic stress disorder and MDD symptoms were assessed using the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9 Item. Risk factors evaluated included preinjury and injury characteristics. Propensity score weights-adjusted multivariable logistic regression models were performed to assess associations with PTSD and MDD. A total of 1155 patients with mTBI (Glasgow Coma Scale score, 13-15) and 230 patients with nonhead orthopedic trauma injuries 17 years and older seen in 11 US hospitals with level 1 trauma centers were included in this study. MAIN OUTCOMES AND MEASURES: Probable PTSD (PTSD Checklist for DSM-5 score, ≥33) and MDD (Patient Health Questionnaire-9 Item score, ≥15) at 3, 6, and 12 months postinjury. RESULTS: Participants were 1155 patients (752 men [65.1%]; mean [SD] age, 40.5 [17.2] years) with mTBI and 230 patients (155 men [67.4%]; mean [SD] age, 40.4 [15.6] years) with nonhead orthopedic trauma injuries. Weights-adjusted prevalence of PTSD and/or MDD in the mTBI vs orthopedic trauma comparison groups at 3 months was 20.0% (SE, 1.4%) vs 8.7% (SE, 2.2%) (P more...

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genomewide association studies (GWAS) of self-assessed (by questionnaire) and outcome-based (incident mental disorders from pre- to post-deployment) resilience among European (EUR) ancestry soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). Self-assessed resilience (N=11,492) was found to have significant common-variant heritability (h2=0.162, se=0.050, p=5.37e-4), and to be significantly negatively genetically correlated with neuroticism (rg= −0.388, p=0.0092). GWAS results from the EUR soldiers revealed a genomewide significant locus (4 SNPs in LD; top SNP: rs4260523, p=5.654e-09) on an intergenic region on Chr 4 upstream from DCLK2 (Doublecortin-Like Kinase 2), a member of the doublecortin (DCX) family of kinases that promote survival and regeneration of injured neurons. A second gene, KLHL36 (Kelch Like Family Member 36) was detected at gene-wise genomewide significance (p=1.89e-06). A polygenic risk score derived from the self-assessed resilience GWAS was not significantly associated with outcome-based resilience. In very preliminary results, genomewide significant association with outcome-based resilience was found for one locus (top SNP: rs12580015) on Chr 12 downstream from SLC15A5 (solute carrier family 15 member 5) in the small group (N=581) of subjects exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress-related psychopathology and potentially point to new avenues for therapeutic intervention. more...

STUDY OBJECTIVES: Insomnia is prevalent among military personnel and may increase risk of mental disorders and suicidal ideation. This study examined associations of pre-deployment insomnia with post-deployment post-traumatic stress disorder (PTSD) and suicidal ideation among US Army soldiers. METHODS: Soldiers from three Brigade Combat Teams completed surveys 1–2 months before deploying to Afghanistan in 2012 (T0), on return from deployment (T1), 3 months later (T2), and 9 months later (T3). Logistic regression was performed to estimate associations of pre-deployment (T0) insomnia with post-deployment (T2 or T3) PTSD and suicidal ideation among respondents who completed surveys at all waves (n = 4645). A hierarchy of models incorporated, increasing controls for pre-deployment risk factors and deployment experiences. RESULTS: Pre-deployment insomnia was associated with increased risk of post-deployment PTSD (adjusted odds ratio [AOR] = 3.14, 95% confidence interval [CI] = 2.58% to 3.82%, p < .0005) and suicidal ideation (AOR = 2.78, 95% CI = 2.07% to 3.74%, p < .0005) in models adjusting for sociodemographic characteristics and prior deployment history. Adjustment for other pre-deployment risk factors and deployment experiences attenuated these associations; however, insomnia remained significantly associated with post-deployment PTSD (AOR = 1.50, 95% CI = 1.19% to 1.89%, p = .001) and suicidal ideation (AOR = 1.43, 95% CI = 1.04% to 1.95%, p = .027). Subgroup models showed that pre-deployment insomnia was associated with incident PTSD (AOR = 1.55, 95% CI = 1.17% to 2.07%, p = .003) and suicidal ideation (AOR = 1.67, 95% CI = 1.16% to 2.40%, p = .006) among soldiers with no pre-deployment history of these problems. CONCLUSIONS: Pre-deployment insomnia contributed to prediction of post-deployment PTSD and suicidal ideation in Army soldiers, suggesting that detection of insomnia could facilitate targeting of risk mitigation programs. Future studies should investigate whether treatment of insomnia helps prevent PTSD and suicidal ideation among deployed service members. more...

BACKGROUND: Prior investigations have found negative associations between military unit cohesion and posttraumatic stress disorder (PTSD); however, most relied on cross-sectional data and few examined relationships of unit cohesion to other mental disorders. This study evaluates prospective associations of perceived unit cohesion with a range of mental health outcomes following combat deployment. METHODS: US Army soldiers were surveyed approximately 1–2 months before deployment to Afghanistan (T0); and 1 month (T1), 3 months (T2), and 9 months (T3) after return from deployment. Logistic regression was performed to estimate associations of perceived unit cohesion at T0 with risk of PTSD, major depressive episode (MDE), generalized anxiety disorder (GAD), alcohol or substance use disorder (AUD/SUD), and suicidal ideation at T2 or T3 among soldiers who completed all study assessments (N=4,645). Models adjusted for socio-demographic and Army service characteristics, pre-deployment history of the index outcome, and deployment stress exposure. RESULTS: Higher perceived unit cohesion at T0 was associated with lower risk of PTSD, MDE, GAD, AUD/SUD, and suicidal ideation at T2 or T3 (AORs=0.72 to 0.85 per standard score increase in unit cohesion; ps more...

Chronic wounds cause significant patient morbidity and mortality. A key factor in their etiology is microbial infection, yet skin host-microbiota interactions during wound repair remain poorly understood. Microbiome profiles of noninfected human chronic wounds are associated with subsequent healing outcome. Furthermore, poor clinical healing outcome was associated with increased local expression of the pattern recognition receptor NOD2. To investigate NOD2 function in the context of cutaneous healing, we treated mice with the NOD2 ligand muramyl dipeptide and analyzed wound repair parameters and expression of antimicrobial peptides. Muramyl dipeptide treatment of littermate controls significantly delayed wound repair associated with reduced re-epithelialization, heightened inflammation, and up-regulation of murine β-defensins 1, 3, and particularly 14. We postulated that although murine β-defensin 14 might affect local skin microbial communities, it may further affect other healing parameters. Indeed, exogenously administered murine β-defensin 14 directly delayed mouse primary keratinocyte scratch wound closure in vitro. To further explore the role of murine β-defensin 14 in wound repair, we used Defb14–/– mice and showed they had a global delay in healing in vivo, associated with alterations in wound microbiota. Taken together, these studies suggest a key role for NOD2-mediated regulation of local skin microbiota, which in turn affects chronic wound etiology. more...

Traumatic brain injury (TBI) is increasingly recognized as a risk factor for deleterious mental health and functional outcomes. The purpose of this study was to examine the strength and specificity of the association between deployment-acquired TBI and subsequent posttraumatic stress and related disorders among U.S. Army personnel.A prospective, longitudinal survey of soldiers in three Brigade Combat Teams was conducted 1-2 months prior to an average 10-month deployment to Afghanistan (T0), upon redeployment to the United States (T1), approximately 3 months later (T2), and approximately 9 months later (T3). Outcomes of interest were 30-day prevalence postdeployment of posttraumatic stress disorder (PTSD), major depressive episode, generalized anxiety disorder, and suicidality, as well as presence and severity of postdeployment PTSD symptoms.Complete information was available for 4,645 soldiers. Approximately one in five soldiers reported exposure to mild (18.0%) or more-than-mild (1.2%) TBI(s) during the index deployment. Even after adjusting for other risk factors (e.g., predeployment mental health status, severity of deployment stress, prior TBI history), deployment-acquired TBI was associated with elevated adjusted odds of PTSD and generalized anxiety disorder at T2 and T3 and of major depressive episode at T2. Suicidality risk at T2 appeared similarly elevated, but this association did not reach statistical significance.The findings highlight the importance of surveillance efforts to identify soldiers who have sustained TBIs and are therefore at risk for an array of postdeployment adverse mental health outcomes, including but not limited to PTSD. The mechanism(s) accounting for these associations need to be elucidated to inform development of effective preventive and early intervention programs. more...

A narrative synthesis was conducted to determine typical patient- and family-centered care (PFCC) components and their link to outcomes in pediatric populations. 68 studies with PFCC interventions and experimental designs were included. Study features were synthesized based on 5 core PFCC components (i.e., education from the provider to the patient and/or family, information sharing from the family to the provider, social-emotional support, adapting care to match family background, and/or s decision-making) and 4 outcome categories (health status; the experience, knowledge, and attitudes of the patient/family; patient/family behavior; or provider behavior). The most common PFCC component was education; the least common was adapting care to family background. The presence of social-emotional support alone, as well as educational interventions augmented with shared decision-making, social-emotional support, or adaptations of care based on family background, predicted improvements in families’ knowledge, attitudes, and experience. Interventions that targeted the family were associated with positive outcomes. more...

Campbell et al. show that intestinal helminth infection generates mucin-mediated host protection at distal mucosal sites driven by interleukin-13 from innate lymphoid cells. This provides an important innate defense mechanism operating against the multiple helminth challenges encountered at mucosal surfaces., Host immunity to parasitic nematodes requires the generation of a robust type 2 cytokine response, characterized by the production of interleukin 13 (IL-13), which drives expulsion. Here, we show that infection with helminths in the intestine also induces an ILC2-driven, IL-13–dependent goblet cell hyperplasia and increased production of mucins (Muc5b and Muc5ac) at distal sites, including the lungs and other mucosal barrier sites. Critically, we show that type 2 priming of lung tissue through increased mucin production inhibits the progression of a subsequent lung migratory helminth infection and limits its transit through the airways. These data show that infection by gastrointestinal-dwelling helminths induces a systemic innate mucin response that primes peripheral barrier sites for protection against subsequent secondary helminth infections. These data suggest that innate-driven priming of mucus barriers may have evolved to protect from subsequent infections with multiple helminth species, which occur naturally in endemic areas. more...

In transformative education, learners are supported to look beyond their own frame of reference to accommodate an alternative. Mezirow’s Transformative Learning Theory (MTLT) proposes that transformative education occurs following an emotional event—a disorientating dilemma. This study aimed to review whether palliative care could be useful in fostering transformative education, and reflected on two questions, a) do shifts in frames of reference occur after disorientating dilemmas, and b) is it useful to see multiple frames of reference? Participants were three nurses and a doctor who were selected as an information-rich data source. A narrative method was employed in which participants were requested in interviews to describe their work in palliative care. Interviews were analysed inductively around the study questions. Participants described usefulness in seeing the perspectives of their patients and shifts in their frame of reference that occurred following disorientating dilemmas. The disorientating dilemmas were around caring for the dying and around changing roles from curative to palliative. However, data revealed complexities around MTLT in that a disorientating dilemma did not always result in a shift of frame of reference and seeing differing frames of reference could lead to complications in care. It is recommended that further study be carried out into MTLT and in particular into associations between disorientating dilemmas and shifts in frames of reference in palliative care practice. Studying palliative care education and training alongside palliative care practice would also enrich knowledge of transformative education. more...

Contains fulltext : 200437.pdf (Publisher’s version ) (Closed access) OBJECTIVES: The impact of nutrition status on outcomes in pediatric severe sepsis is unclear. We studied the association of nutrition status (expressed as body mass index z score) with outcomes in pediatric severe sepsis. DESIGN: Secondary analysis of the Sepsis Prevalence, Outcomes, and Therapies study. Patient characteristics, ICU interventions, and outcomes were compared across nutrition status categories (expressed as age- and sex-adjusted body mass index z scores using World Health Organization standards). Multivariable regression models were developed to determine adjusted differences in all-cause ICU mortality and ICU length of stay by nutrition status. SETTING: One-hundred twenty-eight PICUs across 26 countries. PATIENTS: Children less than 18 years with severe sepsis enrolled in the Sepsis Prevalence, Outcomes, and Therapies study (n = 567). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nutrition status data were available for 417 patients. Severe undernutrition was seen in Europe (25%), Asia (20%), South Africa (17%), and South America (10%), with severe overnutrition seen in Australia/New Zealand (17%) and North America (14%). Severe undernutrition was independently associated with all-cause ICU mortality (adjusted odds ratio, 3.0; 95% CI, 1.2-7.7; p = 0.02), whereas severe overnutrition in survivors was independently associated with longer ICU length of stay (1.6 d; p = 0.01). CONCLUSIONS: There is considerable variation in nutrition status for children with severe sepsis treated across this selected network of PICUs from different geographic regions. Severe undernutrition was independently associated with higher all-cause ICU mortality in children with severe sepsis. Severe overnutrition was independently associated with greater ICU length of stay in childhood survivors of severe sepsis. more...

OBJECTIVE To investigate whether trauma exposure moderates the genetic correlation between substance use disorders and psychiatric disorders, we tested whether trauma exposure modifies the association of genetic risks for mental disorders with alcohol misuse and nicotine dependence (ND) symptoms. METHODS High-resolution polygenic risk scores (PRSs) were calculated for 10 732 US Army soldiers (8346 trauma-exposed and 2386 trauma-unexposed) based on genome-wide association studies of bipolar disorder (BD), major depressive disorder, and schizophrenia. RESULTS The main finding was a significant BD PRS-by-trauma interaction with respect to alcohol misuse (P = 6.07 × 10-3 ). We observed a positive correlation between BD PRS and alcohol misuse in trauma-exposed soldiers (r = 0.029, P = 7.5 × 10-3 ) and a negative correlation in trauma-unexposed soldiers (r = -0.071, P = 5.61 × 10-4 ). Consistent (nominally significant) result with concordant effect, directions were observed in the schizophrenia PRS-by-trauma interaction analysis. The variants included in the BD PRS-by-trauma interaction showed significant enrichments for gene ontologies related to high voltage-gated calcium channel activity (GO:0008331, P = 1.51 × 10-5 ; GO:1990454, P = 4.49 × 10-6 ; GO:0030315, P = 2.07 × 10-6 ) and for Beta1/Beta2 adrenergic receptor signaling pathways (P = 2.61 × 10-4 ). CONCLUSIONS These results indicate that the genetic overlap between alcohol misuse and BD is significantly moderated by trauma exposure. This provides molecular insight into the complex mechanisms that link substance abuse, psychiatric disorders, and trauma exposure. more...

Cross-sectional associations between attention deficit hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) have been observed, but longitudinal studies assessing this association are lacking. This prospective study evaluated the association between predeployment ADHD and postdeployment PTSD among U.S. Army soldiers. Soldiers who deployed to Afghanistan were surveyed before deployment (T0) and approximately 1 month (T1), 3 months (T2), and 9 months (T3) after their return. Logistic regression was performed to estimate the association between predeployment ADHD and postdeployment (T2 or T3) PTSD among 4,612 soldiers with data at all waves and no record of stimulant medication treatment during the study. To evaluate specificity of the ADHD-PTSD association, we examined associations among predeployment ADHD, postdeployment major depressive episode (MDE), generalized anxiety disorder (GAD), and suicidal ideation. Weighted prevalence of ADHD predeployment was 6.1% (SE = 0.4%). Adjusting for other risk factors, predeployment ADHD was associated with risk of postdeployment PTSD, adjusted odds ratio (AOR) = 2.13, 95% CI [1.51, 3.00], p < .001, including incidence among soldiers with no predeployment history of PTSD, AOR = 2.50, 95% CI [1.69, 3.69], p < .001. ADHD was associated with postdeployment MDE, AOR = 2.80, 95% CI [2.01, 3.91], p < .001, and GAD, AOR = 3.04, 95% CI [2.10, 4.42], p < .001, but not suicidal ideation. Recognition of associations between predeployment ADHD and postdeployment PTSD, MDE, and GAD may inform targeted prevention efforts. Future research should examine whether treatment of ADHD is protective against PTSD and related disorders in trauma-exposed individuals. more...

BackgroundInvestigations of drinking behavior across military deployment cycles are scarce, and few prospective studies have examined risk factors for post-deployment alcohol misuse.MethodsPrevalence of alcohol misuse was estimated among 4645 US Army soldiers who participated in a longitudinal survey. Assessment occurred 1–2 months before soldiers deployed to Afghanistan in 2012 (T0), upon their return to the USA (T1), 3 months later (T2), and 9 months later (T3). Weights-adjusted logistic regression was used to evaluate associations of hypothesized risk factors with post-deployment incidence and persistence of heavy drinking (HD) (consuming 5 + alcoholic drinks at least 1–2×/week) and alcohol or substance use disorder (AUD/SUD).ResultsPrevalence of past-month HD at T0, T2, and T3 was 23.3% (s.e. = 0.7%), 26.1% (s.e. = 0.8%), and 22.3% (s.e. = 0.7%); corresponding estimates for any binge drinking (BD) were 52.5% (s.e. = 1.0%), 52.5% (s.e. = 1.0%), and 41.3% (s.e. = 0.9%). Greater personal life stress during deployment (e.g., relationship, family, or financial problems) – but not combat stress – was associated with new onset of HD at T2 [per standard score increase: adjusted odds ratio (AOR) = 1.20, 95% CI 1.06–1.35, p = 0.003]; incidence of AUD/SUD at T2 (AOR = 1.54, 95% CI 1.25–1.89, p < 0.0005); and persistence of AUD/SUD at T2 and T3 (AOR = 1.30, 95% CI 1.08–1.56, p = 0.005). Any BD pre-deployment was associated with post-deployment onset of HD (AOR = 3.21, 95% CI 2.57–4.02, p < 0.0005) and AUD/SUD (AOR = 1.85, 95% CI 1.27–2.70, p = 0.001).ConclusionsAlcohol misuse is common during the months preceding and following deployment. Timely intervention aimed at alleviating/managing personal stressors or curbing risky drinking might reduce risk of alcohol-related problems post-deployment. more...

Background: Staffing of rural healthcare facilities is a challenge, with literature supporting the selection and training of rural-origin students. The Umthombo Youth Development Foundation (UYDF) scholarship scheme supports rural students to train as healthcare professionals and offers a unique support programme. This programme has not been evaluated, and this study sought UYDF-supported students’ perceptions of the programme.Aim: The aim of the study was to assess students’ perceptions of the UYDF support programme.Methods: This was an observational descriptive study. Participants were students supported by UYDF and data were collected by a questionnaire with a Likert scale to assess perceptions of various aspects of the support programme.Results: Students’ perceptions about the UYDF support programme were generally positive, with initial orientation and information sharing perceived as useful. Some respondents did not perceive value in holding discussions around English proficiency. The support required appeared to diminish with increasing years of study.Conclusion: A comprehensive, proactive compulsory support system that provides both academic and social support was perceived as useful by the UYDF students. Further research is required around aspects such as encouraging English proficiency. In future, the support programme could prioritise students in the early years of their study. more...

Background: The World Health Organization has described deliberate self-harm (DSH) as a major global health challenge. Little is known about the profile of patients admitted following DSH at district and regional combo hospitals in KwaZulu-Natal, South Africa.Aim: The aim of this study was to assess the profiles of patients and reasons for admission following DSH.Setting: The study was conducted on data from a busy Accident and Emergency (A&E) department in a combination district and regional hospital situated in Empangeni in northern KwaZulu-Natal.Method: This was a retrospective descriptive study. Data were collected from charts of all patients admitted to the A&E department from April 2012 to March 2013 following DSH. Variables assessed included age, gender, race, occupation, religion, education level, coexisting medical and mental health conditions, and reasons for DSH. Data were entered into SPSS and analysed descriptively.Results: A total of 262 charts were identified and 215 (82%) were selected for inclusion. Most patients admitted following DSH were young, single African women with at least secondary-level education. Most (169/215;78%) admissions were for parasuicide, with relational issues contributing in more than 50% of cases and circumstance challenges contributing in just under 30%.Conclusion: Although an underestimation, DSH is not an uncommon reason for patients to present in the A&E at this district and regional combo hospital. Findings from this study are consistent with those of other studies on DSH and highlight the need for a validated screening tool for the identification of patients at risk of DSH. There is a need to explore community-based intervention, which could address reasons for DSH and prevent future admissions. more...

Background: There is a significant risk of a medical student acquiring a blood-borne pathogen following occupational exposure to blood and other bodily fluids from infected patients in the healthcare setting. Internationally and nationally, interventions have been implemented in medical schools to reduce students’ risk of acquiring a blood-borne pathogen. Few studies in South Africa have evaluated such interventions.Method: The aim of this study was to review the incidence and management of occupational exposure to blood and blood products in final-year medical students. The study was descriptive and cross-sectional. The study participants were final-year medical students. Data were collected using questionnaires and analysed with the SPSS® programme.Results: A quarter of the participants reported occupational exposure. The risk appeared to be higher in certain medical departments and for female students. Some of the students did not receive a risk assessment which is part of university protocol. Over the... more...

Policy makers have increasingly turned to learning collaboratives (LCs) as a strategy for improving usual care through the dissemination of evidence-based practices. The purpose of this review was to characterize the state of the evidence for use of LCs in mental health care.A systematic search of major academic databases for peer-reviewed articles on LCs in mental health care generated 421 unique articles across a range of disciplines; 28 mental health articles were selected for full-text review, and 20 articles representing 16 distinct studies met criteria for final inclusion. Articles were coded to identify the LC components reported, the focus of the research, and key findings.Most of the articles included assessments of provider- or patient-level variables at baseline and post-LC. Only one study included a comparison condition. LC targets ranged widely, from use of a depression screening tool to implementation of evidence-based treatments. Fourteen crosscutting LC components (for example, in-person learning sessions, phone meetings, data reporting, leadership involvement, and training in quality improvement methods) were identified. The LCs reviewed reported including, on average, seven components, most commonly in-person learning sessions, plan-do-study-act cycles, multidisciplinary quality improvement teams, and data collection for quality improvement.LCs are being used widely in mental health care, although there is minimal evidence of their effectiveness and unclear reporting in regard to specific components. Rigorous observational and controlled research studies on the impact of LCs on targeted provider- and patient-level outcomes are greatly needed. more...

Anxiety disorders are prevalent in Latino populations. Findings from epidemiological studies based in the United States (US) suggest that lifetime rates of anxiety disorders among Latinos range from 19–30% (Burnam, Hough, Karno, Escobar, & Telles, 1987; Vega et al., 1998; Vicente et al., 2006). Data also suggest that US born Latinos, particularly those of Mexican origin, are at higher risk than immigrant Latinos, for mood, anxiety, and substance use disorders (Alegria et al., 2008; Grant et al., 2004; Vega et al., 1998). Despite the remarkable presence of anxiety and related disorders, Latinos are less likely than non-Latino Whites to use outpatient mental health services (Miranda & Green, 1999; Ojeda & McGuire, 2006) and are also less likely to receive evidence-based care (U.S. Department of Health and Human Services, 2001). These disparities underscore a treatment need for a large and growing segment of the US population. Cognitive-behavioral therapy (CBT) is the primary evidence-based psychosocial intervention for anxiety disorders (Butler, Chapman, Forman, & Beck, 2006). However, few studies have examined the efficacy of CBT with Latinos (Miranda et al., 2005; U.S. Department of Health and Human Services, 2001). Most randomized controlled trials (RCTs) for adults with anxiety disorders have only recruited small proportions of Latinos, making any kind of ethnic specific analysis impossible. As an example, in a recent review of RCTs for obsessive compulsive disorder, only 1.0% of 2,221 participants from 21 trials were Hispanic/Latino (Williams, Powers, Yun, & Foa, 2009). Studies examining the efficacy of CBT for Latino children and adolescents with anxiety disorders are more common, albeit still few. Findings from these RCTs have found comparable outcomes among Latino and non-Latino White youth on measures of clinical response, remission, symptom severity and overall functioning (Pina, Silverman, Fuentes, Kurtines, & Weems, 2003; Pina, Zerr, Villalta, & Gonzales, 2012; Silverman, Pina, & Viswesvaran, 2008). RCTs that evaluate CBT for Latinos with depression, a distinct but related disorder, are more numerous, particularly in primary care settings (Horrell, 2008; Miranda et al., 2005). Primary care based interventions may be particularly well-suited for Latinos who often experience more barriers to access, and endorse more stigma regarding seeking services from specialty mental health settings (Vega et al., 2007; Vega et al., 1999). Findings from these studies suggest that Latinos with depression, including low-income, and Spanish speaking patients, have comparable responses to CBT as other ethnic groups (Miranda, Azocar, Organista, Dwyer, & Areane, 2003; Munoz et al., 1995). In large scale quality improvement programs, which have included a CBT option, significant short and long term effects have been found for quality of care received by Latinos, African Americans and non-Latino Whites, and significant reductions in depressive symptoms have also been found for Latinos and African Americans (Miranda, Duan et al., 2003; Wells et al., 2005). In smaller, community based studies, favorable responses to CBT have also been found for various Latino ethnic subgroups (Comas-Diaz, 1981; Organista, Munoz, & Gonzalez, 1994; Rossello & Bernal, 1999). While findings offer some support for comparable clinical outcomes among Latino and non-Latino White participants who have received CBT, less attention has been devoted to engagement-related constructs, which typically reflect the extent to which a patient participates in treatment (e.g., treatment uptake, adherence, and attrition). Previous studies have found that lower engagement, as defined by fewer sessions attended, lesser homework adherence, and/or higher rates of attrition, can have negative effects on clinical outcomes (Glenn et al., 2013; O’Brien, Fahmy, & Singh, 2009). Studies which have examined differences in engagement between Latinos and non-Latino Whites have mostly focused on depression; these studies have found higher attrition rates in both pharmacological and psychosocial interventions for Latinos when compared to non-Latino Whites (Arnow et al., 2007; Organista et al., 1994). Additionally, problems with medication compliance, CBT attendance, and completion of CBT homework assignments among Latinos have been reported (Aguilera, Garza, & Munoz, 2010; Ayalon, Arean, & Alvidrez, 2005; Miranda & Cooper, 2004). To our knowledge, no studies have examined engagement outcomes for Latino adults participating in a CBT intervention for anxiety disorders. The current study addresses a gap in the literature on the impact of culture/ethnicity on treatment outcomes for patients with anxiety disorders. In this study, participants were recruited from primary care settings, and received therapist-delivered, computer-assisted CBT for anxiety disorders (“CALM: Tools for Living”) as part of the CALM (Coordinated Anxiety Learning and Management) study (Roy-Byrne et al., 2010; Craske et al., 2011). Clinical outcomes such as symptom reduction and remission as well as engagement-related outcomes including session attendance, treatment completion, homework adherence and acceptance of CBT, were examined. Based on the available literature, we hypothesized that Latinos who received CBT would have similar clinical outcomes as non-Latino Whites at the various assessment points. We also hypothesized that engagement outcomes would be less favorable among Latino compared to non-Latino Whites, however given the limited literature, analyses were somewhat exploratory in this regard. more...

The FANCJ helicase unfolds G-quadruplexes (G4s) in human cells to support DNA replication. This action is coupled to the recruitment of REV1 polymerase to synthesize DNA across from a guanine template. The precise mechanisms of these reactions remain unclear. While FANCJ binds to G4s with an AKKQ motif, it is not known whether this site recognizes damaged G4 structures. FANCJ also has a PIP-like (PCNA Interacting Protein) region that may recruit REV1 to G4s either directly or through interactions mediated by PCNA protein. In this work, we measured the affinities of a FANCJ AKKQ peptide for G4s formed by (TTAGGG)4 and (GGGT)4 using fluorescence spectroscopy and biolayer interferometry (BLI). The effects of 8-oxoguanine (8oxoG) on these interactions were tested at different positions. BLI assays were then performed with a FANCJ PIP to examine its recruitment of REV1 and PCNA. FANCJ AKKQ bound tightly to a TTA loop and was sequestered away from the 8oxoG. Reducing the loop length between guanine tetrads increased the affinity of the peptide for 8oxoG4s. FANCJ PIP targeted both REV1 and PCNA but favored interactions with the REV1 polymerase. The impact of these results on the remodeling of damaged G4 DNA is discussed herein. more...

Mice represent the most commonly used species for preclinical in vivo research. While incisional and excisional acute murine wound models are both frequently employed, there is little agreement on which model is optimum. Moreover, current lack of standardization of wounding procedure, analysis time point(s), method of assessment, and the use of individual wounds vs. individual animals as replicates makes it difficult to compare across studies. Here we have profiled secondary intention healing of incisional and excisional wounds within the same animal, assessing multiple parameters to determine the optimal methodology for future studies. We report that histology provides the least variable assessment of healing. Furthermore, histology alone (not planimetry) is able to detect accelerated healing in a castrated mouse model. Perhaps most importantly, we find virtually no correlation between wounds within the same animal, suggesting that use of wound (not animal) biological replicates is perfectly acceptable. Overall, these findings should guide and refine future studies, increasing the likelihood of detecting novel phenotypes while reducing the numbers of animals required for experimentation. more...

Summary Acute inflammation in response to injury is a tightly regulated process by which subsets of leukocytes are recruited to the injured tissue and undergo behavioural changes that are essential for effective tissue repair and regeneration. The diabetic wound environment is characterised by excessive and prolonged inflammation that is linked to poor progression of healing, and, in humans, the development of diabetic foot ulcers. However, the underlying mechanisms contributing to excessive inflammation remain poorly understood. Here we show in a murine model that the diabetic environment induces stable intrinsic changes in haematopoietic cells. These changes lead to a hyper-responsive phenotype to both pro-inflammatory and anti-inflammatory stimuli, producing extreme M1 and M2 polarised cells. During early wound healing, myeloid cells in diabetic mice show hyper-polarisation towards both M1 and M2 phenotypes, whereas, at late stages of healing, when non-diabetic macrophages have transitioned to an M2 phenotype, diabetic wound macrophages continue to display an M1 phenotype. Intriguingly, we show that this population predominantly consists of Gr-1+ CD11b+ CD14+ cells that have been previously reported as 'inflammatory macrophages' recruited to injured tissue in the early stages of wound healing. Finally, we show that this phenomenon is directly relevant to human diabetic ulcers, for which M2 polarisation predicts healing outcome. Thus, treatments focused at targeting this inflammatory cell subset could prove beneficial for pathological tissue repair. more...

Chronic nonhealing wounds in the elderly population are associated with a prolonged and excessive inflammatory response, which is widely hypothesized to impede healing. Previous studies have linked alterations in local L-arginine metabolism, principally mediated by the enzymes arginase (Arg) and inducible nitric oxide synthase (iNOS), to pathological wound healing. Over subsequent years, interest in Arg/iNOS has focused on the classical versus alternatively activated (M1/M2) macrophage paradigm. Although the role of iNOS during healing has been studied, Arg contribution to healing remains unclear. Here, we report that Arg is dynamically regulated during acute wound healing. Pharmacological inhibition of local Arg activity directly perturbed healing, as did Tie2-cre-mediated deletion of Arg1, revealing the importance of Arg1 during healing. Inhibition or depletion of Arg did not alter alternatively activated macrophage numbers but instead was associated with increased inflammation, including increased influx of iNOS(+) cells and defects in matrix deposition. Finally, we reveal that in preclinical murine models reduced Arg expression directly correlates with delayed healing, and as such may represent an important future therapeutic target. more...

Estrogen deprivation is associated with delayed healing, while Hormone Replacement Therapy (HRT) accelerates acute wound healing and protects against development of chronic wounds. Estrogen exerts its effects on healing via numerous cell types by signalling through the receptors ERα and ERβ, which bind to the Estrogen Responsive Element (ERE) and initiate gene transcription. The ERE–luciferase transgenic mouse model has been influential in assessing real-time in vivo estrogen receptor activation across a range of tissues and pathologies. Using this model we demonstrate novel temporally regulated peri-wound activation of estrogen signalling in female mice. Using histological methods we reveal that this signal is specifically localised to keratinocytes of the neoepidermis and wound margin dermal cells. Moreover using pharmacological agonists we reveal that ERβ induces ERE-mediated signal in both epidermal and dermal cells while ERα induces ERE-mediated signal in dermal cells alone. Collectively these novel data demonstrate rapid and regional activation of estrogen signalling in wounded skin. A more complete understanding of local hormonal signalling during repair is essential for the focussed development of new therapies for wound healing. more...