PHAGE Study: Effects of Supplemental Bacteriophage Intake on Inflammation and Gut Microbiota in Healthy Adults.

The gut microbiota is increasingly recognized as an important modulator of human health. As such, there is a growing need to identify effective means of selectively modifying gut microbial communities. Bacteriophages, which were briefly utilized as clinical antimicrobials in the early 20th century, present an opportunity to selectively reduce populations of undesirable microorganisms. However, whether intentional consumption of specific bacteriophages affects overall gut ecology is not yet known. Using a commercial cocktail of Escherichia coli-targeting bacteriophages, we examined their effects on gut microbiota and markers of intestinal and systemic inflammation in a healthy human population. In a double-blinded, placebo-controlled crossover trial, normal to overweight adults consumed bacteriophages for 28 days. Stool and blood samples were collected and used to examine inflammatory markers, lipid metabolism, and gut microbiota. Reductions in fecal E. coli loads were observed with phage consumption. However, there were no significant changes to alpha and beta diversity parameters, suggesting that consumed phages did not globally disrupt the microbiota. However, specific populations were altered in response to treatment, including increases in members of the butyrate-producing genera Eubacterium and a decreased proportion of taxa most closely related to Clostridium perfringens. Short-chain fatty acid production, inflammatory markers, and lipid metabolism were largely unaltered, but there was a small but significant decrease in circulating interleukin-4 (Il-4). Together, these data demonstrate the potential of bacteriophages to selectively reduce target organisms without global disruption of the gut community.

Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation.

BACKGROUND: Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure. METHODS: This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis. FINDINGS: avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%-9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6-19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable. INTERPRETATION: Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. FUND: National Institutes of Health.

Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis.

BACKGROUND: Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation. METHODS: We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs. RESULTS: Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels. CONCLUSION: Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

Interoceptive Deficits, Nonsuicidal Self-Injury, and Suicide Attempts Among Women with Eating Disorders.

People with eating disorders (EDs) have an elevated risk for both nonsuicidal self-injury (NSSI) and suicide compared to the general population. This study tests two theoretically derived models examining interoceptive deficits as a risk factor for NSSI, and examining interoceptive deficits, NSSI, fearlessness about death, and pain tolerance as risk factors for suicide. Ninety-six adult, treatment-seeking women with EDs completed self-report questionnaires at a single time point. Interoceptive deficits were significantly associated with NSSI, and NSSI was in turn associated with both pain tolerance and fearlessness about death. Further, pain tolerance was in turn associated with past suicide attempts, although fearlessness about death was not associated with suicide attempts. Interoceptive deficits had a direct association with fearlessness about death but not pain tolerance. Results regarding the relation between interoceptive deficits and suicide attempts were mixed, yet overall suggest that interoceptive deficits are related to suicide attempts largely indirectly, through the effects of mediating variables such as NSSI, fearlessness about death, and pain tolerance. Results suggest that interoceptive deficits and pain tolerance merit further investigation as potential risk factors for fatal and nonfatal self-harm among individuals with EDs.

Does the interpersonal-Psychological theory of suicide provide a useful framework for understanding suicide risk among eating disorder patients? A test of the validity of the IPTS.

OBJECTIVE: The current study tested whether the Interpersonal-Psychological Theory of Suicide (IPTS) provides a useful framework for understanding elevated suicide rates among individuals with eating disorders (EDs). METHOD: Based on predictions of the IPTS, we tested whether the combination of thwarted belongingness and perceived burdensomeness was associated with suicidal desire, and whether the combination of thwarted belongingness, perceived burdensomeness, and fearlessness about death was associated with past suicide attempts in an ED sample (n = 100). We also compared these IPTS constructs in an ED sample versus general psychiatric inpatients (n = 85) and college students (i.e., non-clinical comparison group; n = 93). RESULTS: Within the ED sample, no hypothesized interactions were found, but perceived burdensomeness was associated with suicidal desire, and perceived burdensomeness and fearlessness about death were associated with past suicide attempts. The ED and psychiatric samples had greater thwarted belongingness, perceived burdensomeness, and suicidal desire than the non-clinical comparison group. DISCUSSION: The IPTS constructs of perceived burdensomeness and fearlessness about death appear to explain some facets of suicidality among people with EDs, but overall, support for the IPTS was limited. Future research on EDs and suicidality should look beyond the IPTS and consider other biological and sociocultural factors for suicide. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:1082-1086).

Difficulties in emotion regulation in patients with eating disorders.

BACKGROUND: A defining characteristic of eating disorders (EDs) is difficulty with emotion regulation (ER). Previous research indicates that ED subtypes demonstrate differing ER difficulties. Specifically, individuals with Anorexia Nervosa (AN) or Bulimia Nervosa (BN) show greater impairment in their ability to regulate emotions in areas such as achieving goals while upset, reacting impulsively to distress, and effectively using coping strategies, as compared to those with Binge Eating Disorder (BED). However, limited research includes the diagnostic category of Eating Disorder, Not Otherwise Specified (EDNOS). The aim of this study was to better understand ER difficulties for all ED diagnoses, especially EDNOS. It was hypothesized that patients with EDs will demonstrate similar ER difficulties as psychiatric patients without EDs and that patients with EDNOS will be similar in their total level of ER difficulties but will differ in their specific types of difficulties in ER as compared to patients with other EDs. METHODS: Participants included 404 adults presenting to an inpatient psychiatric hospital. Psychiatric diagnoses, including EDs, were determined using the Structured Clinical Interview for DSM Disorders. Differences in specific and overall difficulties with ER were examined across psychiatric patients using the multidimensional Difficulties in Emotion Regulation Scale. RESULTS: Results of this study indicate that individuals with EDs have greater ER difficulties in most domains of ER and that those with BED and EDNOS demonstrate the most significant differences in ER as compared to psychiatric patients without EDs. Additionally, it was found that ED subtypes typically did not differ in terms of specific difficulties in ER. One exception emerged indicating that individuals with BED demonstrated significantly greater difficulty on the Limited Access to Emotion Regulation Strategies subscale as compared to those with EDNOS. CONCLUSIONS: Researchers were able to clarify difficulties in ER across ED diagnoses. Results highlight the importance of providing ER skills training for patients with EDs, particularly those with BED and EDNOS, and give insight into the specific areas of ER that may be important for these patients to focus on throughout recovery.

Associations between eating disorder symptoms and suicidal ideation through thwarted belongingness and perceived burdensomeness among eating disorder patients.

BACKGROUND: Suicidal ideation is relatively common among people with eating disorders (EDs). The Interpersonal-Psychological Theory of Suicide holds that suicidal ideation has two proximal causes: thwarted belongingness and perceived burdensomeness. It is unknown which ED symptoms are positively associated with suicidal ideation, and whether thwarted belongingness and perceived burdensomeness explain those associations. METHOD: We tested two parallel mediation models to determine whether current and lifetime ED symptoms were positively related to suicidal ideation through thwarted belongingness and perceived burdensomeness among ED patients (n=98), controlling for current depression. In each model, ED symptoms and depression were predictors, thwarted belongingness and perceived burdensomeness were mediators, and suicidal ideation was the outcome. RESULTS: The first model included current symptoms; current body dissatisfaction (ab=0.04, 95% CI [0.01, 0.06]) and fasting (ab=0.12, 95% CI [0.01, 0.22]) were indirectly related to increased suicidal ideation through higher burdensomeness, controlling for depression. The second model included lifetime symptoms; lifetime fasting (ab=0.18, 95% CI [0.07, 0.29]) was indirectly related to increased suicidal ideation through higher burdensomeness, controlling for depression. LIMITATIONS: The sample size prevented the use of latent variables for thwarted belongingness and perceived burdensomeness, and the cross-sectional data prevented testing for bidirectional relations among ED symptoms, thwarted belongingness, perceived burdensomeness, and suicidal ideation. CONCLUSIONS: Results underscore the importance of exploring transdiagnostic ED symptoms, including body dissatisfaction and fasting in particular, that may intensify burdensomeness and thereby contribute to suicidal ideation over and above depressive symptoms in this high-risk population.

Increased prevalence of vegetarianism among women with eating pathology.

OBJECTIVE: Prior research has established a link between vegetarianism and disordered eating but has typically sampled vegetarians. This study examined prevalence of and variables related to vegetarianism in three samples with varying severity of eating pathology. METHOD: Sample 1 consisted of female undergraduates who denied history of or current disordered eating (i.e., nonclinical; n=73), or engaged in disordered eating over past month (i.e., subclinical; n=136). Sample 2 included 69 female patients receiving residential treatment at an eating disorder center (i.e., clinical sample). Differences between groups were analyzed using Fisher's exact test. RESULTS: The prevalence of lifetime vegetarianism was lowest in the nonclinical group (6.80%) and highest in the clinical group (34.80%), with the subclinical group falling in between (17.60%). According to Fisher's exact test, all pairwise comparisons between groups were statistically significant (p's<.05). Regarding current vegetarian status, the clinical group was more likely (11.10%) than both other groups to self-identify as current vegetarians. DISCUSSION: Endorsement of vegetarianism was highest among females with severe eating pathology. Future research should use longitudinal data to examine the temporal relationship between these variables, or other underlying factors that may contribute to the co-occurrence of eating pathology and vegetarianism. Clinically, endorsement of vegetarianism may also be an important variable to consider in treatment disordered eating.

Evaluation of benzoic acid derivatives as sirtuin inhibitors.

Employing a genetically modified yeast strain as a screening tool, 4-dimethylaminobenzoic acid (5) was isolated from the marine sediment-derived Streptomyces sp. CP27-53 as a weak yeast sirtuin (Sir2p) inhibitor. Using this compound as a scaffold, a series of disubstituted benzene derivatives were evaluated to elucidate the structure activity relationships for Sir2p inhibition. The results suggested that 4-alkyl or 4-alkylaminobenzoic acid is the key structure motif for Sir2p inhibitory activity. The most potent Sir2p inhibitor, 4-tert-butylbenzoic acid (20), among the tested compounds in this study turned out to be a weak but selective SIRT1 inhibitor. The calculated binding free energies between the selected compounds and the catalytic domain of SIRT1 were well correlated to their measured SIRT1 inhibitory activities.

Peer selection and socialization in adolescent depression: the role of school transitions.

Previous studies have indicated homophily in depressive symptoms among adolescent friends, resulting from both peer selection and socialization processes. However, developmental differences and the role of school transitions in these processes have not been elucidated. A sample of 367 (51% female) adolescents was followed from 6th to 11th grade to investigate prospective relationships between adolescents' and their friends' depressive symptoms in middle school and in high school. Results revealed that students selected friends with similar levels of depressive symptoms after each school transition. Additionally, friends appeared to socialize adolescents to become more similar in depressive affect in late middle school years. These findings suggest normative selection effects after school transitions, followed by socialization effects in middle school, but not high school.