Increased reproductive tract infections among secondary school girls during the COVID-19 pandemic: associations with pandemic related stress, mental health, and domestic safety.

Background: Kenya, like many countries, shuttered schools during COVID-19, with subsequent increases in poor mental health, sexual activity, and pregnancy. We sought to understand how the COVID-19 pandemic may mediate risk of reproductive tract infections. We hypothesized that greater COVID-19 related stress would mediate risk via mental health, feeling safe inside the home, and sexual exposure, given the pandemic mitigation-related impacts of school closures on these factors. Methods: We analyzed data from a cohort of 436 girls enrolled in secondary school in rural western Kenya. Baseline, 6-, 12-, and 18- month study visits occurred April 2018 - December 2019 (pre-COVID), and 30-, 36-, and 48- month study visits occurred September 2020 - July 2022 (COVID period). At study visits, participants self-completed a survey for sociodemographics and sexual practices, and provided self-collected vaginal swabs for Bacterial vaginosis (BV) testing, with STI testing at annual visits. COVID-related stress was measured with a standardized scale and dichotomized at highest quartile. Mixed effects modeling quantified how BV and STI changed over time, and longitudinal mediation analysis quantified how the relationship between COVID-19 stress and increased BV was mediated. Findings: BV and STI prevalence increased from 12.1% and 10.7% pre-COVID to 24.5% and 18.1% during COVID, respectively. This equated to a 26% (95% CI 1.00 - 1.59) and 36% (95% CI 0.98 - 1.88) increased relative prevalence of BV and STIs, respectively, in the COVID-19 period compared to pre-COVID, adjusted for numerous sociodemographic and behavioral factors. Higher COVID-related stress was associated with elevated depressive symptoms and feeling less safe inside the home, which were each associated with increased likelihood of having a boyfriend. In longitudinal mediation analyses, the direct effect of COVID-related stress on BV was small and non-significant, indicating increased BV was due to the constellation of factors that were impacted during the COVID-pandemic. Conclusions: In this cohort of adolescent girls, BV and STIs increased following COVID-related school closures. These results highlight modifiable factors to help maintain sexual and reproductive health resiliency, such as anticipating and mitigating mental health impacts, domestic safety concerns, and maintaining sexual health services to prevent and treat reproductive tract infections.

Vaginal Microbial Network Analysis Reveals Novel Taxa Relationships among Adolescent and Young Women with Incident Sexually Transmitted Infection Compared with Those Remaining Persistently Negative over a 30-Month Period.

A non-optimal vaginal microbiome (VMB) is typically diverse with a paucity of Lactobacillus crispatus and is often associated with bacterial vaginosis (BV) and sexually transmitted infections (STIs). Although compositional characterization of the VMB is well-characterized, especially for BV, knowledge remains limited on how different groups of bacteria relate to incident STIs, especially among adolescents. In this study, we compared the VMB (measured via 16S ribosomal RNA gene amplicon sequencing) of Kenyan secondary school girls with incident STIs (composite of chlamydia, gonorrhea, and trichomoniasis) to those who remained persistently negative for STIs and BV over 30 months of follow-up. We applied microbial network analysis to identify key taxa (i.e., those with the greatest connectedness in terms of linkages to other taxa), as measured by betweenness and eigenvector centralities, and sub-groups of clustered taxa. VMB networks of those who remained persistently negative reflected greater connectedness compared to the VMB from participants with STI. Taxa with the highest centralities were not correlated with relative abundance and differed between those with and without STI. Subject-level analyses indicated that sociodemographic (e.g., age and socioeconomic status) and behavioral (e.g., sexual activity) factors contribute to microbial network structure and may be of relevance when designing interventions to improve VMB health.

Analysis of bacterial vaginosis, the vaginal microbiome, and sexually transmitted infections following the provision of menstrual cups in Kenyan schools: Results of a nested study within a cluster randomized controlled trial.

BACKGROUND: Nonhygienic products for managing menstruation are reported to cause reproductive tract infections. Menstrual cups are a potential solution. We assessed whether menstrual cups would reduce bacterial vaginosis (BV), vaginal microbiome (VMB), and sexually transmitted infections (STIs) as studies have not evaluated this. METHODS AND FINDINGS: A cluster randomized controlled trial was performed in 96 Kenyan secondary schools, randomized (1:1:1:1) to control, menstrual cup, cash transfer, or menstrual cup plus cash transfer. This substudy assessing the impact of menstrual cups on BV, VMB, and STIs, included 6 schools from the control (3) and menstrual cup only (3) groups, both receiving BV and STI testing and treatment at each visit. Self-collected vaginal swabs were used to measure VMB (16S rRNA gene amplicon sequencing), BV (Nugent score), and STIs. STIs were a composite of Chlamydia trachomatis and Neisseria gonorrhoeae (nucleic acid amplification test) and Trichomonas vaginalis (rapid immunochromatographic assay). Participants were not masked and were followed for 30 months. The primary outcome was diagnosis of BV; secondary outcomes were VMB and STIs. Intention-to-treat blinded analyses used mixed effects generalized linear regressions, with random effects term for school. The study was conducted between May 2, 2018, and February 7, 2021. A total of 436 participants were included: 213 cup, 223 control. There were 289 BV diagnoses: 162 among control participants and 127 among intervention participants (odds ratio 0.76 [95% CI 0.59 to 0.98]; p = 0.038). The occurrence of Lactobacillus crispatus-dominated VMB was higher among cup group participants (odds ratio 1.37 [95% CI 1.06 to 1.75]), as was the mean relative abundance of L. crispatus (3.95% [95% CI 1.92 to 5.99]). There was no effect of intervention on STIs (relative risk 0.82 [95% CI 0.50 to 1.35]). The primary limitations of this study were insufficient power for subgroup analyses, and generalizability of findings to nonschool and other global settings. CONCLUSIONS: Menstrual cups with BV and STI testing and treatment benefitted adolescent schoolgirls through lower occurrence of BV and higher L. crispatus compared with only BV and STI testing and treatment during the 30 months of a cluster randomized menstrual cup intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT03051789.

Methylation and expression of glucocorticoid receptor exon-1 variants and FKBP5 in teenage suicide-completers.

A dysregulated hypothalamic-pituitary-adrenal (HPA) axis has repeatedly been demonstrated to play a fundamental role in psychiatric disorders and suicide, yet the mechanisms underlying this dysregulation are not clear. Decreased expression of the glucocorticoid receptor (GR) gene, which is also susceptible to epigenetic modulation, is a strong indicator of impaired HPA axis control. In the context of teenage suicide-completers, we have systematically analyzed the 5'UTR of the GR gene to determine the expression levels of all GR exon-1 transcript variants and their epigenetic state. We also measured the expression and the epigenetic state of the FK506-binding protein 51 (FKBP5/FKBP51), an important modulator of GR activity. Furthermore, steady-state DNA methylation levels depend upon the interplay between enzymes that promote DNA methylation and demethylation activities, thus we analyzed DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and growth arrest- and DNA-damage-inducible proteins (GADD45). Focusing on both the prefrontal cortex (PFC) and hippocampus, our results show decreased expression in specific GR exon-1 variants and a strong correlation of DNA methylation changes with gene expression in the PFC. FKBP5 expression is also increased in both areas suggesting a decreased GR sensitivity to cortisol binding. We also identified aberrant expression of DNA methylating and demethylating enzymes in both brain regions. These findings enhance our understanding of the complex transcriptional regulation of GR, providing evidence of epigenetically mediated reprogramming of the GR gene, which could lead to possible epigenetic influences that result in lasting modifications underlying an individual's overall HPA axis response and resilience to stress.

An Initial miRNA Profile of Persons With Persisting Neurobehavioral Impairments and States of Disordered Consciousness After Severe Traumatic Brain Injury.

OBJECTIVE: To examine the merits of using microRNAs (miRNAs) as biomarkers of disorders of consciousness (DoC) due to traumatic brain injury (TBI). SETTINGS: Acute and subacute beds. PARTICIPANTS: Patients remaining in vegetative and minimally conscious states (VS, MCS), an average of 1.5 years after TBI, and enrolled in a randomized clinical trial ( n = 6). Persons without a diagnosed central nervous system disorder, neurotypical controls ( n = 5). DESIGN: Comparison of whole blood miRNA profiles between patients and age/gender-matched controls. For patients, correlational analyses between miRNA profiles and measures of neurobehavioral function. MAIN MEASURES: Baseline measures of whole blood miRNAs isolated from the cellular and fluid components of blood and measured using miRNA-seq and real-time polymerase chain reaction (RT-PCR). Baseline neurobehavioral measures derived from 7 tests. RESULTS: For patients, relative to controls, 48 miRNA were significantly ( P < .05)/differentially expressed. Cluster analysis showed that neurotypical controls were most similar to each other and with 2 patients (VS: n = 1; and MCS: n = 1). Three patients, all in MCS, clustered separately. The only female in the sample, also in MCS, formed an independent group. For the 48 miRNAs, the enriched pathways identified are implicated in secondary brain damage and 26 miRNAs were significantly ( P < .05) correlated with measures of neurobehavioral function. CONCLUSIONS: Patients remaining in states of DoC an average of 1.5 years after TBI showed a different and reproducible pattern of miRNA expression relative to age/gender-matched neurotypical controls. The phenotypes, defined by miRNA profiles relative to persisting neurobehavioral impairments, provide the basis for future research to determine the miRNA profiles differentiating states of DoC and the basis for future research using miRNA to detect treatment effects, predict treatment responsiveness, and developing targeted interventions. If future research confirms and advances reported findings, then miRNA profiles will provide the foundation for patient-centric DoC neurorehabilitation.

Utilizing Random Effects Machine Learning Algorithms for Identifying Vulnerability to Depression.

Background: Reliable prediction of clinical progression over time can improve the outcomes of depression. Little work has been done integrating various risk factors for depression, to determine the combinations of factors with the greatest utility for identifying which individuals are at the greatest risk. Materials and methods: This study demonstrates that data-driven Machine Learning (ML) methods such as Random Effects/Expectation Maximization (RE-EM) trees and Mixed Effects Random Forest (MERF) can be applied to reliably identify variables that have the greatest utility for classifying subgroups at greatest risk for depression. 185 young adults completed measures of depression risk, including rumination, worry, negative cognitive styles, cognitive and coping flexibilities and negative life events, along with symptoms of depression. We trained RE-EM trees and MERF algorithms and compared them to traditional Linear Mixed Models (LMMs) predicting depressive symptoms prospectively and concurrently with cross-validation. Results: Our results indicated that the RE-EM tree and MERF methods model complex interactions, identify subgroups of individuals and predict depression severity comparable to LMM. Further, machine learning models determined that brooding, negative life events, negative cognitive styles, and perceived control were the most relevant predictors of future depression levels. Conclusion: Random effects machine learning models have the potential for high clinical utility and can be leveraged for interventions to reduce vulnerability to depression.

Sexually Transmitted Disease-Related Reddit Posts During the COVID-19 Pandemic: Latent Dirichlet Allocation Analysis.

BACKGROUND: Sexually transmitted diseases (STDs) are common and costly, impacting approximately 1 in 5 people annually. Reddit, the sixth most used internet site in the world, is a user-generated social media discussion platform that may be useful in monitoring discussion about STD symptoms and exposure. OBJECTIVE: This study sought to define and identify patterns and insights into STD-related discussions on Reddit over the course of the COVID-19 pandemic. METHODS: We extracted posts from Reddit from March 2019 through July 2021. We used a topic modeling method, Latent Dirichlet Allocation, to identify the most common topics discussed in the Reddit posts. We then used word clouds, qualitative topic labeling, and spline regression to characterize the content and distribution of the topics observed. RESULTS: Our extraction resulted in 24,311 total posts. Latent Dirichlet Allocation topic modeling showed that with 8 topics for each time period, we achieved high coherence values (pre-COVID-19=0.41, prevaccination=0.42, and postvaccination=0.44). Although most topic categories remained the same over time, the relative proportion of topics changed and new topics emerged. Spline regression revealed that some key terms had variability in the percentage of posts that coincided with pre-COVID-19 and post-COVID-19 periods, whereas others were uniform across the study periods. CONCLUSIONS: Our study's use of Reddit is a novel way to gain insights into STD symptoms experienced, potential exposures, testing decisions, common questions, and behavior patterns (eg, during lockdown periods). For example, reduction in STD screening may result in observed negative health outcomes due to missed cases, which also impacts onward transmission. As Reddit use is anonymous, users may discuss sensitive topics with greater detail and more freely than in clinical encounters. Data from anonymous Reddit posts may be leveraged to enhance the understanding of the distribution of disease and need for targeted outreach or screening programs. This study provides evidence in favor of establishing Reddit as having feasibility and utility to enhance the understanding of sexual behaviors, STD experiences, and needed health engagement with the public.

Anterior cingulate cortex activation during attentional control as a transdiagnostic marker of psychotherapy response: a randomized clinical trial.

Anterior cingulate cortex (ACC) response during attentional control in the context of task-irrelevant emotional faces is a promising biomarker of cognitive behavioral therapy (CBT) outcome in patients with social anxiety disorder (SAD). However, it is unclear whether this biomarker extends to major depressive disorder (MDD) and is specific to CBT outcome. In the current study, 72 unmedicated patients with SAD (n = 39) or MDD (n = 33) completed a validated emotional interference paradigm during functional magnetic resonance imaging before treatment. Participants viewed letter strings superimposed on task-irrelevant threat and neutral faces under low perceptual load (high interference) and high perceptual load (low interference). Biomarkers comprised anatomy-based rostral ACC (rACC) and dorsal ACC (dACC) response to task-irrelevant threat (>neutral) faces under low and high perceptual load. Patients were randomly assigned to 12 weeks of CBT or supportive therapy (ST) (ClinicalTrials.gov identifier: NCT03175068). Clinician-administered measures of social anxiety and depression severity were obtained at baseline and every 2 weeks throughout treatment (7 assessments total) by an assessor blinded to the treatment arm. A composite symptom severity score was submitted to latent growth curve models. Results showed more baseline rACC activity to task-irrelevant threat>neutral faces under low, but not high, perceptual load predicted steeper trajectories of symptom improvement throughout CBT or ST. Post-hoc analyses indicated this effect was driven by subgenual ACC (sgACC) activation. Findings indicate ACC activity during attentional control may be a transdiagnostic neural predictor of general psychotherapy outcome.

Brain response to emotional faces in anxiety and depression: neural predictors of cognitive behavioral therapy outcome and predictor-based subgroups following therapy.

BACKGROUND: Neuroimaging studies have shown variance in brain response to emotional faces predicts cognitive behavioral therapy (CBT) outcome. An important next step is to determine if individual differences in neural predictors of CBT response represent distinct patient groups. METHODS: In total, 90 patients with internalizing disorders completed a face-matching task during functional magnetic resonance imaging before and after 12 weeks of CBT and 45 healthy controls completed the task before and after 12 weeks. Patients exhibiting a pre-to-post CBT >50% reduction in symptom severity on two measures were considered treatment responders. Regions of interest (ROIs) for angry, fearful, and happy faces were submitted to receiver operating characteristic (ROC) curve analysis. Significant ROIs were then submitted to decision tree analysis to classify responder/non-responder subgroups. Psychophysiological interactions (PPI) were used to explore functional connectivity in the region(s) that delineated subgroups. RESULTS: A total of 51 patients were treatment responders and ROC curve results were significant for all face types though specific regions varied. Decision tree results revealed superior occipital response to angry faces identified patient subgroups such that the subgroup with 'high' occipital activity had more responders than the 'low' occipital subgroup. Following CBT, the high, relative to low, occipital subgroup was less symptomatic. Controls exhibited stable superior occipital activation over time. Whole-brain PPI showed reduced baseline superior occipital-postcentral gyrus functional connectivity in responders compared to non-responders. CONCLUSIONS: Preliminary findings indicate patients characterized by relatively more pre-treatment superior occipital gyrus engagement to angry faces and reduced superior occipital-postcentral gyrus connectivity, relative to non-responders, may represent a phenotype likely to benefit from CBT.

A novel peripheral biomarker for depression and antidepressant response.

In contrast to healthy controls, the heterotrimeric G protein, Gsalpha (Gsα) is ensconced predominantly in lipid rafts in subjects with major depressive disorder (MDD) resulting in impaired stimulation of adenylyl cyclase. In this small proof-of-concept study, we examined the hypothesis that translocation of Gsα from lipid rafts toward a more facile activation of adenylyl cyclase is a biomarker for clinical response to antidepressants. There were 49 subjects with MDD (HamD17 score ≥15) and 59 healthy controls at the screen visit. The AlphaScreen (PerkinElmer) assay measured both basal activity and prostaglandin E1 (PGE1) stimulation of Gsα-adenylyl cyclase to assess the extent of coupling of Gsα with adenylyl cyclase. At screen, platelet samples obtained from MDD subjects revealed significantly lower PGE1 activation of adenylyl cyclase activity than controls (p = 0.02). Subsequently, 19 consenting MDD subjects completed a 6-week open label antidepressant treatment trial. The 11 antidepressant responders (HamD17 improvement ≥50% from screen) revealed significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders (p = 0.05) with an effect size of 0.83 for the PGE1/Gsα lipid-raft biomarker. PGE1 stimulation increased by ≥30% from screen assessment in eight responders (72.7%) and two non-responders (25.0%) [Fisher exact = 0.07] with a positive predictive value for response of 80.0%. In this small, pilot study, increased PGE1 stimulated adenylyl cyclase was associated with antidepressant response in MDD subjects. These data suggest that a simple, high-throughput-capable assay for depression and antidepressant response can be developed. Future studies are needed to evaluate the utility of this biomarker for the treatment of MDD.

High Prevalence of Lactobacillus crispatus Dominated Vaginal Microbiome Among Kenyan Secondary School Girls: Negative Effects of Poor Quality Menstrual Hygiene Management and Sexual Activity.

The vaginal microbiome (VMB) impacts numerous health outcomes, but evaluation among adolescents is limited. We characterized the VMB via 16S rRNA gene amplicon sequencing, and its association with Bacterial vaginosis (BV) and sexually transmitted infections (STIs; chlamydia, gonorrhea, trichomoniasis) among 436 schoolgirls in Kenya, median age 16.9 years. BV and STI prevalence was 11.2% and 9.9%, respectively, with 17.6% of girls having any reproductive tract infection. Three community state types (CST) accounted for 95% of observations: CST-I L.crispatus-dominant (N=178, BV 0%, STI 2.8%, sexually active 21%); CST-III L.iners-dominant (N=152, BV 3.3%, STI 9.7%, sexually active 35%); CST-IV G.vaginalis-dominant (N=83, BV 51.8%, STI 25.3%, sexually active 43%). In multivariable adjusted analyses, sexually active girls had increased odds of CST-III and CST-IV, and use of cloth to manage menses had 1.72-fold increased odds of CST-IV vs. CST-I. The predominance of L.crispatus-dominated VMB, substantially higher than observed in prior studies of young adult and adult women in sub-Saharan Africa, indicates that non-optimal VMB can be an acquired state. Interventions to maintain or re-constitute L.crispatus dominance should be considered even in adolescents.

Chemokines gene expression in the prefrontal cortex of depressed suicide victims and normal control subjects.

Abnormalities of neuroinflammation have been implicated in the pathogenesis of depression and suicide. This is primarily based on the observation that cytokines, which are major inflammatory molecules and play an important role in depression and suicide, are increased in both serum and in postmortem brain of depressed and suicidal subjects. Another class of immune mediators are chemokines which are primarily involved in chemotactic properties and trafficking of immune cells in the central nervous system (CNS). Chemokines also play an important role in CNS function. Whereas chemokines have been studied in the serum of depressed and suicidal patients, their role in brain of depressed or suicidal subjects is relatively unexplored. We studied the gene expression of several chemokines in the prefrontal cortex (PFC) obtained from depressed suicidal (DS) and normal control (NC) subjects. We determined the mRNA expression of several chemokines belonging to CXCL and CCL groups of chemokines using qPCR array technique and qPCR gene expression validation in 24 DS and 24 NC subjects. The postmortem brain samples were obtained from the Maryland Brain Collection. We found that the mRNA expression of chemokines CXCL1, CXCL2, CXCL3 and CCL2 was significantly decreased in the PFC of DS compared with NC subjects. No significant change was observed in CXCL5, CXCL6, CXCL10, CCL8 and CCL19 between DS and NC subjects. Since many of the chemokines are involved in mediating certain important CNS functions, such as neurotrophic effect, neurogenesis, anti-apoptotic growth factor release, modulation of synaptic transmission, brain development and neuronal loss, decreased levels of chemokines can reduce these functions which may be involved in the pathophysiology of depression.

After-School Programs and Children's Mental Health: Organizational Social Context, Program Quality, and Children's Social Behavior.

OBJECTIVE: The current study examined associations among organizational social context, after-school program (ASP) quality, and children's social behavior in a large urban park district. METHOD: Thirty-two park-based ASPs are included in the final sample, including 141 staff and 593 children. Staff reported on organizational culture (rigidity, proficiency, resistance) and climate (engagement, functionality, stress), and children's social skills and problem behaviors. Children and their parents reported on program quality indicators (e.g., activities, routines, relationships). Parents also completed a children's mental health screener. RESULTS: A series of Hierarchical Linear Models revealed that proficiency and stress were the only organizational predictors of program quality; associations between stress and program quality were moderated by program enrollment and aggregated children's mental health need. Higher child- and parent-perceived program quality related to fewer staff-reported problem behaviors, while overall higher enrollment and higher aggregated mental health need were associated with fewer staff-reported social skills. CONCLUSIONS: Data are informing ongoing efforts to improve organizational capacity of urban after-school programs to support children's positive social and behavior trajectories.

Nowcasting Sexually Transmitted Infections in Chicago: Predictive Modeling and Evaluation Study Using Google Trends.

BACKGROUND: Sexually transmitted infections (STIs) pose a significant public health challenge in the United States. Traditional surveillance systems are adversely affected by data quality issues, underreporting of cases, and reporting delays, resulting in missed prevention opportunities to respond to trends in disease prevalence. Search engine data can potentially facilitate an efficient and economical enhancement to surveillance reporting systems established for STIs. OBJECTIVE: We aimed to develop and train a predictive model using reported STI case data from Chicago, Illinois, and to investigate the model's predictive capacity, timeliness, and ability to target interventions to subpopulations using Google Trends data. METHODS: Deidentified STI case data for chlamydia, gonorrhea, and primary and secondary syphilis from 2011-2017 were obtained from the Chicago Department of Public Health. The data set included race/ethnicity, age, and birth sex. Google Correlate was used to identify the top 100 correlated search terms with "STD symptoms," and an autocrawler was established using Google Health Application Programming Interface to collect the search volume for each term. Elastic net regression was used to evaluate prediction accuracy, and cross-correlation analysis was used to identify timeliness of prediction. Subgroup elastic net regression analysis was performed for race, sex, and age. RESULTS: For gonorrhea and chlamydia, actual and predicted STI values correlated moderately in 2011 (chlamydia: r=0.65; gonorrhea: r=0.72) but correlated highly (chlamydia: r=0.90; gonorrhea: r=0.94) from 2012 to 2017. However, for primary and secondary syphilis, the high correlation was observed only for 2012 (r=0.79), 2013 (r=0.77), 2016 (0.80), and 2017 (r=0.84), with 2011, 2014, and 2015 showing moderate correlations (r=0.55-0.70). Model performance was the most accurate (highest correlation and lowest mean absolute error) for gonorrhea. Subgroup analyses improved model fit across disease and year. Regression models using search terms selected from the cross-correlation analysis improved the prediction accuracy and timeliness across diseases and years. CONCLUSIONS: Integrating nowcasting with Google Trends in surveillance activities can potentially enhance the prediction and timeliness of outbreak detection and response as well as target interventions to subpopulations. Future studies should prospectively examine the utility of Google Trends applied to STI surveillance and response.

Neural Connectivity Changes Facilitated by Familiar Auditory Sensory Training in Disordered Consciousness: A TBI Pilot Study.

For people with disordered consciousness (DoC) after traumatic brain injury (TBI), relationships between treatment-induced changes in neural connectivity and neurobehavioral recovery have not been explored. To begin building a body of evidence regarding the unique contributions of treatments to changes in neural network connectivity relative to neurobehavioral recovery, we conducted a pilot study to identify relationships meriting additional examination in future research. To address this objective, we examined previously unpublished neural connectivity data derived from a randomized clinical trial (RCT). We leveraged these data because treatment efficacy, in the RCT, was based on a comparison of a placebo control with a specific intervention, the familiar auditory sensory training (FAST) intervention, consisting of autobiographical auditory-linguistic stimuli. We selected a subgroup of RCT participants with high-quality imaging data (FAST n = 4 and placebo n = 4) to examine treatment-related changes in brain network connectivity and how and if these changes relate to neurobehavioral recovery. To discover promising relationships among the FAST intervention, changes in neural connectivity, and neurobehavioral recovery, we examined 26 brain regions and 19 white matter tracts associated with default mode, salience, attention, and language networks, as well as three neurobehavioral measures. Of the relationships discovered, the systematic filtering process yielded evidence supporting further investigation of the relationship among the FAST intervention, connectivity of the left inferior longitudinal fasciculus, and auditory-language skills. Evidence also suggests that future mechanistic research should focus on examining the possibility that the FAST supports connectivity changes by facilitating redistribution of brain resources. For a patient population with limited treatment options, the reported findings suggest that a simple, yet targeted, passive sensory stimulation treatment may have altered functional and structural connectivity. If replicated in future research, then these findings provide the foundation for characterizing the unique contributions of the FAST intervention and could inform development of new treatment strategies. For persons with severely damaged brain networks, this report represents a first step toward advancing understanding of the unique contributions of treatments to changing brain network connectivity and how these changes relate to neurobehavioral recovery for persons with DoC after TBI. Clinical Trial Registry: NCT00557076, The Efficacy of Familiar Voice Stimulation During Coma Recovery (http://www.clinicaltrials.gov).

A Pilot Trial Examining the Merits of Combining Amantadine and Repetitive Transcranial Magnetic Stimulation as an Intervention for Persons With Disordered Consciousness After TBI.

OBJECTIVE: Report pilot findings of neurobehavioral gains and network changes observed in persons with disordered consciousness (DoC) who received repetitive transcranial magnetic stimulation (rTMS) or amantadine (AMA), and then rTMS+AMA. PARTICIPANTS: Four persons with DoC 1 to 15 years after traumatic brain injury (TBI). DESIGN: Alternate treatment-order, within-subject, baseline-controlled trial. MAIN MEASURES: For group and individual neurobehavioral analyses, predetermined thresholds, based on mixed linear-effects models and conditional minimally detectable change, were used to define meaningful neurobehavioral change for the Disorders of Consciousness Scale-25 (DOCS) total and Auditory-Language measures. Resting-state functional connectivity (rsFC) of the default mode and 6 other networks was examined. RESULTS: Meaningful gains in DOCS total measures were observed for 75% of treatment segments and auditory-language gains were observed after rTMS, which doubled when rTMS preceded rTMS+AMA. Neurobehavioral changes were reflected in rsFC for language, salience, and sensorimotor networks. Between networks interactions were modulated, globally, after all treatments. CONCLUSIONS: For persons with DoC 1 to 15 years after TBI, meaningful neurobehavioral gains were observed after provision of rTMS, AMA, and rTMS+AMA. Sequencing and combining of treatments to modulate broad-scale neural activity, via differing mechanisms, merits investigation in a future study powered to determine efficacy of this approach to enabling neurobehavioral recovery.

The Microbiome Composition of a Man's Penis Predicts Incident Bacterial Vaginosis in His Female Sex Partner With High Accuracy.

Background: We determined the predictive accuracy of penile bacteria for incident BV in female sex partners. In this prospective cohort, we enrolled Kenyan men aged 18-35 and their female sex partners aged 16 and older. We assessed BV at baseline, 1, 6, and 12 months. Incident BV was defined as a Nugent score of 7-10 at a follow-up visit, following a Nugent score of 0-6 at baseline. Amplification of the V3-V4 region of the bacterial 16S rRNA gene was performed on meatal and glans/coronal sulcus swab samples. Majority vote classifier combined the decisions of three machine learning classification algorithms (Random Forest, Support Vector Machine, K Nearest Neighbor). We report the estimate cross-validation predictive accuracy for incident BV based on baseline penile taxa. Results: The incidence of BV was 31% among 168 couples in which the woman did not have BV at baseline: 37.3% if the man was uncircumcised vs. 26.3% if the man was circumcised. Incident BV occurred at 1 month (n = 23), 6 months (n = 20), 12 months (n = 9). The predictive capacity of meatal taxa was high: sensitivity (80.7%), specificity (74.6%), accuracy (77.5%), area under the curve (88.8%). Variable importance ranking identified meatal taxa that in the vagina are associated with BV: Parvimonas, Lactobacillus iners, L. crispatus, Dialister, Sneathia sanguinegens, and Gardnerella vaginalis were among the top 10 most predictive taxa. The accuracy of glans/coronal sulcus taxa to predict incident BV was comparable to meatal taxa accuracy, but with greater variability. Conclusions: Baseline penile microbiota accurately predicted BV incidence in women who did not have BV at baseline, with more than half of incident infections observed at 6- to 12- months after penile microbiome assessment. These results suggest interventions to manipulate the penile microbiome may reduce BV incidence in sex partners, and that potential treatment (antibiotic or live biotherapeutic) will need to be effective in reducing or altering bacteria at both the glans/coronal sulcus and urethral sites (as represented by the meatus). The temporal association clarifies that concordance of penile microbiome with the vaginal microbiome of sex partners is not merely reflecting the vaginal microbiome, but can contribute to it.

Membrane-Associated α-Tubulin Is Less Acetylated in Postmortem Prefrontal Cortex from Depressed Subjects Relative to Controls: Cytoskeletal Dynamics, HDAC6, and Depression.

Cytoskeletal proteins and post-translational modifications play a role in mood disorders. Post-translational modifications of tubulin also alter microtubule dynamics. Furthermore, tubulin interacts closely with Gαs, the G-protein responsible for activation of adenylyl cyclase. Postmortem tissue derived from depressed suicide brain showed increased Gαs in lipid-raft domains compared with normal subjects. Gαs, when ensconced in lipid rafts, couples less effectively with adenylyl cyclase to produce cAMP, and this is reversed by antidepressant treatment. A recent in vitro study demonstrated that tubulin anchors Gαs to lipid rafts and that increased tubulin acetylation (due to HDAC6 inhibition) and antidepressant treatment decreased the proportion of Gαs complexed with tubulin. This suggested that deacetylated-tubulin might be more prevalent in depression. This study examined tubulin acetylation in whole-tissue homogenate, plasma membrane, and lipid-raft membrane domains in tissue from normal control subjects, depressed suicides, and depressed nonsuicides (human males/females). While tissue homogenate showed no changes in tubulin acetylation between control, depressed suicides, and depressed nonsuicides, plasma membrane-associated tubulin showed significant decreases in acetylation from depressed suicides and depressed nonsuicides compared with controls. No change was seen in expression of the enzymes responsible for tubulin acetylation or deacetylation. These data suggest that, during depression, membrane-localized tubulin maintains a lower acetylation state, permitting increased sequestration of Gαs in lipid-raft domains, where it is less likely to couple to adenylyl cyclase for cAMP production. Thus, membrane tubulin may play a role in mood disorders, which could be exploited for diagnosis and treatment.SIGNIFICANCE STATEMENT There is little understanding about the molecular mechanisms involved in the development of depression and, in severe cases, suicide. Evidence for the role of microtubule modifications in progression of depressive disorders is emerging. These postmortem data provide strong evidence for membrane tubulin modification leading to reduced efficacy of the G protein, Gαs, in depression. This study reveals a direct link between decreased tubulin acetylation in human depression and the increased localization of Gαs in lipid-raft domains responsible for attenuated cAMP signaling. The evidence presented here suggest a novel diagnostic and therapeutic locus for depression.

Using resting-state intrinsic network connectivity to identify suicide risk in mood disorders.

BACKGROUND: Little is known about the neural substrates of suicide risk in mood disorders. Improving the identification of biomarkers of suicide risk, as indicated by a history of suicide-related behavior (SB), could lead to more targeted treatments to reduce risk. METHODS: Participants were 18 young adults with a mood disorder with a history of SB (as indicated by endorsing a past suicide attempt), 60 with a mood disorder with a history of suicidal ideation (SI) but not SB, 52 with a mood disorder with no history of SI or SB (MD), and 82 healthy comparison participants (HC). Resting-state functional connectivity within and between intrinsic neural networks, including cognitive control network (CCN), salience and emotion network (SEN), and default mode network (DMN), was compared between groups. RESULTS: Several fronto-parietal regions (k > 57, p < 0.005) were identified in which individuals with SB demonstrated distinct patterns of connectivity within (in the CCN) and across networks (CCN-SEN and CCN-DMN). Connectivity with some of these same regions also distinguished the SB group when participants were re-scanned after 1-4 months. Extracted data defined SB group membership with good accuracy, sensitivity, and specificity (79-88%). CONCLUSIONS: These results suggest that individuals with a history of SB in the context of mood disorders may show reliably distinct patterns of intrinsic network connectivity, even when compared to those with mood disorders without SB. Resting-state fMRI is a promising tool for identifying subtypes of patients with mood disorders who may be at risk for suicidal behavior.

Developing Dimensional, Pandiagnostic Inhibitory Control Constructs With Self-Report and Neuropsychological Data.

Trait markers, or intermediate phenotypes linking different units of analysis (self-report, performance) from the Research Domain Criteria (RDoC) matrix across populations is a necessary step in identifying at-risk individuals. In the current study, 150 healthy controls (HC) and 456 individuals with bipolar disorder (BD) Type I or II, NOS (not otherwise specified) or Schizoaffective BD completed self-report neuropsychological tests of inhibitory control (IC) and executive functioning. Bifactor analyses were used to examine the factor structure of these measures and to evaluate for invariance across groups. Bifactor analyses found modest convergence of items from neuropsychological tests and self-report measures of IC among HC and BD. The factor scores showed evidence of a general IC construct (i.e., subdomain) across measures. Importantly, invariance testing indicated that the same construct was measured equally well across groups. Groups differed on the general factor for three of the four scales. Convergence on a general IC factor and invariance across diagnosis supports the use of combined dimensional measures to identify clinical risk and highlights how prospective RDoC studies might integrate units of analysis.