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.

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.

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.

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.

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.

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.

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.

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.

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.

Principal component analysis and brain-based predictors of emotion regulation in anxiety and depression.

BACKGROUND: Reappraisal, an adaptive emotion regulation strategy, is associated with frontal engagement. In internalizing psychopathologies (IPs) such as anxiety and depression frontal activity is atypically reduced suggesting impaired regulation capacity. Yet, successful reappraisal is often demonstrated at the behavioral level. A data-driven approach was used to clarify brain and behavioral relationships in IPs. METHODS: During functional magnetic resonance imaging, anxious [general anxiety disorder (n = 43), social anxiety disorder (n = 72)] and depressed (n = 47) patients reappraised negative images to reduce negative affect ('ReappNeg') and viewed negative images ('LookNeg'). After each trial, the affective state was reported. A cut-point (i.e. values <0 based on ΔReappNeg-LookNeg) demarcated successful reappraisers. Neural activity for ReappNeg-LookNeg, derived from 37 regions of interest, was submitted to Principal Component Analysis (PCA) to identify unique components of reappraisal-related brain response. PCA factors, symptom severity, and self-reported habitual reappraisal were submitted to discriminant function analysis and linear regression to examine whether these data predicted successful reappraisal (yes/no) and variance in reappraisal ability. RESULTS: Most patients (63%) were successful reappraisers according to the behavioral criterion (values<0; ΔReappNeg-LookNeg). Discriminant function analysis was not significant for PCA factors, symptoms, or habitual reappraisal. For regression, more activation in a factor with high loadings for frontal regions predicted better reappraisal facility. Results were not significant for other variables. CONCLUSIONS: At the individual level, more activation in a 'frontal' factor corresponded with better reappraisal facility. However, neither brain nor behavioral variables classified successful reappraisal (yes/no). Findings suggest individual differences in regions strongly implicated in reappraisal play a role in on-line reappraisal capability.

Innate immunity in the postmortem brain of depressed and suicide subjects: Role of Toll-like receptors.

Abnormalities of Toll-like receptors (TLRs) have been implicated in the pathophysiology of depression and suicide. Interactions of TLRs with pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) initiate signaling through myeloid differentiation primary response-88 (MyD88) and produce cytokines through the activation of the transcription factor nuclear factor kappa beta (NF-kB). We have earlier shown an increase in the protein and mRNA expression of TLR3 and TLR4 in the prefrontal cortex (PFC) of depressed suicide (DS) subjects compared with normal control (NC) subjects. To examine if other TLRs are altered in postmortem brain, we have now determined the protein and mRNA expression of other TLRs (TLR1, TLR2, TLR5, TLR6, TLR7, TLR8, TLR9 and TLR10) in the PFC of DS, depressed non-suicide (DNS), non-depressed suicide (NDS) and NC subjects. We determined the protein expression by Western blot and mRNA expression levels by real-time PCR (qPCR) in the PFC of 24 NC, 24 DS, 12 DNS and 11 NDS subjects. Combined with our previous study of TLR3 and TLR4, we found that the protein expression of TLR2, TLR3, TLR4, TLR6 and TLR10, and mRNA expression of TLR2 and TLR3 was significantly increased in the DS group compared with NC group. This study demonstrated that certain specific TLRs are altered in DS subjects, and hence those TLRs may be appropriate targets for the development of therapeutic agents for the treatment of suicidal behavior.

Developmental changes in resting-state functional networks among individuals with and without internalizing psychopathologies.

BACKGROUND: Three well-established intrinsic connectivity networks (ICNs) involved in cognitive-affective processing include the cognitive control network (CCN), default mode network (DMN), and salience and emotional network (SEN). Despite recent advances in understanding developmental changes in these ICNs, the majority of research has focused on single seeds or networks in isolation with limited age ranges. Additionally, although internalizing psychopathologies (IPs), such as anxiety and depression, are often characterized by maladaptive cognitive-affective processing styles, it is not clear how IP history influences age-related changes in brain networks. METHOD: The current study aimed to characterize the normative development of the CCN, DMN, and SEN across a large age-span (7-29 year olds) of typically developing (TD) individuals (n = 97). We also explore how age may impact differences in network connectivity between TD individuals and patients with IPs (n = 136). RESULTS: Among TD individuals, DMN and CCN connectivity strengthened with age, whereas connectivity between the SEN and ventromedial prefrontal cortex weakened across development. When exploring group (IP vs. TD) differences, the IP group was characterized by greater connectivity between the CCN and cerebellum and between the SEN and caudate from childhood to early adulthood, relative to TD individuals. In addition, patients with IPs, versus TD individuals, exhibited reduced connectivity between the SEN and medial frontal gyrus from adolescence to adulthood. CONCLUSIONS: The current findings shed light on differential age-related changes in brain network patterns among psychiatrically free, TD individuals and those with internalizing disorders, and may provide plausible targets for novel mechanism-based treatments that differ based on developmental stage.

Abnormal protein and mRNA expression of inflammatory cytokines in the prefrontal cortex of depressed individuals who died by suicide

Background: Depression and stress are major risk factors for suicidal behaviour, and some studies show abnormalities of proinflammatory cytokines in the serum and cerebrospinal fluid (CSF) of depressed and suicidal patients. However, it is not clear if similar abnormalities of cytokines are present in the brain of suicidal and depressed patients. Methods: We therefore determined the mRNA (using realtime polymerase chain reaction) and protein (using enzyme-linked immunosorbent assay and Western Blot) expression levels of interleukin (IL)-1ß, IL-6, tumour necrosis factor (TNF)-α, lymphotoxin A, lymphotoxin B, IL-8, IL-10 and IL-13 in the prefrontal cortex (PFC) obtained from 24 depressed individuals who died by suicide and 24 nonpsychiatric controls. Results: We observed that the mRNA and protein levels of IL-1ß, IL-6, TNF-α, and lymphotoxin A were significantly increased, and levels of anti-inflammatory cytokine IL-10, and of IL-1 receptor antagonist (IL-1RA) were significantly decreased in the PFC of depressed individuals who died by suicide compared with controls. There were no significant differences in the protein and mRNA levels of IL-8 and IL-13 in the PFC. Limitations: The main limitation of this study is that some of the suicide group had been taking antidepressant medication at the time of death. Conclusion: Our results suggest that alterations of cytokines may be associated with the pathophysiology of depressed suicide and there may be an imbalance between pro- and anti-inflammatory cytokines in people who die by suicide. The causes of these increases in the brain of people who die by suicide, therefore, need to be investigated further.

Multidimensional prediction of treatment response to antidepressants with cognitive control and functional MRI.

Predicting treatment response for major depressive disorder can provide a tremendous benefit for our overstretched health care system by reducing number of treatments and time to remission, thereby decreasing morbidity. The present study used neural and performance predictors during a cognitive control task to predict treatment response (% change in Hamilton Depression Rating Scale pre- to post-treatment). Forty-nine individuals diagnosed with major depressive disorder were enrolled with intent to treat in the open-label study; 36 completed treatment, had useable data, and were included in most data analyses. Participants included in the data analysis sample received treatment with escitalopram (n = 22) or duloxetine (n = 14) for 10 weeks. Functional MRI and performance during a Parametric Go/No-go test were used to predict per cent reduction in Hamilton Depression Rating Scale scores after treatment. Haemodynamic response function-based contrasts and task-related independent components analysis (subset of sample: n = 29) were predictors. Independent components analysis component beta weights and haemodynamic response function modelling activation during Commission errors in the rostral and dorsal anterior cingulate, mid-cingulate, dorsomedial prefrontal cortex, and lateral orbital frontal cortex predicted treatment response. In addition, more commission errors on the task predicted better treatment response. Together in a regression model, independent component analysis, haemodynamic response function-modelled, and performance measures predicted treatment response with 90% accuracy (compared to 74% accuracy with clinical features alone), with 84% accuracy in 5-fold, leave-one-out cross-validation. Convergence between performance markers and functional magnetic resonance imaging, including novel independent component analysis techniques, achieved high accuracy in prediction of treatment response for major depressive disorder. The strong link to a task paradigm provided by use of independent component analysis is a potential breakthrough that can inform ways in which prediction models can be integrated for use in clinical and experimental medicine studies.

The Expression of the Suicide-Associated Gene SKA2 Is Decreased in the Prefrontal Cortex of Suicide Victims but Not of Nonsuicidal Patients.

BACKGROUND: Recent study of genome-wide DNA methylation profiling in the postmortem brain of suicidal and nonsuicidal subjects found that gene expression of spindle and kinetochore associated complex subunit 2 (SKA2) is decreased in the postmortem brain of suicide victims compared with nonsuicidal, nonpsychiatric control subjects. METHODS: To determine if decreased SKA2 is specific to suicide and independent of diagnosis, we determined gene and protein expression of SKA2 in the prefrontal cortex obtained from suicide victims (n= 52), nonsuicidal psychiatric subjects (n= 27), and normal controls (n= 24). We determined gene expression by quantitative PCR technique and protein expression by Western blot. The postmortem brain samples were obtained from the Maryland Psychiatric Research Center. RESULTS: We found that protein and gene expression of SKA2 was significantly reduced in the prefrontal cortex of suicide victims compared with normal control subjects and nonsuicidal patients. We also found that SKA2 protein and gene expression in depressed suicide victims, schizophrenic suicide victims, and suicide victims with substance abuse and/or conduct disorders was significantly decreased compared with normal control subjects and also with nonsuicidal depressed or schizophrenic subjects. CONCLUSIONS: This study shows that decreased gene and protein expression of SKA2 observed in the prefrontal cortex of suicide victims is specific to suicide, which was not observed in the brain of nonsuicidal patients. It also indicates reduced SKA2 expression in suicide is independent of psychiatric diagnosis, since it is observed in all diagnostic groups studied. Therefore, SKA2 may be a potential biomarker for suicide.

Detection and prediction limits for identifying highly confusable drug names from experimental data.

Confusions between drug names that look and sound alike are common, costly, harmful, and difficult to prevent. One prevention strategy is to screen proposed new drug names for confusability before approving them. Widespread acceptance of preapproval tests of confusability is compromised by the lack of experimental designs and statistical methods to support valid inferences about whether a proposed new name is unacceptably confusing. One way of identifying confusing names is to conduct memory and perception experiments on a set of drug names which would include both the new name and a set of control names (e.g., names already on the market). The experiment would yield an observed error rate for every name. Inferences about the acceptability of the new name can be made by comparing the error rate of the new name to the distribution of error rates of the control names. We describe four memory and perception experiments on drug names, carried out using clinicians as participants. Each experiment included drug names designated as test and control names. We demonstrate how to use a combination of logistic regression, Poisson prediction limits, and highly assured credible intervals to identify and apply a threshold for identifying unacceptably confusing names. Our models show an excellent fit to the data. These experimental designs and analytic methods should be useful in the preapproval testing of proposed new drug names and in similar regulatory scenarios where it is necessary to draw inferences about the comparative safety or effectiveness of new vs. old products.

Sample size determination for longitudinal designs with binary response.

In this article, we develop appropriate statistical methods for determining the required sample size while comparing the efficacy of an intervention to a control with repeated binary response outcomes. Our proposed methodology incorporates the complexity of the hierarchical nature of underlying designs and provides solutions when varying attrition rates are present over time. We explore how the between-subject variability and attrition rates jointly influence the computation of sample size formula. Our procedure also shows how efficient estimation methods play a crucial role in power analysis. A practical guideline is provided when information regarding individual variance component is unavailable. The validity of our methods is established by extensive simulation studies. Results are illustrated with the help of two randomized clinical trials in the areas of contraception and insomnia.

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.

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.