Bipolar depression remains difficult to treat, and people often experience ongoing residual symptoms, decreased functioning and impaired quality of life. Adjunctive therapies targeting novel pathways can provide wider treatment options and improve clinical outcomes. Garcinia mangostana Linn. (mangosteen) pericarp has serotonogenic, antioxidant anti-inflammatory and neurogenic properties of relevance to the mechanisms of bipolar depression.

The current 28-week randomised, multisite, double-blind, placebo-controlled trial investigated mangosteen pericarp extract as an adjunct to treatment-as-usual for treatment of bipolar depression.

This trial was prospectively registered on the Australia New Zealand Clinical Trials Registry (no. ACTRN12616000028404). Participants aged 18 years and older with a diagnosis of bipolar I or II and with at least moderate depressive symptoms were eligible for the study. A total of 1016 participants were initially approached or volunteered for the study, of whom 712 did not progress to screening, with an additional 152 screened out. Seventy participants were randomly allocated to mangosteen and 82 to a placebo control. Fifty participants in the mangosteen and 64 participants in the placebo condition completed the treatment period and were analysed.

Results indicated limited support for the primary hypothesis of superior depression symptom reduction following 24 weeks of treatment. Although overall changes in depressive symptoms did not substantially differ between conditions over the course of the trial, we observed significantly greater improvements for the mangosteen condition at 24 weeks, compared with baseline, for mood symptoms, clinical impressions of bipolar severity and social functioning compared with controls. These differences were attenuated at week 28 post-discontinuation assessment.

Adjunctive mangosteen pericarp treatment appeared to have limited efficacy in mood and functional symptoms associated with bipolar disorder, but not with manic symptoms or quality of life, suggesting a novel therapeutic approach that should be verified by replication.

A key step toward understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organisation at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organisation of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex.

We aimed to evaluate the impact of sex on the spatial organisation of person-specific functional brain networks.

We leveraged person-specific atlases of functional brain networks, defined using non-negative matrix factorisation, in a sample of n = 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalised additive models to uncover associations between sex and the spatial layout (topography) of personalised functional networks (PFNs). We also trained support vector machines to classify participants’ sex from multivariate patterns of PFN topography.

Sex differences in PFN topography were greatest in association networks including the frontoparietal, ventral attention and default mode networks. Machine learning models trained on participants’ PFNs were able to classify participant sex with high accuracy.

Sex differences in PFN topography are robust, and replicate across large-scale samples of youth. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence.

Posttraumatic stress disorder (PTSD) has been associated with advanced epigenetic age cross-sectionally, but the association between these variables over time is unclear. This study conducted meta-analyses to test whether new-onset PTSD diagnosis and changes in PTSD symptom severity over time were associated with changes in two metrics of epigenetic aging over two time points.

We conducted meta-analyses of the association between change in PTSD diagnosis and symptom severity and change in epigenetic age acceleration/deceleration (age-adjusted DNA methylation age residuals as per the Horvath and GrimAge metrics) using data from 7 military and civilian cohorts participating in the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (total N = 1,367).

Meta-analysis revealed that the interaction between Time 1 (T1) Horvath age residuals and new-onset PTSD over time was significantly associated with Horvath age residuals at T2 (meta β = 0.16, meta p = 0.02, p-adj = 0.03). The interaction between T1 Horvath age residuals and changes in PTSD symptom severity over time was significantly related to Horvath age residuals at T2 (meta β = 0.24, meta p = 0.05). No associations were observed for GrimAge residuals.

Results indicated that individuals who developed new-onset PTSD or showed increased PTSD symptom severity over time evidenced greater epigenetic age acceleration at follow-up than would be expected based on baseline age acceleration. This suggests that PTSD may accelerate biological aging over time and highlights the need for intervention studies to determine if PTSD treatment has a beneficial effect on the aging methylome.

Antibiotic stewardship programs (ASPs) target hospitalized children, but most do not routinely review antibiotic prescriptions at discharge, despite 30% of discharged children receiving additional antibiotics. Our objective is to describe discharge antibiotic prescribing in children hospitalized for uncomplicated community-acquired pneumonia (CAP), skin/soft tissue infection (SSTI), and urinary tract infection (UTI).

Retrospective cohort study.

Four academic children’s hospitals with established ASPs.

ICD-10 codes identified 3,847 encounters for children <18 years admitted from January 1, 2021 to December 31, 2021 and prescribed antibiotics at discharge for uncomplicated CAP, SSTI, or UTI. After excluding children with medical complexity and encounters with concomitant infections, >7 days hospital stay, or intensive care unit stay, 1,206 encounters were included.

Primary outcomes were the percentage of subjects prescribed optimal (1) total (inpatient plus outpatient) duration of therapy (DOT) and (2) antibiotic choice based on current national guidelines and available evidence.

Of 226 encounters for CAP, 417 for UTI, and 563 for SSTI, the median age was 4 years, 52% were female, and the median DOT was 9 days (8 for CAP, 10 for UTI, and 9 for SSTI). Antibiotic choice was optimal for 77%, and DOT was optimal for 26%. Only 20% of antibiotic courses included both optimal DOT and antibiotic choice.

At 4 children’s hospitals with established ASPs, 80% of discharge antibiotic courses for CAP, UTI, and SSTI were suboptimal either by choice of antibiotic or DOT. Discharge antibiotic prescribing represents an opportunity to improve antibiotic use in children.

Despite the central role that patient and community engagement plays in translational science and health equity research, there remain significant institutional barriers for researchers and their community partners to engage in this work meaningfully and sustainably. The goal of this paper is to describe the process and outcomes of Engage for Equity PLUS at Stanford School of Medicine, which was aimed at understanding and addressing institutional barriers and facilitators for community-engaged research (CEnR).

A Stanford champion team of four faculty and two community partners worked with the University of New Mexico team to conduct two workshops (n = 26), focus groups (n = 2), interviews with leaders (n = 4), and an Institutional Multi-Stakeholder Survey (n = 35). These data were employed for action planning to identify strategies to build institutional support for CEnR.

Findings revealed several key institutional barriers to CEnR, such as the need to modify organizational policies and practices to expedite and simplify CEnR administration, silos in collaboration, and the need for capacity building. Facilitators included several offices devoted to and engaging in innovative CEnR efforts. Based on these findings, action planning resulted in three priorities: 1) Addressing IRB barriers, 2) Addressing barriers in post-award policies and procedures, and 3) Increasing training in CEnR within Stanford and for community partners.

Addressing institutional barriers is critical for Academic Medical Centers and their partners to meaningfully and sustainably engage in CEnR. The Engage for Equity PLUS process offers a roadmap for Academic Medical Centers with translational science and health equity goals.

Research participants” feedback about their participation experiences offers critical insights for improving programs. A shared Empowering the Participant Voice (EPV) infrastructure enabled a multiorganization collaborative to collect, analyze, and act on participants’ feedback using validated participant-centered measures.

A consortium of academic research organizations with Clinical and Translational Science Awards (CTSA) programs administered the Research Participant Perception Survey (RPPS) to active or recent research participants. Local response data also aggregated into a Consortium database, facilitating analysis of feedback overall and for subgroups.

From February 2022 to June 2024, participating organizations sent surveys to 28,096 participants and received 5045 responses (18%). Respondents were 60% female, 80% White, 13% Black, 2% Asian, and 6% Latino/x. Most respondents (85–95%) felt respected and listened to by study staff; 68% gave their overall experience the top rating. Only 60% felt fully prepared by the consent process. Consent, feeling valued, language assistance, age, study demands, and other factors were significantly associated with overall experience ratings. 63% of participants said that receiving a summary of the study results would be very important to joining a future study. Intersite scores differed significantly for some measures; initiatives piloted in response to local findings raised experience scores.

RPPS results from 5045 participants from seven CTSAs provide a valuable evidence base for evaluating participants’ research experiences and using participant feedback to improve research programs. Analyses revealed opportunities for improving research practices. Sites piloting local change initiatives based on RPPS findings demonstrated measurable positive impact.

Anhedonia, a multidimensional domain including the reduced ability to experience pleasure, is a core diagnostic symptom of major depressive disorder (MDD) and a common residual symptom. In patients with MDD, anhedonia has been associated with poor treatment outcomes, suicide and reduced functioning and quality of life. This post-hoc analysis of data from a phase 3 trial (NCT03738215) evaluated the efficacy of adjunctive cariprazine (CAR) treatment on anhedonia symptoms in patients with MDD.

Patients with MDD and inadequate response to ongoing antidepressant therapy (ADT) were randomized to CAR 1.5 mg/d + ADT, CAR 3 mg/d + ADT, or placebo + ADT for 6 weeks of double-blind treatment. Post hoc analyses evaluated the change from baseline to Week 6 in Montgomery–Åsberg Depression Rating Scale (MADRS) total score, MADRS anhedonia subscale score (items: 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]), and MADRS anhedonia item 8 in the overall modified intent-to-treat (mITT) population and in subgroups of patients with baseline MADRS anhedonia item 8 score of ≥4 or baseline anhedonia subscale score of ≥18. Least square (LS) mean change from baseline to Week 6 was analyzed using a mixed-effects model for repeated measures.

There were 751 patients in the mITT population (CAR + ADT: 1.5 mg/d=250, 3 mg/d=252; placebo + ADT=249). At baseline, 508 (67.6%) patients had MADRS anhedonia item 8 scores ≥4, and 584 (77.8%) had MADRS anhedonia subscale scores ≥18. In the overall mITT population, LS mean change from baseline to Week 6 in anhedonia subscale score was significantly greater for CAR 1.5 mg/d + ADT (-8.4) and CAR 3 mg/d + ADT (-7.9) than for placebo + ADT (-6.8; both P<.05). The LS mean change from baseline in MADRS individual item 8 was also significantly greater for CAR 1.5 mg/d + ADT (-1.7) vs placebo + ADT (-1.3; P=.0085). In both subgroups of patients with baseline anhedonia, CAR 1.5 mg/d + ADT was associated with significantly greater reduction in MADRS total score, MADRS anhedonia subscale score, and MADRS item 8 score compared with placebo + ADT (all P<.05). In the CAR 3 mg/d + ADT group, significantly greater reductions vs placebo + ADT were observed for MADRS total score and MADRS anhedonia subscale score in the subgroup of patients with baseline anhedonia subscale scores ≥18 (both P<.05).

Adjunctive treatment with CAR was associated with a reduction in symptoms of anhedonia relative to adjunctive placebo in patients with MDD and inadequate response to ADT alone. In subgroups of patients with moderate-to-severe anhedonia at baseline, CAR + ADT demonstrated greater improvements than placebo + ADT in overall depressive symptoms and symptoms of anhedonia. These results suggest that adjunctive CAR treatment may be effective for improving symptoms of anhedonia in patients with MDD who have symptoms of anhedonia.

AbbVie

Inappropriate diagnosis and treatment of urinary tract infections (UTIs) contribute to antibiotic overuse. The Inappropriate Diagnosis of UTI (ID-UTI) measure uses a standard definition of asymptomatic bacteriuria (ASB) and was validated in large hospitals. Critical access hospitals (CAHs) have different resources which may make ASB stewardship challenging. To address this inequity, we adapted the ID-UTI metric for use in CAHs and assessed the adapted measure’s feasibility, validity, and reliability.

Retrospective observational study

10 CAHs

From October 2022 to July 2023, CAHs submitted clinical information for adults admitted or discharged from the emergency department who received antibiotics for a positive urine culture. Feasibility of case submission was assessed as the number of CAHs achieving the goal of 59 cases. Validity (sensitivity/specificity) and reliability of the ID-UTI definition were assessed by dual-physician review of a random sample of submitted cases.

Among 10 CAHs able to participate throughout the study period, only 40% (4/10) submitted >59 cases (goal); an additional 3 submitted >35 cases (secondary goal). Per the ID-UTI metric, 28% (16/58) of cases were ASB. Compared to physician review, the ID-UTI metric had 100% specificity (ie all cases called ASB were ASB on clinical review) but poor sensitivity (48.5%; ie did not identify all ASB cases). Measure reliability was high (93% [54/58] agreement).

Similar to measure performance in non-CAHs, the ID-UTI measure had high reliability and specificity—all cases identified as ASB were considered ASB—but poor sensitivity. Though feasible for a subset of CAHs, barriers remain.

In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.

A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.

We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.

The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.

Asymptomatic bacteriuria (ASB) treatment is a common form of antibiotic overuse and diagnostic error. Antibiotic stewardship using the inappropriate diagnosis of urinary tract infection (ID-UTI) measure has reduced ASB treatment in diverse hospitals. However, critical access hospitals (CAHs) have differing resources that could impede stewardship. We aimed to determine if stewardship including the ID-UTI measure could reduce ASB treatment in CAHs.

From October 2022 to July 2023, ten CAHs participated in an Intensive Quality Improvement Cohort (IQIC) program including 3 interventions to reduce ASB treatment: 1) learning labs (ie, didactics with shared learning), 2) mentoring, and 3) data-driven performance reports including hospital peer comparison based on the ID-UTI measure. To assess effectiveness of the IQIC program, change in the ID-UTI measure (ie, percentage of patients treated for a UTI who had ASB) was compared to two non-equivalent control outcomes (antibiotic duration and unjustified fluoroquinolone use).

Ten CAHs abstracted a total of 608 positive urine culture cases. Over the cohort period, the percentage of patients treated for a UTI who had ASB declined (aOR per month = 0.935, 95% CI: 0.873, 1.001, P = 0.055) from 28.4% (range across hospitals, 0%-63%) in the first to 18.6% (range, 0%-33%) in the final month. In contrast, antibiotic duration and unjustified fluoroquinolone use were unchanged (P = 0.768 and 0.567, respectively).

The IQIC intervention, including learning labs, mentoring, and performance reports using the ID-UTI measure, was associated with a non-significant decrease in treatment of ASB, while control outcomes (duration and unjustified fluoroquinolone use) did not change.