Faculty Bibliography

The differential influence of sex on premature mortality in schizophrenia is unclear. This study assessed the differences in all-cause and specific cause mortality risks in people with schizophrenia compared to several control groups stratified by sex. We conducted a PRISMA 2020-compliant systematic review and random-effects meta-analysis of cohort studies assessing mortality relative risk (RR) for people with schizophrenia, comparing by sex. We measured publication bias and conducted a quality assessment through the Newcastle-Ottawa scale. We meta-analyzed 43 studies reporting on 2,700,825 people with schizophrenia. Both males and females with schizophrenia had increased all-cause mortality vs. comparison groups (males, RR=2.62, 95%CI 2.35-2.92; females, RR=2.56, 95%CI 2.27-2.87), suicide (males, RR=9.02, 95%CI 5.96-13.67; females, RR=12.09, 95%CI 9.00-16.25), and natural cause mortality (males, RR=2.11, 95%CI 1.88-2.38; females, RR=2.14, 95%CI 1.93-2.38). No statistically significant differences in sex-dependent mortality risk emerged. There was an age-group-dependent increased mortality risk in females < 40 years vs. >/=40 years old (RR=4.23/2.17), and significantly higher risk of death due to neurological disorders (dementia) in males vs. females (RR=5.19/2.40). Increased mortality risks were often associated with specific modifiable risk factors. The increased mortality risk did not improve over time, calling for more studies to identify modifiable factors, and for better physical healthcare for males and females with schizophrenia.

PURPOSE OF REVIEW/OBJECTIVE:There is a mental health crisis affecting youth, and the utility of existing treatments is often limited by lack of effectiveness and tolerability. The aim of this review is to report on outcomes of clinical trials for psilocybin-assisted psychotherapy for adults with depression and MDMA-assisted psychotherapy for adults with post-traumatic stress disorder (PTSD) and discuss recommendations for exploring these treatments in adolescent populations. RECENT FINDINGS/RESULTS:There have been encouraging data supporting the use of psilocybin-assisted psychotherapy for depression, including previously treatment-resistant symptoms. MDMA-assisted psychotherapy is showing similar promise in treating PTSD, with excellent response and remission rates that appear durable. However, no studies have looked at the use of these treatments in younger patients. The safety and efficacy of psychedelic- and MDMA-assisted psychotherapies should be investigated in adolescents, especially considering the burden of untreated and undertreated psychiatric illness in youth, and the benefits of a potentially earlier, more effective, and more tolerable recovery process. Research and implementation should be tailored to the needs of this population, and equity and access should be considered at every stage. In this novel and rapidly evolving landscape, the psychiatric community is encouraged to advocate for safe, appropriate, and inclusive inquiry into, and application and scaling of these treatment models in adolescent patients.

OBJECTIVE:To better understand the value of DNR orders for critically ill infants in the NICU. METHODS:A prospective mixed-methods approach was utilized including chart review of infants who died in a regional NICU over a twenty-six-month period and surveys of their neonatologists, neonatal fellows, and nurses. RESULTS:40 infants died during the study period and 120 staff surveys were completed. Infants with DNR orders were of a higher gestational age at birth and a higher chronological age at death. Nurses were more likely to perceive benefit from DNR orders than physicians. Medical staff recollection of the existence of DNR orders was not always accurate. Time and fear of adding unnecessary emotional burden to parents were identified as barriers to DNR order implementation. An advanced care planning model built on open communication instead of DNR order documentation was deemed the best approach. CONCLUSION/CONCLUSIONS:Though DNR orders are beneficial for a subset of infants, DNR orders are likely not applicable for all infants who die in the NICU. More important is supportive, individualized communication between families and the medical team to ensure quality end-of-life care. IMPACT/CONCLUSIONS:In the adult and pediatric ICU literature, DNR orders are associated with improved qualitative "good death" assessments and decreased familial decision regret. In the NICU, rates of DNR usage aren't well reported and their overall utility is unclear. Though DNR orders can help guide clinical decision making in the NICU and may be associated with higher quality ethical discussion, our data suggest that they are not applicable in all patient cases. We hope that this work will help guide approaches to end-of-life care in the NICU and underscore the importance of frequent, open communication between families and their medical team.

Methionine aminopeptidase 2 (MetAP2) plays an important role in the regulation of protein synthesis and post-translational processing. Preclinical/clinical applications of MetAP2 inhibitors for the treatment of various diseases have been explored because of their antiangiogenic, anticancer, antiobesity, antidiabetic, and immunosuppressive properties. However, the effects of MetAP2 inhibitors on CNS diseases are rarely examined despite the abundant presence of MetAP2 in the brain. Previously, we synthesized a novel boron-containing MetAP2 inhibitor, BL6, and found that it suppressed angiogenesis and adipogenesis yet improved glucose uptake. Here, we studied the anti-inflammatory effects of BL6 in SIM-A9 microglia and in a mouse model of Alzheimer's disease generated by the intracerebroventricular (icv) injection of streptozotocin (STZ). We found that BL6 reduced proinflammatory molecules, such as nitric oxide, iNOS, IL-1β, and IL-6, together with phospho-Akt and phospho-NF-κB p65, which were elevated in lipopolysaccharide (LPS)-activated microglial SIM-A9 cells. However, the LPS-induced reduction in Arg-1 and CD206 was attenuated by BL6, suggesting that BL6 promotes microglial M1 to M2 polarization. BL6 also decreased glial activation along with a reduction in phospho-tau and an elevation in synaptophysin in the icv-STZ mouse model. Thus, our experiments demonstrate an anti-neuroinflammatory action of BL6, suggesting possible clinical applications of MetAP2 inhibitors for brain disorders in which neuroinflammation is involved.

OBJECTIVE/UNASSIGNED:This study assessed the utility and effectiveness of the new general health integration (GHI) framework among community behavioral health organizations designated as certified community behavioral health clinics (CCBHCs) or in the process of applying to become a CCBHC. METHODS/UNASSIGNED:Nineteen licensed community behavioral health clinics, 18 of which had CCBHC status, participated in a 12-month learning collaborative. They used the GHI framework to assess their integration stage for 15 subdomains within eight domains of evidence-based practice. The clinics worked to improve their GHI practices with the support of monthly learning collaborative webinars, individual consultation calls, and technical assistance sessions. Clinics reported on performance quality metrics aligned with national CCBHC standards. Outcome measures included GHI framework scores at baseline and 1-year follow-up, capacity to report quality metrics at baseline and at the end of the collaborative, and average performance on the quality metrics at baseline versus at the end of the collaborative. RESULTS/UNASSIGNED:Clinics showed overall improvement in integration stage over the study period. Of note, higher baseline GHI framework scores demonstrated a significant association with greater-quality performance at baseline (r=0.577, p=0.024) and follow-up (r=0.782, p=0.001). Capacity to track and report quality metrics increased significantly during the learning collaborative, as did average performance on quality metrics. CONCLUSIONS/UNASSIGNED:Community behavioral health clinics using the GHI framework were able to advance their GHI practices with a 12-month learning collaborative project. The framework has the potential to serve as a useful tool for clinics aiming to enhance GHI practices.

OBJECTIVE/UNASSIGNED:receptor antagonist ondansetron. The present study employed an experimental medicine approach to test the effects of 4 weeks of high-dose ondansetron compared to placebo on SP severity and brain connectivity in a cohort of individuals with OCD and/or Tourette's disorder. METHODS/UNASSIGNED:Of 51 participants who completed the study, 27 were assigned to receive 24 mg/day of ondansetron and 24 to receive placebo. Analyses examined changes in SP severity and, for participants with OCD, overall OCD severity from baseline to final visit. Functional MRI data were collected at both visits for analysis of intrinsic functional connectivity metrics characterizing global correlation (reflecting area "hubness") and local correlation (reflecting near-neighbor coherence). RESULTS/UNASSIGNED:There were no significant differences between ondansetron and placebo in the reduction of SP or overall OCD severity in the full sample. In a subsample of participants with OCD taking concomitant serotonin reuptake inhibitors (SRIs), ondansetron was associated with a significant decrease in overall OCD severity and global connectivity of the medial sensorimotor cortex compared with placebo. Longitudinal reductions in SP severity were related to decreases in right sensorimotor hubness in both groups, and to brainstem local coherence only in participants taking ondansetron. CONCLUSIONS/UNASSIGNED:There was no effect of high-dose ondansetron on SP. However, when used as an augmentation to SRIs, ondansetron reduced overall OCD severity, which may be related to changes in the "hubness" of the sensorimotor cortex. Ondansetron's ability to modulate brainstem connectivity may underlie its variable effectiveness in reducing SP.

BACKGROUND:The prevalence of trauma among individuals with HIV has prompted efforts to integrate trauma-informed care (TIC) into HIV care and treatment to improve health outcomes. A TIC Implementation Model, developed by a US capacity-building organization focuses on organizational changes, aligning cultural and physical environments, emphasizing values like safety and trustworthiness, engaging leadership, and training staff in skills-based TIC services. Despite growing research, gaps remain in understanding the relationship between organizational capacity, provider knowledge, and the dosage of technical assistance (TA) required to sustain TIC integration. Researchers investigated how the project team adapted the type and amount of TA based on initial Cultural Assessment scores (measuring core TIC values) and its impact on Implementation Status scores. METHODS:This study focuses on eight of 20 HIV care agencies in New Jersey that had largely met their TIC implementation goals by Spring 2022. As part of the TIC Implementation Model to measure agency capacity and implementation progress over time, agency staff and clients completed a Cultural Assessment (n = 72) and Physical Assessment (n = 43); staff completed a Pre/Post Training Survey (n = 296); and implementation teams at 8 agencies completed an Implementation Status Assessment Tool. Additionally, TA Logs capturing the details of TA meetings with the eight agencies were recorded by project staff. Data from these tools were analyzed in aggregate by agency using descriptive and correlational analyses. RESULTS:Results demonstrated responsive TA correlated with agencies' baseline capacity. Agencies with lower capacity received significantly more frequent and extended TA encounters, which were associated with higher implementation scores and improvements in cultural environments for staff and clients (e.g., new protocols for staff response plans). CONCLUSIONS:These findings underscore the importance of tailored TA in fostering diverse organizational cultures conducive to TIC implementation. For HIV care agencies, successful TIC implementation can impact health behaviors and outcomes for clients impacted by trauma. The TIC Implementation Model significantly advanced organizations' ability to transform their culture and systems, increasing their capacity to implement and sustain TIC integration. These results align with existing research that emphasizes when time is invested to shift organizational culture and develop leadership, new practices can effectively be implemented and scaled-up.

The diagnosis of autism is currently based on the developmental history, direct observation of behavior, and reported symptoms, supplemented by rating scales/interviews/structured observational evaluations-which is influenced by the clinician's knowledge and experience-with no established diagnostic biomarkers. A growing body of research has been conducted over the past decades to improve diagnostic accuracy. Here, we provide an overview of the current diagnostic assessment process as well as of recent and ongoing developments to support diagnosis in terms of genetic evaluation, telemedicine, digital technologies, use of machine learning/artificial intelligence, and research on candidate diagnostic biomarkers. Genetic testing can meaningfully contribute to the assessment process, but caution is required when interpreting negative results, and more work is needed to strengthen the transferability of genetic information into clinical practice. Digital diagnostic and machine-learning-based analyses are emerging as promising approaches, but larger and more robust studies are needed. To date, there are no available diagnostic biomarkers. Moving forward, international collaborations may help develop multimodal datasets to identify biomarkers, ensure reproducibility, and support clinical translation.

INTRODUCTION/BACKGROUND:Friedreich's Ataxia (FRDA) is a multi-system disorder caused by frataxin deficiency. FRDA-related diabetes mellitus (DM) is common. Frataxin supports skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, a mediator of insulin sensitivity. Our objective was to test the association between skeletal muscle health and insulin sensitivity and secretion in adults with FRDA without DM. METHODS:Case-control study (NCT02920671). Glucose and insulin metabolism (stable-isotope oral glucose tolerance tests), body composition (dual-energy x-ray absorptiometry), physical activity (self-report), and skeletal muscle OXPHOS capacity (creatine chemical exchange saturation transfer MRI) were assessed. RESULTS:Participants included 11 individuals with FRDA (4 female), median age 27y (IQR 23, 39), BMI 26.9kg/m2 (24.1, 29.4), and 24 controls (11 female), 29y (26, 39), 24.4kg/m2 (21.8, 27.0). Fasting glucose was higher in FRDA (91 vs. 83mg/dL (5.0 vs. 4.6mmol/L), p<0.05). Individuals with FRDA had lower insulin sensitivity (WBISI 2.8 vs. 5.3, p<0.01), higher post-prandial insulin secretion (insulin secretory rate iAUC 30-180 minutes, 24,652 vs. 17,858, p<0.05), and more suppressed post-prandial endogenous glucose production (-0.9% vs. 26.9% of fasting EGP, p<0.05). In regression analyses, lower OXPHOS and inactivity explained some of the difference in insulin sensitivity. More visceral fat contributed to lower insulin sensitivity independent of FRDA. Insulin secretion accounting for sensitivity (disposition index) was not different. CONCLUSIONS:Lower mitochondrial OXPHOS capacity, inactivity, and visceral adiposity contribute to lower insulin sensitivity in FRDA. Higher insulin secretion appears compensatory, and when inadequate, could herald DM. Further studies are needed to determine if muscle- or adipose-focused interventions could delay FRDA-related DM.