Predicting Conversion to Insulin Sensitivity With Metformin: A Promising Tool for Clinicians in Addressing Insulin Resistance and Improving Outcomes in Patients With Treatment Resistant Bipolar Depression.

BACKGROUND: Insulin resistance (IR) changes the trajectory of responsive bipolar disorder to a treatment-resistant course. A clinical trial conducted by our group demonstrated that IR reversal by metformin improved clinical and functional outcomes in treatment-resistant bipolar depression (TRBD). To aid clinicians identify which metformin-treated TRBD patients might reverse IR, and given strong external evidence for their association with IR, we developed a predictive tool using body mass index (BMI) and homeostatic model assessment-insulin resistance (HOMA-IR). METHODS: The predictive performance of baseline BMI and HOMA-IR was tested with a logistic regression model using known metrics: area under the receiver operating curve, sensitivity, and specificity. In view of the high benefit to low risk of metformin in reversing IR, high sensitivity was favored over specificity. RESULTS: In this BMI and HOMA-IR model for IR reversal, the area under the receiver operating curve is 0.79. At a cutoff probability of conversion of 0.17, the model's sensitivity is 91% (95% confidence interval [CI], 57%-99%), and the specificity is 56% (95% CI, 36%-73%). For each unit increase in BMI or HOMA-IR, there is a 15% (OR, 0.85; 95% CI, 0.71-0.99) or 43% (OR, 0.57; CI, 0.18-1.36) decrease in the odds of conversion, respectively. CONCLUSIONS: In individuals with TRBD, this tool using BMI and HOMA-IR predicts IR reversal with metformin with high sensitivity. Furthermore, these data suggest early intervention with metformin at lower BMI, and HOMA-IR would likely reverse IR in TRBD.

A qualitative study examining the impact of COVID-19 on capacity for sustainability of tobacco control programs.

BACKGROUND: The coronavirus (COVID-19) pandemic presented a significant stressor on the public health system in the United States. While we know the immediate effects of the pandemic on public health programming, no literature has examined the resultant long-term impact on programmatic capacity for sustainability. This paper aims to identify the impact that the COVID-19 pandemic had on state tobacco control program's capacity for sustainability. METHODS: From December 2018 to January 2022, we conducted 46 technical assistance calls with tobacco control program employees from 11 states. Calls were audio recorded and professionally transcribed. We analyzed calls (n = 20) that took place during the COVID-19 pandemic. Thematic analysis focused on the impact the COVID-19 pandemic had on tobacco control program's capacity for sustainability. RESULTS: We identified six domains of sustainability that were impacted by COVID-19: (1) funding stability; (2) organizational capacity; (3) partnerships; (4) communication; (5) strategic planning; and (6) program adaptation. CONCLUSIONS: Our study is the first to identify the impact of the pandemic on capacity for sustainability of tobacco control programs. Having an understanding of COVID-19's influence on these sustainability domains could help with future public health programming during significant public health events and emergency preparedness. GOV IDENTIFIER: NCT03598114. REGISTRATION DATE: Retrospectively registered 02-07-2018.

Barriers and Facilitators to Program Sustainability Among State Tobacco Control Programs.

Public health programs, particularly tobacco control programs (TCPs) in state health departments, face numerous barriers and facilitators to sustainability, which affect delivery and, consequently, health outcomes achieved. We used the Program Sustainability Framework to review and analyze qualitative interview data from states that received training and technical assistance during the Plans, Actions, and Capacity to Sustain Tobacco Control (PACT) study to better understand the barriers and facilitators to sustainability capacity that these public health programs face at the state level. The PACT study was a multiyear, randomized controlled trial to assess the effectiveness of an action planning workshop and technical assistance in improving capacity for sustainability among 11 intervention and 12 control TCPs. Technical assistance calls focused on the progress and barriers of implementing the sustainability action plan created during the in-person workshops. Calls were audio recorded and professionally transcribed. Thematic analysis focused on the codes describing barriers and facilitators faced by TCPs in increasing their capacity for sustainability. Barriers were reported in the Organization Capacity, Environmental Support, Partnerships, Communication, and Funding Stability domains of the Program Sustainability Framework. Facilitators to action planning and building capacity for program sustainability were primarily in the Strategic Planning, Program Evaluation, Program Adaptation, and Partnership domains. Our study is the first to identify barriers and facilitators to increasing the capacity of program sustainability in TCPs. This work advances the understanding of program sustainability capacity and technical assistance for public health programs.

Variation of Clozapine Use for Treatment of Schizophrenia: Evidence from Pennsylvania Medicaid and Dually Eligible Enrollees.

While clozapine is the most effective antipsychotic treatment for treatment-resistant schizophrenia, it remains underutilized across the United States, warranting a more comprehensive understanding of variation in use at the county level, as well as characterization of existing prescribing patterns. Here, we examined both Medicaid and Medicare databases to (1) characterize temporal and geographic variation in clozapine prescribing and, (2) identify patient-level characteristics associated with clozapine use. We included Medicaid and Fee for Service Medicare data in the state of Pennsylvania from January 1, 2013, through December 31, 2019. We focused on individuals with continuous enrollment, schizophrenia diagnosis, and multiple antipsychotic trials. Geographic variation was examined across counties of Pennsylvania. Regression models were constructed to determine demographic and clinical characteristics associated with clozapine use. Out of 8,255 individuals who may benefit from clozapine, 642 received treatment. We observed high medication burden, overall, including multiple antipsychotic trials. We also identified variation in clozapine use across regions in Pennsylvania with a disproportionate number of prescribers in urban areas and several counties with no identified clozapine prescribers. Finally, demographic, and clinical determinants of clozapine use were observed including less use in people identified as non-Hispanic Black, Hispanic, or with a substance use disorder. In addition, greater medical comorbidity was associated with increased clozapine use. Our work leveraged both Medicaid and Medicare data to characterize and surveil clozapine prescribing. Our findings support efforts monitor disparities and opportunities for the optimization of clozapine within municipalities to enhance clinical outcomes.

Histotripsy ablation for the treatment of feline injection site sarcomas: a first-in-cat in vivo feasibility study.

PURPOSE: Feline soft tissue sarcoma (STS) and injection site sarcoma (fISS) are rapidly growing tumors with low metastatic potential, but locally aggressive behavior. Histotripsy is a non-invasive focused ultrasound therapy using controlled acoustic cavitation to mechanically disintegrate tissue. In this study, we investigated the in vivo safety and feasibility of histotripsy to treat fISS using a custom 1 MHz transducer. MATERIALS AND METHODS: Three cats with naturally-occurring STS were treated with histotripsy before surgical removal of the tumor 3 to 6 days later. Gross and histological analyses were used to characterize the ablation efficacy of the treatment, and routine immunohistochemistry and batched cytokine analysis were used to investigate the acute immunological effects of histotripsy. RESULTS: Results showed that histotripsy ablation was achievable and well-tolerated in all three cats. Precise cavitation bubble clouds were generated in all patients, and hematoxylin & eosin stained tissues revealed ablative damage in targeted regions. Immunohistochemical results identified an increase in IBA-1 positive cells in treated tissues, and no significant changes in cytokine concentrations were identified post-treatment. CONCLUSIONS: Overall, the results of this study demonstrate the safety and feasibility of histotripsy to target and ablate superficial feline STS and fISS tumors and guide the clinical development of histotripsy devices for this application.

Investigating cell death responses associated with histotripsy ablation of canine osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most frequently occurring primary bone tumor in dogs and people and innovative treatment options are profoundly needed. Histotripsy is an emerging tumor ablation modality, and it is essential for the clinical translation of histotripsy to gain knowledge about the outcome of nonablated tumor cells that could remain postablation. The objective of this study was to characterize the cell death genetic signature and proliferation response of canine OS cells post a near complete histotripsy ablation (96% ± 1.5) and to evaluate genetic cell death signatures associated with histotripsy ablation and OS in vivo. METHODS: In the current study, we ablated three canine OS cell lines with a histotripsy dose that resulted in near complete ablation to allow for a viable tumor cell population for downstream analyses. To assess the in vivo cell death genetic signature, we characterized cell death genetic signature in histotripsy-ablated canine OS tumors collected 24-h postablation. RESULTS: Differential gene expression changes observed in the 4% viable D17 and D418 cells, and histotripsy-ablated OS tumor samples, but not in Abrams cells, were associated with immunogenic cell death (ICD). The 4% viable OS cells demonstrated significantly reduced proliferation, compared to control OS cells, in vitro. CONCLUSION: Histotripsy ablation of OS cell lines leads to direct and potentially indirect cell death as evident by, reduced proliferation in remaining viable OS cells and cell death genetic signatures suggestive of ICD both in vitro and in vivo.

Ultrasound-guided noninvasive pancreas ablation using histotripsy: feasibility study in an in vivo porcine model.

Pancreatic cancer is a malignant disease associated with poor survival and nearly 80% present with unresectable tumors. Treatments such as chemotherapy and radiation therapy have shown overall improved survival benefits, albeit limited. Histotripsy is a noninvasive, non-ionizing, and non-thermal focused ultrasound ablation modality that has shown efficacy in treating hepatic tumors and other malignancies. In this novel study, we investigate histotripsy for noninvasive pancreas ablation in a pig model. In two studies, histotripsy was applied to the healthy pancreas in 11 pigs using a custom 32-element, 500 kHz histotripsy transducer attached to a clinical histotripsy system, with treatments guided by real-time ultrasound imaging. A pilot study was conducted in 3 fasted pigs with histotripsy applied at a pulse repetition frequency (PRF) of 500 Hz. Results showed no pancreas visualization on coaxial ultrasound imaging due to overlying intestinal gas, resulting in off-target injury and no pancreas damage. To minimize gas, a second group of pigs (n = 8) were fed a custard diet containing simethicone and bisacodyl. Pigs were euthanized immediately (n = 4) or survived for 1 week (n = 4) post-treatment. Damage to the pancreas and surrounding tissue was characterized using gross morphology, histological analysis, and CT imaging. Results showed histotripsy bubble clouds were generated inside pancreases that were visually maintained on coaxial ultrasound (n = 4), with 2 pigs exhibiting off-target damage. For chronic animals, results showed the treatments were well-tolerated with no complication signs or changes in blood markers. This study provides initial evidence suggesting histotripsy's potential for noninvasive pancreas ablation and warrants further evaluation in more comprehensive studies.

From Office-Based Treatment to Telehealth: Comparing Clinical Outcomes and Patient Participation in a Psychiatric Intensive Outpatient Program with a Large Transdiagnostic Sample.

Introduction: Patient participation and clinical outcomes of a precoronavirus disease 2019 (COVID-19) office-based transdiagnostic psychiatric intensive outpatient program (IOP) were compared with those of telehealth IOP during COVID-19. Materials and Methods: Weeks of enrollment, Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) assessments, and sociodemographic and clinical factors (including group track and diagnosis) were collected during pre-COVID-19 (n = 191) and during COVID-19 (n = 200). Continuous and categorical measures of GAD-7 and PHQ-9 were analyzed; potential sociodemographic and clinical covariates to scores were also explored. Results: There were no statistically significant differences in participation between time periods. Associations were observed between PHQ-9/GAD-7 score improvement and number of assessments. Significant score reductions occurred in both periods, and differences in change scores were not significant. Sociodemographic and clinical factors were not significantly different between time periods. Patients with commercial insurance had significantly higher improvement in both mean and categorical PHQ-9 scores (t = 2.77, p = 0.006; χ2 = 10.47, df = 1, p = 0.001) and GAD-7 scores (t = 2.29, p = 0.023; χ2 = 8.58, df = 1, p = 0.003) than those with public insurance. Patients with anxiety disorders had significantly greater improvements (F = 4.49, p = 0.004; χ2 = 9.15, df = 3, p = 0.027) in GAD-7 during COVID-19. Discussion: Significant improvements in PHQ-9/GAD-7 scores and measures of participation were not significantly different between telehealth and office-based IOP, nor were they greatly influenced by clinical or sociodemographic factors. Further study is needed of possible care disparities for publicly insured patients. Conclusion: Despite some limitations, telehealth IOP appears to be a clinically appropriate option for a diverse sociodemographic and diagnostically heterogeneous psychiatric population.

Rapid expansion of direct-to-consumer telemental health during the COVID-19 pandemic: A case series.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic brought many challenges to patient care delivery. The need for social distancing and relaxing of federal and state telemental health regulations paved the way for widespread adoption of direct-to-consumer (DTC) ambulatory mental health video visits. METHODS: We present cases that demonstrate the use of video visits across 6 clinical areas, each serving a unique population of patients, in a large behavioral health system. The benefits and limitations of this modality are illustrated in children, adults, and older adults with mood disorders, anxiety disorders, intellectual disability, substance use disorders, neurocognitive disorders, and schizophrenia. RESULTS: Although telephone visits were acceptable and necessary to serve some patients, there are many advantages to video visits in providing best patient care. Education and support for telemental health-delivered to both patients and clinicians-is critical to the success of the DTC model. CONCLUSIONS: DTC telemental health is a widespread clinical tool used during the COVID-19 pandemic. Because this model has many strengths and advantages compared with traditional telemental health delivered in a clinic, regulators and insurers should be open to its continued use postpandemic when clinically appropriate.

Less is more: Deprescribing anticholinergic medications in persons with severe mental illness.

BACKGROUND: Long-term prescribing of anticholinergic medications (ACM) for antipsychotic-associated extrapyramidal symptoms (EPS) is not recommended, yet is widely prevalent. Adverse effects of ACM include memory impairment, dry mouth, constipation, blurred vision, urinary retention, and tachycardia, which can seriously impact quality of life. This quality improvement deprescription project sought to reduce chronic ACM use in patients with serious mental illness (SMI). METHODS: Education directed at psychiatrists combined with clinical pharmacy support for deprescription was used to target clinically stable patients diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder with no EPS and ACM prescriptions of ≥6 months. Scales were used to assess anticholinergic adverse effects, memory impairment, and quality of life. ACMs were tapered and discontinued over 1 to 6 months. RESULTS: More than 75% of targeted patients successfully tapered or discontinued ACM, which coincided with significant improvements in anticholinergic adverse effects, memory impairment, and quality of life. Approximately 10% of patients were restarted on ACM for re-emergent EPS. CONCLUSIONS: For most clinically stable patients with SMI without EPS, our findings suggest that gradual deprescription of chronic ACM is clinically appropriate, well tolerated, and improves quality of life. A randomized trial could provide more definitive answers.

Racial Differences in S100b Levels in Persons with Schizophrenia.

The calcium-binding protein S100b is secreted by glial cells in the brain and is also expressed by melanocytes. In nanomolar concentrations, S100b is considered to be a neurotrophic factor, but in micromolar concentrations, it is thought to reflect CNS injury and inflammation. Seen as a potential biomarker in traumatic brain injury, meta-analytic data from several studies report that S100b levels are significantly higher in persons with long standing schizophrenia, but also among first-episode patients compared to healthy control subjects. However, ethnic or racial differences are typically not mentioned when reporting levels of S100b. We assessed serum S100b levels in persons with schizophrenia (n = 136) who were participants in two independent research studies using the same enzyme-linked immunoassay (ELISA). African-American subjects had significantly higher levels of S100b (41.9 pg/ml ± 62.2) than Caucasian subjects (24.9 pg/ml ± 45.4) in the combined dataset (Mann-Whitney U = 1307, p < 0.001), as well as in each independent study. There were no significant differences in S100b levels between men and women. No significant correlations were observed between S100b levels and demographic or clinical variables. These data suggest that ethnicity or race should be given serious consideration when studying and interpreting S100b levels in persons with schizophrenia.

Effects of a standardized extract of Withania somnifera (Ashwagandha) on depression and anxiety symptoms in persons with schizophrenia participating in a randomized, placebo-controlled clinical trial.

BACKGROUND: Extracts of Withania somnifera (WSE), or Ashwagandha, has traditionally been used as an adaptogen in Ayurvedic medicine, and evidence suggests that it may have efficacy in the treatment of psychiatric disorders, including schizophrenia. This secondary analysis reviewed change in depression and anxiety symptoms in a study using WSE as an adjunctive treatment in patients with schizophrenia experiencing an exacerbation of positive symptoms. METHODS: We enrolled patients with schizophrenia in a 12-week, randomized, placebo-controlled, double-blind study. Active treatment was with 1,000 mg of standardized WSE. This analysis reviewed outcomes for 66 patients with depression and anxiety symptoms by examining the singleitem depression and anxiety-depression cluster subscores extracted from the Positive and Negative Syndrome Scale. RESULTS: Medium effect sizes of 0.683 (95% confidence interval [CI], 0.16 to 1.21) and 0.686 (95% CI, 0.16 to 1.21) favoring WSE over placebo were observed for depression single-item and anxiety-depression cluster scores, respectively. Adverse events were mild and transient. CONCLUSIONS: Our findings suggest that WSE may hold promise in the treatment of depression and anxiety symptoms in schizophrenia. While the mechanism of its clinical efficacy requires more exploration, the data suggest.

Evaluation of Branched-Narrative Virtual Patients for Interprofessional Education of Psychiatry Residents.

OBJECTIVE: This pilot study evaluated the utility of branched-narrative virtual patients in an interprofessional education series for psychiatry residents. METHODS: Third-year psychiatry residents attended four interprofessional education advanced psychopharmacology sessions that involved completion of a branched-narrative virtual patient and a debriefing session with a psychiatric pharmacist. Pre- and post-assessments analyzed resident learning and were administered around each virtual patient. Simulation 4 served as a comprehensive review. The primary outcome was differences in pre- and post-assessment scores. Secondary outcomes included resident satisfaction with the virtual patient format and psychiatric pharmacist involvement. RESULTS: Post-test scores for simulations 1, 2, and 3 demonstrated significant improvement (p < 0.05) from pre-test scores. Scores for simulation 4 did not retain significance. Resident satisfaction with the branched-narrative virtual patient format and psychiatric pharmacist involvement was high throughout the series (100 %; n = 18). CONCLUSIONS: Although there are important methodological limitations to this study including a small sample size and absence of a comparator group, this pilot study supports the use of branched-narrative virtual patients in an interprofessional education series for advanced learners.

Development of an Injectable Hydrogel for Histotripsy Ablation Toward Future Glioblastoma Therapy Applications.

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor. Even after surgery and chemoradiotherapy, residual GBM cells can infiltrate the healthy brain parenchyma to form secondary tumors. To mitigate GBM recurrence, we recently developed an injectable hydrogel that can be crosslinked in the resection cavity to attract, collect, and ablate residual GBM cells. We previously optimized a thiol-Michael addition hydrogel for physical, chemical, and biological compatibility with the GBM microenvironment and demonstrated CXCL12-mediated chemotaxis can attract and entrap GBM cells into this hydrogel. In this study, we synthesize hydrogels under conditions mimicking GBM resection cavities and assess feasibility of histotripsy to ablate hydrogel-encapsulated cells. The results showed the hydrogel synthesis was bio-orthogonal, not shear-thinning, and can be scaled up for injection into GBM resection mimics in vitro. Experiments also demonstrated ultrasound imaging can distinguish the synthetic hydrogel from healthy porcine brain tissue. Finally, a 500 kHz transducer applied focused ultrasound treatment to the synthetic hydrogels, with results demonstrating precise histotripsy bubble clouds could be sustained in order to uniformly ablate red blood cells encapsulated by the hydrogel for homogeneous, mechanical fractionation of the entrapped cells. Overall, this hydrogel is a promising platform for biomaterials-based GBM treatment.

Action planning for building public health program sustainability: results from a group-randomized trial.

BACKGROUND: Public health programs are charged with implementing evidence-based interventions to support public health improvement; however, to achieve long-term population-based benefits, these interventions must be sustained. Empirical evidence suggests that program sustainability can be improved through training and technical assistance, but few resources are available to support public health programs in building capacity for sustainability. METHODS: This study sought to build capacity for sustainability among state tobacco control programs through a multiyear, group-randomized trial that developed, tested, and evaluated a novel Program Sustainability Action Planning Model and Training Curricula. Using Kolb's experiential learning theory, we developed this action-oriented training model to address the program-related domains proven to impact capacity for sustainability as outlined in the Program Sustainability Framework. We evaluated the intervention using a longitudinal mixed-effects model using Program Sustainability Assessment (PSAT) scores from three time points. The main predictors in our model included group (control vs intervention) and type of dosage (active and passive). Covariates included state-level American Lung Association Score (proxy for tobacco control policy environment) and percent of CDC-recommended funding (proxy for program resources). RESULTS: Twenty-three of the 24 state tobacco control programs were included in the analyses: 11 received the training intervention and 12 were control. Results of the longitudinal mixed-effects linear regression model, where the annual PSAT score was the outcome, showed that states in the intervention condition reported significantly higher PSAT scores. The effects of CDC-recommended funding and American Lung Association smoke-free scores (proxy for policy environment) were small but statistically significant. CONCLUSION: This study found that the Program Sustainability Action Planning Model and Training Curricula was effective in building capacity for sustainability. The training was most beneficial for programs that had made less policy progress than others, implying that tailored training may be most appropriate for programs possibly struggling to make progress. Finally, while funding had a small, statistically significant effect on our model, it virtually made no difference for the average program in our study. This suggests that other factors may be more or equally important as the level of funding a program receives. CLINICALTRIALS: gov, NCT03598114. Registered on July 26, 2018.

A conceptual model for building program sustainability in public health settings: Learning from the implementation of the program sustainability action planning model and training curricula.

Background: The emergence of implementation science has driven an increase in research examining the implementation of evidence-based programs and policies. However, there has been less attention through program sustainability. To achieve the full benefit of investment in program development and implementation, there must be an understanding of the factors that relate to sustainability; additionally, there is a need for a robust set of tools and trainings to support strategic long-term program sustainability. This paper presents results of our sustainability training intervention and a new conceptual model of sustainability. The proposed conceptual model builds upon the intervention design, further specifying the implementation strategy, strategy-mechanism linkages, and effect modifiers. Methods: This research is part of the larger randomized control trial evaluating the effectiveness of the Program Sustainability Action Planning Model and Training Curricula. Specifically, this multimethod study establishes a conceptual model for program sustainability and related capacity-building interventions. The training intervention was delivered through workshops and technical assistance to 11 state tobacco control programs, principally entailing the development and implementation of a sustainability action plan. We utilize descriptive statistics and participant perspectives to evaluate the training intervention and propose an empirically-grounded conceptual model for sustainability capacity-building interventions in public health settings. Results: Participants found intervention components (workshop, workbook, instructor and resources) to be effective. Overall, participants found the intervention improved their ability to develop sustainability action plans and assess their program and partners. Throughout the study, program managers emphasized the importance of the workshop in providing direction for their sustainability work and the value of robust, ongoing technical assistance. Program managers identified several factors that interfered with intervention reception including staff turnover, competing priorities, partnership challenges, and the COVID-19 pandemic. Conclusion: The present study documents the development and implementation of a novel Program Sustainability Action Planning Model and Training Curricula, one of the first interventions designed to improve program sustainability. In addition, we present an empirically-grounded conceptual model for program sustainability. Considering the paucity of research in this understudied and undefined topic area, this is an important contribution that can serve as a framework for similar intervention designs and implementation efforts. Clinical Trail Registration: ClinicalTrails.gov identification number is NCT03598114.