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.

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.

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 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.

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.

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.

Ablative and Immunostimulatory Effects of Histotripsy Ablation in a Murine Osteosarcoma Model.

Background: Osteosarcoma (OS) is the most frequently occurring malignant bone tumor in humans, primarily affecting children and adolescents. Significant advancements in treatment options for OS have not occurred in the last several decades, and the prognosis remains grim with only a 70% rate of 5-year survival. The objective of this study was to investigate the focused ultrasound technique of histotripsy as a novel, noninvasive treatment option for OS. Methods: We utilized a heterotopic OS murine model to establish the feasibility of ablating OS tumors with histotripsy in a preclinical setting. We investigated the local immune response within the tumor microenvironment (TME) via immune cell phenotyping and gene expression analysis. Findings: We established the feasibility of ablating heterotopic OS tumors with ablation characterized microscopically by loss of cellular architecture in targeted regions of tumors. We observed greater populations of macrophages and dendritic cells within treated tumors and the upregulation of immune activating genes 72 h after histotripsy ablation. Interpretation: This study was the first to investigate histotripsy ablation for OS in a preclinical murine model, with results suggesting local immunomodulation within the TME. Our results support the continued investigation of histotripsy as a novel noninvasive treatment option for OS patients to improve clinical outcomes and patient prognosis.

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.

Successful In Situ Targeting of Pancreatic Tumors in a Novel Orthotopic Porcine Model Using Histotripsy.

OBJECTIVE: New therapeutic strategies and paradigms are direly needed to treat pancreatic cancer. The absence of a suitable pre-clinical animal model of pancreatic cancer is a major limitation to biomedical device and therapeutic development. Traditionally, pigs have proven to be ideal models, especially in the context of designing human-sized instruments, perfecting surgical techniques and optimizing clinical procedures for use in humans. However, pig studies have typically focused on healthy tissue assessments and are limited to general safety evaluations because of the inability to effectively model human tumors. METHODS: Here, we establish an orthotopic porcine model of human pancreatic cancer using RAG2/IL2RG double-knockout immunocompromised pigs and treat the tumors ex vivo and in vivo with histotripsy. RESULTS: Using these animals, we describe the successful engraftment of Panc-1 human pancreatic cancer cell line tumors and characterize their development. To illustrate the utility of these animals for therapeutic development, we determine for the first time, the successful targeting of in situ pancreatic tumors using histotripsy. Treatment with histotripsy resulted in partial ablation in vivo and reduction in collagen content in both in vivo tumor in pig pancreas and ex vivo patient tumor. CONCLUSION: This study presents a first step toward establishing histotripsy as a non-invasive treatment method for pancreatic cancer and exposes some of the challenges of ultrasound guidance for histotripsy ablation in the pancreas. Simultaneously, we introduce a highly robust model of pancreatic cancer in a large mammal model that could be used to evaluate a variety biomedical devices and therapeutic strategies.

Applying Shared Decision Making to the Process of Medication Deprescribing in Schizophrenia.

Deprescribing, the identification and discontinuation of medications that are no longer indicated or that cause adverse effects that outweigh clinical benefit, relies on the integration of clinical expertise and patient values using shared decision making (SDM). This case series describes the application of SDM to the process of deprescribing in patients with serious mental illness, illustrating the ways in which SDM builds a therapeutic alliance between patient, psychiatrist, family members, and other health care professionals to collaboratively develop treatment plans.

Action Planning for Building 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 benefit 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 for 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 in 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. Trial registration: NCT03598114, Registered on July 26, 2018 (clnicaltrials.gov/NCT03598114).

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.

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.

Community-Based Service Use After Clozapine Treatment: A Mirror-Image Analysis of Public Claims Data.

Although clozapine demonstrates unique efficacy for treatment-resistant schizophrenia, its impact on community-based services remains largely underexplored. The authors examined changes in use of community-based services after clozapine treatment among a sample of 163 patients with schizophrenia by using public claims data in Allegheny County, Pennsylvania. Mirror-image analyses of service utilization were used to compare the 180-day period before treatment initiation with the 180-day period that began after 6 months of adherent treatment, accounting for age, race, and gender. Across demographic variables, clozapine treatment was associated with increased use of community-based services and decreased use of psychiatric inpatient services (p<0.05, Bonferroni corrected), suggesting that clozapine treatment shifts service needs from emergency care to community-based care and recovery.

Characterizing the Ablative Effects of Histotripsy for Osteosarcoma: In Vivo Study in Dogs.

Osteosarcoma (OS) is a malignant bone tumor treated by limb amputation or limb salvage surgeries and chemotherapy. Histotripsy is a non-thermal, non-invasive focused ultrasound therapy using controlled acoustic cavitation to mechanically disintegrate tissue. Recent ex vivo and in vivo pilot studies have demonstrated the ability of histotripsy for ablating OS but were limited in scope. This study expands on these initial findings to more fully characterize the effects of histotripsy for bone tumors, particularly in tumors with different compositions. A prototype 500 kHz histotripsy system was used to treat ten dogs with suspected OS at an intermediate treatment dose of 1000 pulses per location. One day after histotripsy, treated tumors were resected via limb amputation, and radiologic and histopathologic analyses were conducted to determine the effects of histotripsy for each patient. The results of this study demonstrated that histotripsy ablation is safe and feasible in canine patients with spontaneous OS, while offering new insights into the characteristics of the achieved ablation zone. More extensive tissue destruction was observed after histotripsy compared to that in previous reports, and radiographic changes in tumor size and contrast uptake following histotripsy were reported for the first time. Overall, this study significantly expands our understanding of histotripsy bone tumor ablation and informs future studies for this application.

Mechanical High-Intensity Focused Ultrasound (Histotripsy) in Dogs With Spontaneously Occurring Soft Tissue Sarcomas.

INTRODUCTION: Histotripsy is a non-invasive focused ultrasound therapy that uses controlled acoustic cavitation to mechanically disintegrate tissue. To date, there are no reports investigating histotripsy for the treatment of soft tissue sarcoma (STS). OBJECTIVE: This study aimed to investigate the in vivo feasibility of ablating STS with histotripsy and to characterize the impact of partial histotripsy ablation on the acute immunologic response in canine patients with spontaneous STS. METHODS: A custom 500 kHz histotripsy system was used to treat ten dogs with naturally occurring STS. Four to six days after histotripsy, tumors were surgically resected. Safety was determined by monitoring vital signs during treatment and post-treatment physical examinations, routine lab work, and owners' reports. Ablation was characterized using radiologic and histopathologic analyses. Systemic immunological impact was evaluated by measuring changes in cytokine concentrations, and tumor microenvironment changes were evaluated by characterizing changes in infiltration with tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) using multiplex immunohistochemistry and differential gene expression. RESULTS: Results showed histotripsy ablation was achievable and well-tolerated in all ten dogs. Immunological results showed histotripsy induced pro-inflammatory changes in the tumor microenvironment. Conclusion & Significance: Overall, this study demonstrates histotripsy's potential as a precise, non-invasive treatment for STS.

Histotripsy Ablation of Spontaneously Occurring Canine Bone Tumors In Vivo.

OBJECTIVE: Osteosarcoma (OS) is a devastating primary bone tumor in dogs and humans with limited non-surgical treatment options. As the first completely non-invasive and non-thermal ablation technique, histotripsy has the potential to significantly improve the standard of care for patients with primary bone tumors. INTRODUCTION: Standard of care treatment for primary appendicular OS involves surgical resection via either limb amputation or limb-salvage surgery for suitable candidates. Biological similarities between canine and human OS make the dog an informative comparative oncology research model to advance treatment options for primary OS. Evaluating histotripsy for ablating spontaneous canine primary OS will build a foundation upon which histotripsy can be translated clinically into a standard of care therapy for canine and human OS. METHODS: Five dogs with suspected spontaneous OS were treated with a 500 kHz histotripsy system guided by real-time ultrasound image guidance. Spherical ablation volumes within each tumor (1.25-3 cm in diameter) were treated with single cycle histotripsy pulses applied at a pulse repetition frequency of 500 Hz and a dose of 500 pulses/point. RESULTS: Tumor ablation was successfully identified grossly and histologically within the targeted treatment regions of all subjects. Histotripsy treatments were well-tolerated amongst all patients with no significant clinical adverse effects. Conclusion & Significance: Histotripsy safely and effectively ablated the targeted treatment volumes in all subjects, demonstrating its potential to serve as a non-invasive treatment modality for primary bone tumors.