Demystifying the virtualization process: A call for standard reporting of virtual modifications to evidence-based psychotherapies, using the FRAME model.

The sudden onset of the coronavirus disease led to a rapid expansion of video telehealth to deliver mental healthcare. Although video telehealth was not a new clinical practice, there was limited guidance on how best to modify evidence-based psychotherapies (EBPs) for virtual delivery (a process also referred to as virtualization). The virtualization process for EBPs remains unclear as newly emerging reports on this topic do not consistently report modification decisions. This commentary calls attention to the need to improve documentation practices to allow a greater understanding of modifications needed to maximize the positive effects of EBPs transported to a virtual format. We used the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) to capture details about the nature, process, and outcomes of intervention modifications across a given clinical setting or population. To illustrate the use of the FRAME, we present a case example describing our experiences with transporting a 1-day in-person Acceptance and Commitment Therapy group workshop to a virtual format. Workshop modifications primarily involved changes to the delivery format, administration procedures, and content. The case example walks through how, why, and by whom specific modifications were made as well as the degree to which fidelity was maintained. In the wake of the telemedicine revolution, further investigation into the virtualization process for EBPs is warranted. Improving reporting practices by using the FRAME or a similar adaptation framework will promote a more rigorous study of virtual modifications to EBPs that inform future guidelines and best practices.

Video telehealth rapidly expanded during COVID-19 as a preferred method for delivering mental health treatment. The sudden, unexpected onset of the pandemic left healthcare systems and individual clinicians little time to shift their services to this virtual format. In addition, there was and remains limited information on the most effective ways to modify evidence-based psychotherapies for virtual delivery (a process known as virtualization). To fill this knowledge gap, this commentary calls for improved documentation and evaluation of the virtualization process. We provide a case example demonstrating how to use the Framework for Reporting Adaptations and Modifications-Expanded­a comprehensive system to detail the nature and process of treatment modifications within a given context. Routine use of this or similar adaptation models within the field of behavioral and social sciences will provide a better understanding of changes needed to ensure the continuity and integrity of evidence-based psychotherapies modified for video telehealth delivery.

Ceramide as an endothelial cell surface receptor and a lung-specific lipid vascular target for circulating ligands.

The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins. Here, we show that an endothelial lung-homing peptide (CGSPGWVRC) interacts with C16-ceramide, a bioactive sphingolipid that mediates several biological functions. Upon binding to cell surfaces, CGSPGWVRC triggers ceramide-rich platform formation, activates acid sphingomyelinase and ceramide production, without the associated downstream apoptotic signaling. We also show that the lung selectivity of CGSPGWVRC homing peptide is dependent on ceramide production in vivo. Finally, we demonstrate two potential applications for this lipid vascular targeting system: i) as a bioinorganic hydrogel for pulmonary imaging and ii) as a ligand-directed lung immunization tool against COVID-19. Thus, C16-ceramide is a unique example of a lipid-based receptor system in the lung vascular endothelium targeted in vivo by circulating ligands such as CGSPGWVRC.

Integrated metabolic and genetic analysis reveals distinct features of human differentiated thyroid cancer.

BACKGROUND: Differentiated thyroid cancer (DTC) affects thousands of lives worldwide each year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) quality of life and might be unnecessary in indolent DTC cases. On the other hand, the lack of biomarkers indicating a potential metastatic thyroid cancer imposes an additional challenge to managing and treating patients with this disease. AIM: The presented clinical setting highlights the unmet need for a precise molecular diagnosis of DTC and potential metastatic disease, which should dictate appropriate therapy. MATERIALS AND METHODS: In this article, we present a differential multi-omics model approach, including metabolomics, genomics, and bioinformatic models, to distinguish normal glands from thyroid tumours. Additionally, we are proposing biomarkers that could indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. RESULTS: Normal and tumour thyroid tissue from DTC patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumour cells. The consistency of the DTC metabolic profile allowed us to build a bioinformatic classification model capable of clearly distinguishing normal from tumor thyroid tissues, which might help diagnose thyroid cancer. Moreover, based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intra-tumour heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. DISCUSSION: Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. CONCLUSIONS: Well-designed, prospective translational clinical trials will ultimately show the value of this integrated multi-omics approach and early diagnosis of DTC and potential metastatic PTC.

Care transitions from the specialty to the primary care setting: A scoping literature review of potential barriers and facilitators with implications for mental health care.

BACKGROUND, AIMS AND OBJECTIVES: This scoping review aimed to understand potential barriers and facilitators in transitioning patients from specialty to primary care settings, to inform the implementation of an intervention to promote active consideration of psychiatrically stable patients for transition from the specialty mental health setting back to primary care. METHODS: Guided by Levac and colleagues' six-stage methodological framework for conducting scoping studies, we systematically searched electronic article databases for peer-reviewed literature from January 2000 to May 2016. We included identified articles that discuss findings related to potential barriers and facilitators in transitioning patients from specialty to primary care settings. We performed descriptive and thematic analyses of results to generate emergent codes and their categorizations. RESULTS: Our database search yielded 906 unique articles, 23 of which we included in our scoping review. All but one of the included studies were conducted in North America. Identified potential barriers and facilitators spanned eight emergent themes-(i) primary care accessibility, especially in terms of timely availability of appointments, (ii) clarity in respective roles of specialty care and primary care in managing a patient, (iii) timely exchange of information, (iv) transition process management, (v) perceived ability of primary care providers to manage specialty conditions, (vi) perceived ability of patients to self-manage, (vii) leadership support and (viii) support for implementing initiatives to promote transitions. CONCLUSIONS: Findings from this scoping review enable an increased understanding of current practices and considerations regarding care transitions from specialty to primary care settings. The importance of role clarification, shared clinical information systems, confidence in care competency, and adequate organizational support to promote appropriate transitions were themes most widely reported across the reviewed studies. Few studies specifically examined the transition from specialty mental health to primary care. Future studies should account for mental health-specific symptomatic patterns and recovery trajectories, such as prevalent chronicity and frequency of relapse, in planning and conducting transitions from specialty mental health back to primary care.

Integrated metabolic and genetic analysis reveals distinct features of primary differentiated thyroid cancer and its metastatic potential in humans.

Differentiated thyroid cancer (DTC) affects thousands of lives worldwide every year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) the quality of life and might be unnecessary in indolent DTC cases. This clinical setting highlights the unmet need for a precise molecular diagnosis of DTC, which should dictate appropriate therapy. Here we propose a differential multi-omics model approach to distinguish normal gland from thyroid tumor and to indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. Based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intratumor heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. Specifically, normal and tumor thyroid tissues from these patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumor cells. Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. Well-designed, prospective translational clinical trials will ultimately show the value of this targeted molecular approach. TRANSLATIONAL RELEVANCE: In this article, we propose a new integrated metabolic, genomic, and cytopathologic methods to diagnose Differentiated Thyroid Cancer when the conventional methods failed. Moreover, we suggest metabolic and genomic markers to help predict high-risk Papillary Thyroid Cancer. Both might be important tools to avoid unnecessary surgery and/or radioiodine therapy that can worsen the quality of life of the patients more than living with an indolent Thyroid nodule.

Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts.

Background: We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression. Methods: The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence. Results: We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages. Conclusions: We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted. Funding: We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial.

Background: Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases. Methods: We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel. Results: These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status. Conclusions: Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations. Funding: R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953. Clinical trial number: NCT03941782.

The epigenetic reader PHF21B modulates murine social memory and synaptic plasticity-related genes.

Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B-depleted (Phf21b-depleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b's roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity-related genes and a candidate therapeutic target for neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.

Genetic and Structural Analysis of SARS-CoV-2 Spike Protein for Universal Epitope Selection.

Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662-C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662-C671 epitope were performed. Mathematical tools were employed to determine its mutational cost. We found that the amino acid sequence of C662-C671 epitope is entirely conserved across the observed major variants of SARS-CoV-2 in addition to SARS-CoV. Its conformation and accessibility are predicted to be conserved, even in the highly mutated Omicron variant. Costly mutational rate in the context of energy expenditure in genome replication and translation can explain this strict conservation. These observations may herald an approach to developing vaccine candidates for universal protection against emergent variants of coronavirus.

Apropos of Universal Epitope Discovery for COVID-19 Vaccines: A Framework for Targeted Phage Display-Based Delivery and Integration of New Evaluation Tools.

Targeted bacteriophage (phage) particles are potentially attractive yet inexpensive platforms for immunization. Herein, we describe targeted phage capsid display of an immunogenically relevant epitope of the SARS-CoV-2 Spike protein that is empirically conserved, likely due to the high mutational cost among all variants identified to date. This observation may herald an approach to developing vaccine candidates for broad-spectrum, towards universal, protection against multiple emergent variants of coronavirus that cause COVID-19.

Acceptance and Commitment Training for Veterans with Polytrauma: A randomized controlled trial protocol.

BACKGROUND: Mild traumatic brain injury (mTBI) is a signature wound of Veterans of operations in Iraq and Afghanistan (i.e., OIF/OEF/OND). Most Veterans with mTBI also experience stress-based psychopathology (e.g., depression, posttraumatic stress disorder) and chronic pain. This combination - referred to as polytrauma - results in detrimental long-term effects on social, occupational, and community reintegration. This study will compare the efficacy of a one-day Acceptance and Commitment Training plus Education, Resources, and Support (ACT+ERS) workshop to a one-day active control group (ERS) on symptoms of distress and social, occupational, and community reintegration. We will also examine mediators and moderators of treatment response. METHODS: This is an ongoing randomized clinical trial. 212 OIF/OEF/OND Veterans with polytrauma are being recruited. Veterans are randomly assigned to a one-day ACT+ERS or a one-day ERS workshop with two individualized booster sessions approximately two- and four-weeks post-workshop. Veterans complete assessments prior to the workshop and again at six weeks, three months, and six months post-workshop. Of note, workshops were converted to a virtual format due to the COVID-19 pandemic. RESULTS: The primary outcomes are symptoms of distress and reintegration; secondary outcomes are post-traumatic stress disorder symptoms and pain interference. Secondary analyses will assess whether changes in avoidance at three months mediate changes in distress and reintegration at six months. CONCLUSION: Facilitating the psychological adjustment and reintegration of Veterans with polytrauma is critical. The results of this study will provide important information about the impact of a brief intervention for Veterans with these concerns.

Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain.

Development of effective vaccines against coronavirus disease 2019 (COVID-19) is a global imperative. Rapid immunization of the entire human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and different vaccine approaches are being pursued. Engineered filamentous bacteriophage (phage) particles have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the development and initial evaluation of two targeted phage-based vaccination approaches against SARS-CoV-2: dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. For peptide-targeted phage, we performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein. One of these epitopes displayed on the major capsid protein pVIII of phage induced a specific and sustained humoral response when injected in mice. These phage were further engineered to simultaneously display the peptide CAKSMGDIVC on the minor capsid protein pIII to enable their transport from the lung epithelium into the systemic circulation. Aerosolization of these "dual-display" phage into the lungs of mice generated a systemic and specific antibody response. In the second approach, targeted AAVP particles were engineered to deliver the entire S protein gene under the control of a constitutive CMV promoter. This induced tissue-specific transgene expression, stimulating a systemic S protein-specific antibody response in mice. With these proof-of-concept preclinical experiments, we show that both targeted phage- and AAVP-based particles serve as robust yet versatile platforms that can promptly yield COVID-19 vaccine prototypes for translational development.

Improving the transition of patients with mental health disorders back to primary care: A protocol for a partnered, mixed-methods, stepped-wedge implementation trial.

The current study protocol regards a partnered, mixed-methods, cluster-randomized stepped wedge trial of the implementation and effectiveness of the FLOW program. FLOW (not an acronym) is a collection of resources and strategies to assist in determining which recovered or stabilized specialty mental health (SMH) patients should transition back to primary care (PC) and tools to make the transition seamless. Transitioning appropriate patients to PC can increase access and timeliness of mental health care for newly referred mental health patients. Nine sites in one US region will be randomized to one of three waves in which they will receive implementation-facilitation to implement the FLOW program. Primary outcomes will include the reach of FLOW, provider adoption of the program, effectiveness in increasing access in SMH, implementation fidelity, and maintenance over time. A mixed-methods analysis of implementation factors associated with implementation success will also be conducted, including the following as possible predictors: staffing ratios, site resources, leadership and provider support for the program, and local champion characteristics. This study's results will provide evidence for the effectiveness of FLOW in increasing access and may provide generalizable information about characteristics of sites that are likely to be successful with implementing similar programs.

Design and proof-of-concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain.

Development of effective vaccines against Coronavirus Disease 2019 (COVID-19) is a global imperative. Rapid immunization of the world human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and many different vaccine approaches are being pursued to meet this task. Engineered filamentous bacteriophage (phage) have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the design, development, and initial evaluation of targeted phage-based vaccination approaches against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) by using dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. Towards a unique phage- and AAVP-based dual-display candidate approach, we first performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein for display on the recombinant major capsid coat protein pVIII. Targeted phage particles carrying one of these epitopes induced a strong and specific humoral response. In an initial experimental approach, when these targeted phage particles were further genetically engineered to simultaneously display a ligand peptide (CAKSMGDIVC) on the minor capsid protein pIII, which enables receptor-mediated transport of phage particles from the lung epithelium into the systemic circulation (termed "dual-display"), they enhanced a systemic and specific spike (S) protein-specific antibody response upon aerosolization into the lungs of mice. In a second line of investigation, we engineered targeted AAVP particles to deliver the entire S protein gene under the control of a constitutive cytomegalovirus (CMV) promoter, which induced tissue-specific transgene expression stimulating a systemic S protein-specific antibody response. As proof-of-concept preclinical experiments, we show that targeted phage- and AAVP-based particles serve as robust yet versatile enabling platforms for ligand-directed immunization and promptly yield COVID-19 vaccine prototypes for further translational development. SIGNIFICANCE: The ongoing COVID-19 global pandemic has accounted for over 2.5 million deaths and an unprecedented impact on the health of mankind worldwide. Over the past several months, while a few COVID-19 vaccines have received Emergency Use Authorization and are currently being administered to the entire human population, the demand for prompt global immunization has created enormous logistical challenges--including but not limited to supply, access, and distribution--that justify and reinforce the research for additional strategic alternatives. Phage are viruses that only infect bacteria and have been safely administered to humans as antibiotics for decades. As experimental proof-of-concept, we demonstrated that aerosol pulmonary vaccination with lung-targeted phage particles that display short epitopes of the S protein on the capsid as well as preclinical vaccination with targeted AAVP particles carrying the S protein gene elicit a systemic and specific immune response against SARS-CoV-2 in immunocompetent mice. Given that targeted phage- and AAVP-based viral particles are sturdy yet simple to genetically engineer, cost-effective for rapid large-scale production in clinical grade, and relatively stable at room temperature, such unique attributes might perhaps become additional tools towards COVID-19 vaccine design and development for immediate and future unmet needs.

Combination outreach and wellness intervention for distressed rural veterans: results of a multimethod pilot study.

We partnered with veteran-serving nonprofits in order to identify distressed rural veterans and provide them with a mental health workshop in community-based settings. Community organizations helped recruit veterans and provided space for 1-day (5-h) Acceptance and Commitment Therapy (ACT) group workshops conducted in rural locations. Qualitative interviews were conducted at 1- and 3-months post-intervention to assess acceptability. Quantitative measures were conducted at baseline, 1- and 3-months post-intervention to measure effectiveness. We successfully engaged community partners throughout every stage of the research and delivered workshops to thirty-one veterans in rural community-based locations. Veterans appreciated the structure, content, and environment of the workshops; most implemented ACT skills into their daily lives and some initiated new treatment following workshop participation. Quantitative measures showed improvements in functioning (Cohen's d ranging from .27 to .40), reintegration (Cohen's d = .45), meaning and purpose (Cohen's d = .40), and reductions in distress (Cohen's d ranging from .28 to .40) 3-months following workshop participation. Collaborating with rural veteran-serving nonprofit organizations holds promise for engaging hard-to-reach distressed veterans in mental health care.

Comparing integrative cognitive-affective therapy and guided self-help cognitive-behavioral therapy to treat binge-eating disorder using standard and naturalistic momentary outcome measures: A randomized controlled trial.

OBJECTIVE: Innovative treatments and outcome measures are needed for binge-eating disorder (BED). This randomized controlled trial compared Integrative Cognitive-Affective Therapy (ICAT-BED), an individual psychotherapy targeting momentary behavioral and emotional precipitants of binge eating, with an established cognitive-behavioral guided self-help (CBTgsh) treatment using standard and ecological momentary assessment (EMA) outcome measures. METHOD: A total of 112 participants were randomized to 17 weeks of treatment (21 sessions for ICAT-BED and 10 sessions for CBTgsh). Binge-eating frequency was assessed with the Eating Disorder Examination (EDE) as well as EMA using cell phone-based real-time, naturalistic assessment at end of treatment (EOT) and 6-month follow-up. Hypothesized maintenance mechanisms were assessed using self-report questionnaires. RESULTS: Binge-eating frequency as measured by the EDE and real-time assessment showed significant reductions at EOT and follow-up, with no significant differences between treatments. Hypothesized maintenance mechanisms, including emotion regulation, cognitive self-discrepancy, self-directed style, as well as measures of associated eating disorder psychopathology, depression, anxiety, impulsivity, and negative affect, showed similar improvement at EOT and follow-up with no differences between treatments. Abstinence rates at EOT (ICAT-BED: 57.1%; CBTgsh: 42.9%) and 6-month follow-up (ICAT-BED: 46.4%; CBTgsh: 42.9%) were not significantly different. Treatment retention was significantly higher for ICAT-BED (87.5%) than CBTgsh (71.4%). DISCUSSION: These findings suggest that ICAT-BED and CBTgsh were associated with similar improvements in binge eating, psychopathology, and putative maintenance mechanisms as measured by traditional self-report and momentary, naturalistic assessments and that these changes were generally sustained at 6-month follow-up.

Meropenem as an antidote for intentional valproic acid overdose.

Valproic acid (VPA) is a broad-spectrum antiepileptic drug indicated for monotherapy and adjunctive therapy of seizures, and complex manic episodes associated with bipolar disorder [1]. While uncommon due to monitoring, VPA can cause toxicity at supratherapeutic levels [1, 2]. Traditional treatment for VPA toxicity is primarily supportive care, however activated charcoal, l-carnitine, and hemodialysis have been successful in removing free VPA [2]. An interaction between carbapenem antibiotics and VPA is well-established and listed in respective package inserts as a combination to be avoided due to decreased VPA efficacy [1, 3]. Recent literature suggests co-administration of meropenem with VPA reduces mean plasma VPA levels by 50-80% [4, 6]. This case report describes the successful use of carbapenems to intentionally lower toxic VPA levels in a 42 year old female that presented to the emergency department with VPA toxicity from an overdose with divalproex sodium.

"It didn't fit for me:" A qualitative examination of dropout from prolonged exposure and cognitive processing therapy in veterans.

Trauma-focused psychotherapies, such as prolonged exposure and cognitive processing therapy, are the most effective forms of treatment for posttraumatic stress disorder. These treatments are commonly delivered in the Veterans Health Administration; however, dropout means that some veterans fail to benefit. Ending treatment prematurely is a common problem across psychotherapies, with on average, 20% to 25% of patients dropping out. The purpose of this study was to examine veterans' self-reported reasons for dropping out of prolonged exposure or cognitive processing therapy. Veterans who dropped out from prolonged exposure or cognitive processing therapy (N = 28) completed qualitative interviews about their experiences. Interviews were coded by 2 coders using grounded theory. Therapy-related barriers were the largest category reported, and included lack of buy-in to the rationale or specific therapy tasks, believing that treatment was not working, alliance issues, or switching to a different treatment. Practical barriers and finding treatment "too stressful" were also common reasons for dropout. This research provides information that can shape how PTSD treatments are delivered in health care settings. Therapy-related barriers were the largest group, suggesting that providers may need to find more effective ways to communicate the rationale for these therapies or to tailor them to individual patients' needs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Targeted AAVP-based therapy in a mouse model of human glioblastoma: a comparison of cytotoxic versus suicide gene delivery strategies.

Glioblastoma persists as a uniformly deadly diagnosis for patients and effective therapeutic options are gravely needed. Recently, targeted gene therapy approaches are reemerging as attractive experimental clinical agents. Our ligand-directed hybrid virus of adeno-associated virus and phage (AAVP) is a targeted gene delivery vector that has been used in several formulations displaying targeting ligand peptides to deliver clinically applicable transgenes. Here we compared different constructs side-by-side in a tumor model, an orthotopic model of xenograft human glioblastoma cells stereotactically implanted in immunodeficient mice. We have used divergent therapeutic strategies for two AAVP constructs, both displaying a double-cyclic RGD4C motif ligand specific for alpha V integrins expressed in tumor vascular endothelium, but carrying different genes of interest for the treatment of intracranial xenografted tumors. One construct delivered tumor necrosis factor (TNF), a purely cytotoxic gene for antitumor activity (RGD4C-AAVP-TNF); in the other construct, we delivered Herpes simplex virus thymidine kinase (HSVtk) for in tandem molecular-genetic imaging and targeted therapy (RGD4C-AAVP-HSVtk) utilizing ganciclovir (GCV) for a suicide gene therapy. Both AAVP constructs demonstrated antitumor activity, with damage to the tumor-associated neovasculature and induction of cell death evident after treatment. In addition, the ability to monitor transgene expression with a radiolabeled HSVtk substrate pre and post GCV treatment demonstrated the theranostic potential of RGD4C-AAVP-HSVtk. We conclude that targeted AAVP constructs delivering either cytotoxic TNF or theranostic HSVtk followed by suicide gene therapy with GCV have comparable preclinical efficacy, at least in this standard experimental model. The results presented here provide a blueprint for future studies of targeted gene delivery against human glioblastomas and other brain tumors.

Next-generation of targeted AAVP vectors for systemic transgene delivery against cancer.

Bacteriophage (phage) have attractive advantages as delivery systems compared with mammalian viruses, but have been considered poor vectors because they lack evolved strategies to confront and overcome mammalian cell barriers to infective agents. We reasoned that improved efficacy of delivery might be achieved through structural modification of the viral capsid to avoid pre- and postinternalization barriers to mammalian cell transduction. We generated multifunctional hybrid adeno-associated virus/phage (AAVP) particles to enable simultaneous display of targeting ligands on the phage's minor pIII proteins and also degradation-resistance motifs on the very numerous pVIII coat proteins. This genetic strategy of directed evolution bestows a next-generation of AAVP particles that feature resistance to fibrinogen adsorption or neutralizing antibodies and ability to escape endolysosomal degradation. This results in superior gene transfer efficacy in vitro and also in preclinical mouse models of rodent and human solid tumors. Thus, the unique functions of our next-generation AAVP particles enable improved targeted gene delivery to tumor cells.