Improving Shape-Sensing Robotic-Assisted Bronchoscopy Outcomes with Mobile Cone-Beam Computed Tomography Guidance.

BACKGROUND: Computed tomography to body divergence (CTBD) is one of the main barriers to bronchoscopic techniques for the diagnosis of peripherally located lung nodules. Cone-beam CT (CBCT) guidance is being rapidly adopted to correct for this phenomenon and to potentially increase diagnostic outcomes. In this trial, we hypothesized that the addition of mobile CBCT (m-CBCT) could improve the rate of tool in lesion (TIL) and the diagnostic yield of shape-sensing robotic-assisted bronchoscopy (SS-RAB). METHODS: This was a prospective, single-arm study, which enrolled patients with peripheral lung nodules of 1-3 cm and compared the rate of TIL and the diagnostic yield of SS-RAB alone and combined with mCBCT. RESULTS: A total of 67 subjects were enrolled, the median nodule size was 1.7 cm (range, 0.9-3 cm). TIL was achieved in 23 patients (34.3%) with SS-RAB alone, and 66 patients (98.6%) with the addition of mCBCT (p < 0.0001). The diagnostic yield of SS-RAB alone was 29.9% (95% CI, 29.3-42.3%) and it was 86.6% (95% CI, 76-93.7%) with the addition of mCBCT (p < 0.0001). There were no pneumothoraxes or any bronchoscopy-related complications, and the median total dose-area product (DAP) was 50.5 Gy-cm2. CONCLUSIONS: The addition of mCBCT guidance to SS-RAB allows bronchoscopists to compensate for CTBD, leading to an increase in TIL and diagnostic yield, with acceptable radiation exposure.

Overcoming challenges in conducting early phase breast cancer prevention trials: Bazedoxifene and conjugated estrogens vs waitlist control.

BACKGROUND: The combination of bazedoxifene 20 mg (BZA) and conjugated estrogens 0.45 mg (CE) marketed as Duavee® is approved for vasomotor symptom relief and osteoporosis prevention. Our pilot study suggested it had potential breast cancer risk reduction, and we proposed a multisite Phase IIB primary prevention trial assessing change in breast imaging and tissue risk biomarkers. By the time funding was acquired in February 2021, Duavee® was unavailable with an uncertain return date. A redesign was needed to salvage the study. METHODS: The basic trial design was minimally altered. Women age 45-64 at elevated risk for breast cancer with vasomotor symptoms and no menses for at least 2 months have mammography, phlebotomy, and benign breast tissue sampling before and after 6 months of intervention. However, instead of Duavee® (single pill) vs placebo, women are randomized to 6 months of BZA + CE vs Waitlist. Those initially randomized to Waitlist can receive BZA + CE after 6 months. The primary endpoint is between arm difference in change in a fully automated measure of mammographic density with blood and tissue-based secondary endpoints. OUTCOMES: Accrual initiation was delayed due to contractual difficulties surrounding BZA importation during COVID-19 and deploying a fully automated method (Volpara®) to assess the primary endpoint. To accommodate this delay, a mid-grant no cost extension along with amended eligibility requirements were employed. 61/120 participants needed were entered in the initial 27 months of accrual and 37 months of funding. Despite a late start, accrual is likely to be completed within the funding period.

The Interrater Reliability of a Coding System for Measuring Mental Health Professionals' Decisions and Actions.

OBJECTIVE: The clinical decisions and actions of evidence-based practice in psychology (EBPP) are largely underspecified and poorly understood, in part due to the lack of measurement methods. We tested the reliability of a behavioral coding system that characterizes a flow of interrelated activities that includes problem detection and prioritization, intervention selection and implementation, and review of intervention integrity and impact. METHOD: The context included two publicly funded youth mental health service organizations located in geographically distinct and underresourced communities in the U.S. where service inequities are common. We sampled 84 digitally recorded and transcribed supervision events that included a sample of professionals who were mostly women (93.02%) and BIPOC (86.04%) whose self-reported race/ethnicity matched the youth populations they served. We coded these events for activities (e.g., considering) and their predicate content (i.e., problems or practices) and examined reliability of these codes applied to excerpts (i.e., small contiguous units of dialogue) as well as to complete events. RESULTS: Interrater reliability estimates showed that, overall, coders reliably rated the occurrence and extensiveness of activities and content. Excerpt coding was generally more reliable than event coding. However, mathematical aggregation of excerpt coding offered a superior method for estimating event codes reliably, reducing individual subjectivity while providing event level synthesis of activities that are grounded in excerpt level details. CONCLUSIONS: The assessment of clinical decisions and actions has the potential to unpack the black box of EBPP, with different methods best suited to different research questions and resource considerations.

The refined Pathways to Cures Research Roadmap for multiple sclerosis cures.

BACKGROUND: Multiple sclerosis is a chronic immune-mediated disease of the central nervous system affecting nearly 3 million people worldwide. Although much progress has been made in the understanding and treatment of MS, cures remain elusive. OBJECTIVES: To accelerate the development of cures for MS by updating the Pathways to Cures Research Roadmap based on a contemporary understanding of disease. The refined Roadmap will help to promote research in scientific areas with great potential to reveal insights leading to cures and inspire greater coordination of global resources. METHODS: Refinements to the Roadmap were achieved during a Global Summit that included close to 200 academic and industry scientists, health care providers, policy makers, funders, and people with MS from 15 countries. RESULTS: The refined Roadmap describes three pathways that target opportunities for generating scientific insights leading to cures. Recommendations for accelerating research progress include, lowering barriers for global data sharing, enhancing collaboration and coordination among research supporters, committing to sustained funding, considering implications for implementation, engaging PwMS and committing to diversity, equity, and inclusion in the global MS movement. CONCLUSION: The refined roadmap provides a strategic framework for tackling the complexities of MS and advancing prevention strategies, effective treatments, and cures.

Pilot study of implementing Managing and Adapting Practice in a German psychotherapy master's program.

Despite a significant accumulation of research, there has been little systemic implementation of evidence-based practices (EBP) in youth mental health care. The fragmentation of the evidence base complicates implementation efforts. In light of this challenge, we sought to pilot a system that consolidates and coordinates the entire evidence base in a single direct service model (i.e., Managing and Adapting Practice; MAP) in the context of a legal reform of psychotherapy training in Germany. This pilot study aimed to evaluate the feasibility of the implementation of MAP into the curriculum of the reformed German master's program. Eligible participants were students in the master's program at Philipps-University Marburg during the winter-term 2022/2023. Students first learned about MAP through introductions and role plays (seminar 1), followed by actively planning and conducting interventions using MAP resources for patients in a case seminar under supervision (seminar 2). A repeated-measures survey was conducted to investigate students' knowledge gains, perception of MAP and changes in their self-rated confidence to use EBP. Results indicated that students perceive MAP to be manageable to learn. Positive progress was achieved with regard to their knowledge and self-reported confidence to use EBP, although interpretation and generalization of the results are limited by small and homogeneous samples, lack of statistical power and missing comparison groups. The feasibility of the implementation and suitability of measures are discussed. Important implications could be drawn with regard to future investigations.

Dosimetry: Was and Is an Absolute Requirement for Quality Radiation Research.

This review aims to trace the evolution of dosimetry, highlight its significance in the advancement of radiation research, and identify the current trends and methodologies in the field. Key historical milestones, starting with the first publications in the journal in 1954, will be synthesized before addressing contemporary practices in radiation medicine and radiobiological investigation. Finally, possibilities for future opportunities in dosimetry will be offered. The overarching goal is to emphasize the indispensability of accurate and reproducible dosimetry in enhancing the quality of radiation research and practical applications of ionizing radiation.

Allopregnanolone and its antagonist modulate neuroinflammation and neurological impairment.

Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.

Using Adherence and Competence Measures Based on Practice Elements to Evaluate Treatment Fidelity for Two CBT Programs for Youth Anxiety.

Measures designed to assess the quantity and quality of practices found across treatment programs for specific youth emotional or behavioral problems may be a good fit for evaluating treatment fidelity in effectiveness and implementation research. Treatment fidelity measures must demonstrate certain reliability and validity characteristics to realize this potential. This study examines the extent to which two observational measures, the Cognitive-Behavioral Treatment for Anxiety in Youth Adherence Scale (CBAY-A) and the CBAY Competence Scale (CBAY-C), can assess the quantity (the degree to which prescribed therapeutic techniques are delivered as intended) or quality (the competence with which prescribed techniques are delivered) of practices found in two distinct treatment programs for youth anxiety. Treatment sessions (N = 796) from 55 youth participants (M age = 9.89 years, SD = 1.71; 46% female; 55% White) with primary anxiety problems who participated in an effectiveness study were independently coded by raters who coded quantity, quality, and the youth-clinician alliance. Youth received one of three treatments: (a) standard (i.e., cognitive-behavioral therapy program), (b) modular (i.e., a cognitive-behavioral and parent-training program), and (c) usual clinical care. Interrater reliability for the CBAY-A items was good across the standard and modular conditions but mixed for the CBAY-C items. Across the standard and modular conditions, the CBAY-A Model subscale scores demonstrated evidence of construct validity, but the CBAY-C Model subscale scores showed mixed evidence. The results provide preliminary evidence that the CBAY-A can be used across different treatment programs but raise concerns about the generalizability of the CBAY-C.

Managers' Micro-Communities Matter: The Impact of Clinical Supervision Team on Therapist Perception of the Organization.

Positive organizational climate - employee perceptions of their work environment and the impact of this environment on well-being and functioning - is associated with desirable organizational and client-level outcomes in mental health organizations. Clinical supervisors are well-positioned to impact organizational climate, as they serve as intermediaries between higher-level administrators who drive the policies and procedures and the therapists impacted by such decisions. This cross-sectional study examined the role of clinical supervisors as drivers of therapist perceptions of organizational climate within supervisory teams. Specifically, the present study investigated: (1) shared perceptions of organizational climate among therapists on the same supervisory team; (2) predictors of therapist climate perceptions. Eighty-six therapists were supervised by 22 supervisors. Indices of interrater agreement and interrater reliability of therapists on the same supervisory team were examined to determine shared or distinct perceptions of organizational climate. Multi-level models were used to examine whether supervisor attitudes towards evidence-based practices and therapist perceptions of supervisor communication predicted perceived organizational climate. Results showed perceptions of organizational cohesion and autonomy were shared among therapists on the same supervisory team and distinct from therapists on different supervisory teams. Therapist perceptions of their supervisor's communication was positively associated with perceptions of organizational cohesion and autonomy. These findings align with emerging evidence that middle managers shape their employees' experience of their work environment through communication strategies. These findings also point to the potential for intervening at lower organizational levels to improve overall organizational climate.

The Content of Usual Clinical Care for Youth with Primary Anxiety Problems.

The current study was designed to describe usual clinical care for youth with primary anxiety problems in community mental health centers. The observer-rated Therapy Process Observational Coding System for Child Psychotherapy - Revised Strategies scale (TPOCS-RS), designed to assess therapeutic techniques from five theory-based domains, was used to code sessions (N = 403) from the usual clinical care group of two randomized effectiveness trials: (a) Youth Anxiety Study (YAS) with 21 youth (M age = 10.44 years, SD = 1.91; 49.2% Latinx; 46.6%, 53.4% male) and 16 clinicians (77.5% female; 43.8% White), and (b) Child STEPS Multisite Trial with 17 youth (M age = 10.00 years, SD = 1.87; 58.8% male; 41.2% White) and 13 clinicians (M age = 40.00 years; SD = 9.18; 76.9% female; 61.5% White). The average number of TPOCS-RS items observed per treatment session was more than 10, and multiple techniques were used together in each session. All TPOCS-RS items were observed at least once throughout a clinical case, and most items reoccurred (i.e., observed in two or more sessions). The dosage of TPOCS-RS in all items was below 5 on a 7-point scale. In conclusion, clinicians in both usual care samples used a wide range of techniques from several theory-based domains at a low to medium dose. However, the type and dosage of the techniques used did vary across the two samples.

SARS-CoV-2 Spike Protein-Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78.

The human glucose-regulated protein GRP78 is a human chaperone that translocactes to the cell surface when cells are under stress. Theoretical studies suggested it could be involved in SARS-CoV-2 virus entry to cells. In this work, we used in vitro surface plasmon resonance-based assays to show that human GRP78 indeed binds to SARS-CoV-2 spike protein. We have designed and synthesised cyclic peptides based on the loop structure of amino acids 480-488 of the SARS-CoV-2 spike protein S1 domain from the Wuhan and Omicron variants and showed that both peptides bind to GRP78. Consistent with the greater infectiousness of the Omicron variant, the Omicron-derived peptide displays slower dissociation from the target protein. Both peptides significantly inhibit the binding of wild-type S1 protein to the human protein GRP78 suggesting that further development of these cyclic peptide motifs may provide a viable route to novel anti-SARS-CoV-2 agents.

Could Life Have Started on Mars? Planetary Conditions That Assemble and Destroy Protocells.

Early Mars was likely habitable, but could life actually have started there? While cellular life emerged from prebiotic chemistry through a pre-Darwinian selection process relevant to both Earth and Mars, each planet posed unique selection 'hurdles' to this process. We focus on drivers of selection in prebiotic chemistry generic to Earth-like worlds and specific to Mars, such as an iron-rich surface. Iron, calcium, and magnesium cations are abundant in hydrothermal settings on Earth and Mars, a promising environment for an origin of life. We investigated the impact of cations on the stability and disruption of different primitive cell membranes under different pH conditions. The relative destabilizing effect of cations on membranes observed in this study is Ca2+ > Fe2+ > Mg2+. Cation concentrations in Earth systems today are too low to disrupt primitive membranes, but on Mars concentrations could have been elevated enough to disrupt membranes during surface dehydration. Membranes and RNA interact during dehydration-rehydration cycles to mutually stabilize each other in cation-rich solutions, and optimal membrane composition can be 'selected' by environmental factors such as pH and cation concentrations. We introduce an approach that considers how life may have evolved differently under the Martian planetary conditions and selective pressures.

Thermoneutral temperature exposure enhances slow-wave sleep with a correlated improvement in amyloid pathology in a triple-transgenic mouse model of Alzheimer's disease.

Accumulation of amyloid-ß (Aß) plays an important role in Alzheimer's disease (AD) pathology. There is growing evidence that disordered sleep may accelerate AD pathology by impeding the physiological clearance of Aß from the brain that occurs in normal sleep. Therapeutic strategies for improving sleep quality may therefore help slow disease progression. It is well documented that the composition and dynamics of sleep are sensitive to ambient temperature. We therefore compared Aß pathology and sleep metrics derived from polysomnography in 12-month-old female 3xTg-AD mice (n = 8) exposed to thermoneutral temperatures during the light period over 4 weeks to those of age- and sex-matched controls (n = 8) that remained at normal housing temperature (22°C) during the same period. The treated group experienced greater proportions of slow wave sleep (SWS)-i.e. epochs of elevated 0.5-2 Hz EEG slow wave activity during non-rapid eye movement (NREM) sleep-compared to controls. Assays performed on mouse brain tissue harvested at the end of the experiment showed that exposure to thermoneutral temperatures significantly reduced levels of DEA-soluble (but not RIPA- or formic acid-soluble) Aß40 and Aß42 in the hippocampus, though not in the cortex. With both groups pooled together and without regard to treatment condition, NREM sleep continuity and any measure of SWS within NREM at the end of the treatment period were inversely correlated with DEA-soluble Aß40 and Aß42 levels, again in the hippocampus but not in the cortex. These findings suggest that experimental manipulation of SWS could offer useful clues into the mechanisms and treatment of AD.

The Development and Characterization of a Next-Generation Oncolytic Virus Armed with an Anti-PD-1 sdAb for Osteosarcoma Treatment In Vitro.

Osteosarcoma (OS) is a primary bone malignancy characterized by an aggressive nature, limited treatment options, low survival rate, and poor patient prognosis. Conditionally replicative adenoviruses (CRAds) armed with immune checkpoint inhibitors hold great potential for enhanced therapeutic efficacy. The present study aims to investigate the anti-tumor efficacy of CAV2-AU-M2, a CAV2-based CRAd armed with an anti-PD-1 single-domain antibody (sdAb), against OS cell lines in vitro. The infection, conditional replication, cytopathic effects, and cytotoxicity of CAV2-AU-M2 were tested in four different OS cell lines in two-dimensional (2D) and three-dimensional (3D) cell cultures. CAV2-AU-M2 showed selective replication in the OS cells and induced efficient tumor cell lysis and death. Moreover, CAV2-AU-M2 produced an anti-PD-1 sdAb that demonstrated effective binding to the PD-1 receptors. This study demonstrated the first CRAd armed with an anti-PD-1 sdAb. This combined approach of two distinct immunotherapies is intended to enhance the anti-tumor immune response in the tumor microenvironment.

An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells.

Introduction: Osteosarcoma (OSA) is an aggressive form of bone cancer in both dogs and humans. The treatment options for metastatic (stage III) OSA are currently limited and the prognosis is poor. Zoledronate, a second generation amino-bisphosphonate, is commonly used for palliation of cancer induced bone pain. Zoledronate has also demonstrated anti-cancer properties and possibly enhances the cytotoxicity of doxorubicin in a canine histiocytosis cell line and human prostatic cancer cell line. The goal of this study was to evaluate the combination effect of zoledronate and various chemotherapeutic drugs in canine OSA cells. Methods: Canine OSA cell line (D17), cells from two canine primary OSAs, and MDCK, a canine kidney cell line, were used to evaluate the therapeutic potential of these drugs. Carboplatin, doxorubicin, vinorelbine, toceranib, and isophosphoramide mustard (active metabolite of ifosfamide) were used as chemotherapeutic agents. First, cells were treated with either zoledronate or chemotherapy drug alone for 72 hours. Cell viability was assessed using CellTiter Glo and IC5, IC10, IC20, and IC50 were calculated. Second, cells were treated with a combination of zoledronate and each chemotherapeutic agent at their IC5, IC10, IC20, and IC50 concentrations. After 72 hours, cell viability was assessed by CellTiter Glo. Results and discussion: Zoledronate, carboplatin, doxorubicin, vinorelbine, and isophosphoramide mustard showed concentration dependent decrease in cell viability. Toceranib showed decreased cell viability only at higher concentrations. When zoledronate was used in combination with chemotherapy drugs, while it showed potential synergistic effects with toceranib, potential antagonistic effects with vinorelbine and isophosphoramide mustard were observed. However, the results differed by cell line and thus, further evaluation is warranted to understand the exact mechanism of action.

Selective REM sleep restriction in mice using a device designed for tunable somatosensory stimulation.

BACKGROUND: Sleep perturbation is widely used to investigate the physiological mechanisms that mediate sleep-wake dynamics, and to isolate the specific roles of sleep in health and disease. However, state-of-the-art methods to accomplish sleep perturbation in preclinical models are limited in their throughput, flexibility, and specificity. NEW METHOD: A system was developed to deliver vibro-tactile somatosensory stimulation aimed at controlled, selective sleep perturbation. The frequency and intensity of stimulation can be tuned to target a variety of experimental applications, from sudden arousal to sub-threshold transitions between light and deep stages of NREM sleep. This device was activated in closed-loop to selectively interrupt REM sleep in mice. RESULTS: Vibro-tactile stimulation effectively and selectively interrupted REM sleep - significantly reducing the average REM bout duration relative to matched, unstimulated baseline recordings. As REM sleep was repeatedly interrupted, homeostatic mechanisms prompted a progressively quicker return to REM sleep. These effects were dependent on the parameters of stimulation applied. COMPARISON WITH EXISTING METHODS: Existing sleep perturbation systems often require moving parts within the cage and/or restrictive housing. The system presented is unique in that it interrupts sleep without invading the animal's space. The ability to vary stimulation parameters is a great advantage over existing methods, as it allows for adaptation in response to habituation and/or circadian/homeostatic changes in arousal threshold. CONCLUSIONS: The proposed method of stimulation demonstrates feasibility in affecting mouse sleep within a standard home cage environment, thus limiting environmental stress. Furthermore, the ability to tune frequency and intensity of stimulation allows for graded control over the extent of sleep perturbation, which potentially expands the utility of this technology beyond applications related to sleep.

Getting More Out of Clinical Documentation: Can Clinical Dashboards Yield Clinically Useful Information?

This study investigated coded data retrieved from clinical dashboards, which are decision-support tools that include a graphical display of clinical progress and clinical activities. Data were extracted from clinical dashboards representing 256 youth (M age = 11.9) from 128 practitioners who were trained in the Managing and Adapting Practice (MAP) system (Chorpita & Daleiden in BF Chorpita EL Daleiden 2014 Structuring the collaboration of science and service in pursuit of a shared vision. 43(2):323 338. 2014, Chorpita & Daleiden in BF Chorpita EL Daleiden 2018 Coordinated strategic action: Aspiring to wisdom in mental health service systems. 25(4):e12264. 2018) in 55 agencies across 5 regional mental health systems. Practitioners labeled up to 35 fields (i.e., descriptions of clinical activities), with the options of drawing from a controlled vocabulary or writing in a client-specific activity. Practitioners then noted when certain activities occurred during the episode of care. Fields from the extracted data were coded and reliability was assessed for Field Type, Practice Element Type, Target Area, and Audience (e.g., Caregiver Psychoeducation: Anxiety would be coded as Field Type = Practice Element; Practice Element Type = Psychoeducation; Target Area = Anxiety; Audience = Caregiver). Coders demonstrated moderate to almost perfect interrater reliability. On average, practitioners recorded two activities per session, and clients had 10 unique activities across all their sessions. Results from multilevel models showed that clinical activity characteristics and sessions accounted for the most variance in the occurrence, recurrence, and co-occurrence of clinical activities, with relatively less variance accounted for by practitioners, clients, and regional systems. Findings are consistent with patterns of practice reported in other studies and suggest that clinical dashboards may be a useful source of clinical information. More generally, the use of a controlled vocabulary for clinical activities appears to increase the retrievability and actionability of healthcare information and thus sets the stage for advancing the utility of clinical documentation.

Toward Efficient, Sustainable, and Scalable Methods of Treatment Characterization: An Investigation of Coding Clinical Practice from Chart Notes.

PURPOSE: Chart notes provide a low-cost data source that could help characterize what occurs in treatment with sufficient precision to improve management of care. This study assessed the interrater reliability of treatment content coded from chart notes and evaluated its concordance with content coded from transcribed treatment sessions. METHOD: Fifty randomly selected and digitally recorded treatment events were transcribed and coded for practice content. Independent coders then applied the same code system to chart notes for these same treatment events. ANALYSIS: We measured reliability and concordance of practice occurrence and extensiveness at two levels of specificity: practices (full procedures) and steps (subcomponents of those procedures). RESULTS: For chart notes, practices had moderate interrater reliability (M k = 0.50, M ICC = 0.56) and steps had moderate (M ICC = 0.74) to substantial interrater reliability (M k = 0.78). On average, 2.54 practices and 5.64 steps were coded per chart note and 4.53 practices and 13.10 steps per transcript. Across sources, ratings for 64% of practices and 41% of steps correlated significantly, with those with significant correlations generally demonstrating moderate concordance (practice M r = 0.48; step M r = 0.47). Forty one percent of practices and 34% of steps from transcripts were also identified in the corresponding chart notes. CONCLUSION: Chart notes provide an accessible data source for evaluating treatment content, with different levels of specificity posing tradeoffs for validity and reliability, which in turn may have implications for chart note interfaces, training, and new metrics to support accurate, reliable, and efficient measurement of clinical practice.