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Background: Blended care therapy models are intended to increase the efficiency and effectiveness of evidence-based psychotherapy by combining synchronous and asynchronous components of care., Objective: This retrospective cohort study evaluated the clinical effects of synchronous video therapy sessions and asynchronous guided practice session elements on anxiety and depression in a blended care therapy program, with a novel focus on asynchronous provider feedback messages., Methods: Participants were adults (N=33,492) with clinical symptoms of anxiety (Generalized Anxiety Disorder 7-item scale [GAD-7] score of ≥8) and depression (Patient Health Questionnaire 9-item scale [PHQ-9] score of ≥10) at intake. Symptom trajectories were evaluated via individual growth curve models. Time-varying covariates evaluated effects of synchronous video session attendance and the presence or absence of each asynchronous guided practice session element occurring within 7 days and 8-14 days prior to each clinical outcome assessment. Guided practice session elements included client digital lesson completion, client digital exercise completion, and feedback messages sent by providers., Results: Approximately 86.6% (29,012/33,492) of clients met criteria for clinical improvement by end of care (median 6, IQR 4-8 synchronous sessions). Synchronous video session attendance and client digital lesson completion in the past 7 days and in the past 8-14 days were each uniquely and significantly associated with lower GAD-7 scores (video session effects: b session7 =-0.82, b session8-14 =-0.58, P values<.001; digital lesson effects: b lesson7 =-0.18, b lesson8-14 =-0.26, P values <.001) and PHQ-9 scores (video session effects: b session7 =-0.89, b session8-14 =-0.67, P values <.001; digital lesson effects: b lesson7 =-0.12, b lesson8-14 =-0.30, P values <.001). Client digital exercise completion in the past 8-14 days was significantly associated with lower GAD-7 scores (b exercise8-14 =-0.10; P<.001) but exercise completion in the 7 days prior to clinical outcome assessment was not (b exercise7 =0.00; P=.89). Exercise completion in the past 7 days was significantly associated with lower PHQ-9 scores (b exercise7 =-0.16; P<.001) but exercise completion in the past 8-14 days was not (b exercise8-14 =-0.05; P=.09). Provider feedback messaging in the past 7 days and in the past 8-14 days was significantly associated with lower GAD-7 and PHQ-9 scores, respectively (GAD-7: b feedback7 =-0.12, P<.001; b feedback8-14 =-0.07, P=.004; PHQ-9: b feedback7 =-0.15, P<.001; b feedback8-14 =-0.08, P=.01)., Conclusions: Provider feedback between synchronous therapy sessions provided significant benefit for symptom reduction, beyond the effects of client digital engagement and synchronous video sessions. When guided practice sessions are well integrated into care, blended care therapy provides meaningful improvements upon the traditional, synchronous session-only therapy model. Provider guidance and feedback for clients between synchronous sessions support more efficient and effective mental health care overall., (©Hallie M Espel-Huynh, Lu Wang, Emily G Lattie, Robert E Wickham, Alethea Varra, Connie E Chen, Anita Lungu, Jennifer L Lee. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 18.10.2024.)

Background: Patients with cardiovascular disease (CVD) comorbidities are often excluded from participating in breast cancer clinical trials. Consequently, data to inform treatment decisions for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and CVD are limited., Objective: We compared the effectiveness of first-line palbociclib plus an aromatase inhibitor (AI) vs an AI alone and evaluated palbociclib treatment patterns in patients with HR+/HER2- mBC and CVD in routine clinical practice., Methods: Data from the Flatiron Health Analytic Database were captured for patients with HR+/HER2- mBC and CVD who initiated first-line treatment with palbociclib plus an AI or an AI alone between February 2015 and March 2020 (data cutoff: September 30, 2020). Overall survival (OS), real-world progression-free survival (PFS), and treatment patterns were evaluated., Results: Of the 469 patients with identifiable CVD, 160 received palbociclib plus an AI, and 309 received an AI alone. After stabilized inverse probability treatment weighting, both median OS (40.7 vs 26.5 months; hazard ratio [HR], 0.732 [95% CI, 0.537-0.997]; P = .048) and median real-world PFS (20.0 vs 12.5 months; HR, 0.679 [95% CI, 0.512-0.900]; P = .007) were significantly prolonged in patients treated with palbociclib plus an AI vs an AI alone. Among patients with a documented palbociclib starting dose, 78.5% started palbociclib at 125 mg/day, and 38.6% experienced dose adjustment., Conclusions: In this real-world analysis, first-line palbociclib plus an AI was associated with improved effectiveness compared with an AI alone in patients with HR+/HER2- mBC and CVD., Trial Registration: NCT05361655 (ClinicalTrials.gov)., (© The Author(s) 2024. Published by Oxford University Press.)

Endoplasmic reticulum (ER)-mitochondria contact sites play a critical role in cell health and homeostasis, such as the regulation of Ca 2+ and lipid homeostasis, mitochondrial dynamics, autophagosome and mitophagosome biogenesis, and apoptosis. Failure to maintain normal ER-mitochondrial coupling is implicated in many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegia. It is of considerable significance to explore how the dysregulation of ER-mitochondrial contacts could lead to cell death and whether repairing these contacts to the normal level could ameliorate neurodegenerative conditions. Thus, improved assays that measure the level of these contacts could help to illuminate the pathogenic mechanisms of these diseases. Ultimately, establishing simple and reliable assays will facilitate the development of new therapeutic strategies. Here we describe a split-luciferase assay to quantitatively measure the level of ER-mitochondria contacts in live cells. This assay can be used to study the pathophysiological role of these contacts as well as to identify their modulators in high-throughput screening.

The presence of residual undifferentiated pluripotent stem cells (PSCs) in PSC-derived cell therapy products (CTPs) is a major safety issue for their clinical application, due to the potential risk of PSC-derived tumor formation. An international multidisciplinary multisite study to evaluate a droplet digital PCR (ddPCR) approach to detect residual undifferentiated PSCs in PSC-derived CTPs was conducted as part of the Health and Environmental Sciences Institute Cell Therapy-TRAcking, Circulation & Safety Technical Committee. To evaluate the use of ddPCR in quantifying residual iPSCs in a cell sample, different quantities of induced pluripotent stem cells (iPSCs) were spiked into a background of iPSC-derived cardiomyocytes (CMs) to mimic different concentrations of residual iPSCs. A one step reverse transcription ddPCR (RT-ddPCR) was performed to measure mRNA levels of several iPSC-specific markers and to evaluate the assay performance (precision, sensitivity, and specificity) between and within laboratories. The RT-ddPCR assay variability was initially assessed by measuring the same RNA samples across all participating facilities. Subsequently, each facility independently conducted the entire process, incorporating the spiking step, to discern the parameters influencing potential variability. Our results show that a RT-ddPCR assay targeting ESRG, LINC00678, and LIN28A genes offers a highly sensitive and robust detection of impurities of iPSC-derived CMs and that the main contribution to variability between laboratories is the iPSC-spiking procedure, and not the RT-ddPCR. The RT-ddPCR assay would be generally applicable for tumorigenicity evaluation of PSC-derived CTPs with appropriate marker genes suitable for each CTP., (© The Author(s) 2024. Published by Oxford University Press.)

Aim: To evaluate the impact of palbociclib treatment on health-related quality of life (HRQoL) in patients with hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer (HR+/HER2- aBC) or metastatic breast cancer (mBC) in both the clinical and real-world setting. Materials & methods: A systematic literature review was conducted to identify clinical trials and real-world evidence studies up to June 2023 that reported HRQoL outcomes in patients with HR+/HER2- aBC or mBC treated with Palbociclib. Results: 15 unique studies reported across 35 records were identified. Of these, seven were randomized controlled trials (RCTs), three were single-arm clinical trials and five were real-world evidence (RWE) studies. HRQoL was generally found to be maintained in patients with HR+/HER2- aBC or mBC across RCTs, single-arm clinical trials and RWE studies. HRQoL measures across instruments, study types and line of therapy, were largely reported to be at least maintained if not improved from baseline among patients treated with palbociclib and were observed to be comparable or better in the palbociclib group versus monotherapy control arm in RCTs. Similar results were seen for treatment-related outcomes (e.g., sexual functioning, upset by hair loss, systemic therapy side effects etc.), and important individual patient outcomes, including pain, fatigue and physical functioning. Findings were also consistent across key clinical characteristics (visceral metastases, neutropenia), as well as patient populations often underrepresented in clinical trials (Asian patients, older adults). Conclusion: Overall, current evidence suggests that HRQoL is largely preserved with the addition of palbociclib to endocrine therapy in patients with HR+/HER2- aBC or mBC across study types and populations.

Purpose: To examine the safety and efficacy of soft multifocal contact lenses on slowing the rate of myopia progression., Methods: A prospective, randomized, double-masked clinical trial was conducted including 115 children (55 boys and 60 girls) aged 8 to 15 years. Children were assigned to wear one of two daily disposable soft contact lens designs; a multifocal design (Pegavision) or a dual-focus design (MiSight, Coopervision) in both eyes for at least 8 h per day for one year. All contact lenses were replaced on a daily basis. Measurements were obtained using a logMAR vision meter, including objective refraction, handheld retinoscopy, high (96 %) and low (12 %) contrast sensitivity, and distance and near visual acuity. Axial length was measured every 6 months., Results: After one year, the spherical equivalent refractive error and axial length of the experimental group (Pegavision) increased by -0.50 ± 0.48 D and 0.24 ± 0.16 mm, respectively, in the right eye and -0.47 ± 0.37 D and 0.23 ± 0.16 mm, respectively, in the left eye. The spherical equivalent refractive error and axial length of the control group (MiSight) increased by -0.48 ± 0.47 D and 0.22 ± 0.13 mm, respectively, in the right eye and by -0.50 ± 0.44 D and 0.23 ± 0.14 mm, respectively, in the left eye, with no significant differences observed between the two lens types., Conclusions: The one-year results from this clinical trial show that the multifocal soft contact lenses used in the experimental group have a similar myopia control efficacy with respect to spherical equivalent refraction and axial length elongation as a commercially available dual focus soft contact lens design., (Copyright © 2024. Published by Elsevier Ltd.)

Exosomes are membranous structures measuring between 40-120 nm that are secreted by various cells of the human body into the body fluid system. Exosomes contain proteins, mRNA, miRNA, and signaling molecules, and physiologically they assist in the intercellular transport of proteins and RNA molecules. In this study, we used an immunoaffinity filter paper platform combined with scanning electron microscopy and microfluidic systems to detect the size of exosomes within the aqueous humor. Eight aqueous humor samples showed three distinct sizes of exosomes that were significantly different on scanning electron microscopy( P  < 0.01). We further used nanoparticle tracking analysis to assess the size distribution of exosomes within the aqueous humor. We found significantly different distributions of exosomes between patients with three different ocular diseases and patients with normal cataracts as controls. An obvious peak of exomeres(size around 35 nm)was found in the patients with central retinal vein occlusion and vitreous hemorrhage. Flare-ups of large exosomes(size 90-120 nm)were found in the patients with the inflammatory ocular disease pars planitis. No obvious peaks in exomeres or large exosomes were found in the control group. There was a high association between the distribution of exosomes and the pathogenesis of ocular diseases. After intravitreal anti-vascular endothelial growth factor treatment, the aqueous humor from the patients with neovascular diseases showed a significant reduction in exosomes in nanoparticle tracking analysis. These findings suggest that at least three distinct sizes of exosomes exist in the aqueous humor:(1)exomeres:<35 nm;(2)small exosomes:60-80 nm; and (3)large exosomes:90-120 nm. Different sizes of exosomes may have different implications in normal or diseased eyes.

Background and Objective: Stress urinary incontinence (SUI) is the involuntary loss of urine affecting 1-3% of the male population. To manage leakage, patients may try a plethora of penile clamps. and may even consider artificial urinary sphincters (AUS) or sling implantation. We aimed to synthesize the evolution of the modern clamp, AUS, and sling through a comprehensive patent search., Methods: Patents were found through the databases of United States Patent and Trademark Office (USPTO), GooglePatents, and the World Intellectual Property Office Patentscope, covering patents published through January 6, 2024., Key Content and Findings: We found 30 different patents (10 clamps, 13 AUS, and 7 slings), including the patents pertaining to the functionalities and design of five commercially available penile clamps, the American Medical System 800 (AMS 800), the InVance, AdVance, AdVance XP, and Virtue Slings. The clamps, spanning back to 1938 with Bard Cunningham's clamp, have undergone significant refinements. For example, inventors such as Edson S. Outwin and Juan F. V. Wiesner, have modified the location of the primary pressure point. Accessibility has also improved with inventors, such as Gerald French and John W. Timmons, fastening the clamps with Velcro ® , as opposed to the screw and ratchet catch closing mechanism, as in Cunningham's clamp. Similarly, the AUS has greatly evolved since Foley's 1947 "Artificial Sphincter and Method", which was the primary AUS precedent to Mark Polyak's AUS invention, which covered the essential elements and functionalities, such as the incorporation of a balloon reservoir, for the AMS 800. In addressing AUS limitations, inventors such as David W. Anderson and Louisa Thomas have created non-hydraulic AUSs. Likewise, the male sling has seen an evolution in the method of securement, from the use of fixed bone anchors in the InVance sling to the transobturator route used in the AdVance XP, avoiding bone complications. Additionally, innovation in sling adjustment of urethral compression allows for adjustable urethral elevation and distal compression respectively. Recent patents have claimed technological integration for clamps, AUS, and slings, especially concerning automation., Conclusions: Overall, patents have built upon the limitations of previous devices. However, there is still a need to innovate for increased clamp comfort and reduced reoperation rates for the AUS and sling., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-115/coif). A.J.C. reports that he supplemented the patent search with one patent filed by him titled “Memory Shape Alloy”. The other authors have no conflicts of interest to declare., (2024 Translational Andrology and Urology. All rights reserved.)

Corneal techniques for enhancing near and intermediate vision to correct presbyopia include surgical and contact lens treatment modalities. Broad approaches used independently or in combination include correcting one eye for distant and the other for near or intermediate vision, (termed monovision or mini-monovision depending on the degree of anisometropia) and/or extending the eye's depth of focus [1]. This report reviews the evidence for the treatment profile, safety, and efficacy of the current range of corneal techniques for managing presbyopia. The visual needs and expectations of the patient, their ocular characteristics, and prior history of surgery are critical considerations for patient selection and preoperative evaluation. Contraindications to refractive surgery include unstable refraction, corneal abnormalities, inadequate corneal thickness for the proposed ablation depth, ocular and systemic co-morbidities, uncontrolled mental health issues and unrealistic patient expectations. Laser refractive options for monovision include surface/stromal ablation techniques and keratorefractive lenticule extraction. Alteration of spherical aberration and multifocal ablation profiles are the primary means for increasing ocular depth of focus, using surface and non-surface laser refractive techniques. Corneal inlays use either small aperture optics to increase depth of field or modify the anterior corneal curvature to induce corneal multifocality. In presbyopia correction by conductive keratoplasty, radiofrequency energy is applied to the mid-peripheral corneal stroma, leading to mid-peripheral corneal shrinkage and central corneal steepening. Hyperopic orthokeratology lens fitting can induce spherical aberration and correct some level of presbyopia. Postoperative management, and consideration of potential complications, varies according to technique applied and the time to restore corneal stability, but a minimum of 3 months of follow-up is recommended after corneal refractive procedures. Ongoing follow-up is important in orthokeratology and longer-term follow-up may be required in the event of late complications following corneal inlay surgery., Competing Interests: Declaration of competing interest Jennifer P. Craig, Connie Chen, Obinwanne Chukwuemeka Jr, Lucia Pelosini, Michael T.M. Wang, Mohammed Ziaei have no declarations of competing interest. Allon Barsamm is a paid Consultant for Schwind eye tech solutions. Neema Ghorbani-Mojarrad provides consultancy to CooperVision, Eyerising International and Hoya and has had grant funding from CooperVision, Eyerising International, Hoya, Menicon, Rodenstock and SILMO Academy. Florian Kretz provides consultancy to Carl Zeiss Meditech, Teleon, VSY, BVI and Elios. Langis Michaud provides consultancy to Johnson and Johnson Vision, Bausch + Lomb. Johnny Moore provides consultancy to Zeiss and Cristalens. Andrew M J Turnbull is a paid consultant for Rayner, Thea, Scope and Bausch + Lomb. Stephen J. Vincent has had grant funding from CooperVision and Menicon. James S. Wolffsohn has received grant funding from Alcon and Rayner, is a paid consultant for Alcon, Atia Vision and Bausch + Lomb, and has stock ownership in Wolffsohn Research Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Clinical Relevance: Contact lens neophytes often learn about contact lens insertion and removal through YouTube videos of unknown quality., Background: This study evaluates the quality of soft contact lens insertion and removal videos on YouTube., Methods: A search for the keywords 'Contact lens insertion', 'Contact lens removal', 'Put in contact lens', and 'Take off contact lens' was performed on YouTube. The first 50 videos for each keyword were evaluated. The number of views, source of the publisher, days since upload, and video quality were scored based on the content in the videos. The maximum score of insertion and removal videos were 7 and 5 respectively. The videos were classified into three groups by publisher category: videos published by eye care professionals, companies and YouTubers., Results: Only 45 contact lens insertion and 44 removal videos met the inclusion criteria and were analysed. Insertion and removal videos published by YouTubers had the highest view and view rate. However, their quality scores were significantly lower than videos published by eye care professionals and companies. Videos uploaded by companies had the highest scores (insertion: 5.00 ± 1.10; removal: 3.25 ± 0.75). The mean scores of insertion and removal videos published by YouTubers were 1.65 ± 0.93 and 1.00 ± 0.89, respectively, while the insertion and removal videos uploaded by eye care professionals scored 3.58 ± 2.07 and 2.75 ± 1.53, respectively. There was also a negative correlation between the quality scores and view rate ( p  = 0.008, r  = -0.41)., Conclusion: Contact lens insertion and removal videos uploaded by YouTubers had the highest view rate but the lowest quality. Videos made by companies included most essential elements.

Resident cardiac macrophages are critical mediators of cardiac function. Despite their known importance to cardiac electrophysiology and tissue maintenance, there are currently no stem-cell-derived models of human engineered cardiac tissues (hECTs) that include resident macrophages. In this study, we made an induced pluripotent stem cell (iPSC)-derived hECT model with a resident population of macrophages (iM0) to better recapitulate the native myocardium and characterized their impact on tissue function. Macrophage retention within the hECTs was confirmed via immunofluorescence after 28 days of cultivation. The inclusion of iM0s significantly impacted hECT function, increasing contractile force production. A potential mechanism underlying these changes was revealed by the interrogation of calcium signaling, which demonstrated the modulation of β-adrenergic signaling in +iM0 hECTs. Collectively, these findings demonstrate that macrophages significantly enhance cardiac function in iPSC-derived hECT models, emphasizing the need to further explore their contributions not only in healthy hECT models but also in the contexts of disease and injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Joint access is essential for arthrocentesis, or joint aspiration of fluids. Joint treatments that are not performed properly can result in avoidable patient issues such as damage to the muscles, tendons, and blood vessels surrounding the joint. The use of ultrasound has become the gold standard for this procedure and proven to be a support in the skill learning process. However, success with this equipment, particularly in small joints like the wrist, depends on a clinician's capacity to recognize the crucial landmarks that guide these procedures. Prior to executing on a real patient, task trainers have proven to be an effective way for doctors to practice and prepare for procedures. However, shortcomings of current solutions include high purchase costs, incompatibility with ultrasound imaging, and low reusability. In addition, since this is a procedure that is not performed frequently, there may not be space or resources available in healthcare facilities to accommodate one at the point of care. This study aimed to close the existing gap by developing a DIY ultrasound compatible task trainer for wrist joint access training., Results: We developed a novel ultrasound compatible wrist joint model that can be made from sustainable materials and reusable parts, thus reducing the costs for acquisition and environmental impact. Our model, which was produced utilizing small-batch production methods, is made up of 3D-printed bones enclosed in an ultrasound-compatible gelatin mixture. It can be easily remade after each practice session, removing needle tracks that are visible under ultrasound for conventional phantoms. The ultrasonic properties of this model were tested through pixel brightness analysis and visual inspection of simulated anatomical structures., Conclusion: Our results report the advantages and limitations of the proposed model regarding production, practice, and ultrasound compatibility. While future work entails the transfer to patients of the same skill, this reusable and replicable model has proven, when presented to experts, to be successful in representing the physical characteristics and ultrasound profile of significant anatomical structures. This novel DIY product could be an effective alternative to teach procedures in the context of resource-restrained clinical simulation centers., (© 2024. The Author(s).)

Mutations in aristaless-related homeobox ( ARX ) are associated with neurodevelopmental disorders including developmental epilepsies, intellectual disabilities, and autism spectrum disorders, with or without brain malformations. Aspects of these disorders have been linked to abnormal cortical interneuron (cIN) development and function. To further understand ARX's role in cIN development, multiple Arx mutant mouse lines were interrogated. We found that ARX is critical for controlling cIN numbers and distribution, especially, in the developing marginal zone (MZ). Single cell transcriptomics and ChIP-seq, combined with functional studies, revealed ARX directly or indirectly regulates genes involved in proliferation and the cell cycle (e.g., Bub3 , Cspr3 ), fate specification (e.g., Nkx2.1 , Maf , Mef2c ), and migration (e.g., Nkx2.1 , Lmo1 , Cxcr4 , Nrg1 , ErbB4 ). Our data suggest that the MZ stream defects primarily result from disordered cell-cell communication. Together our findings provide new insights into the mechanisms underlying cIN development and migration and how they are disrupted in several disorders.

Background: Palbociclib in combination with endocrine therapy is approved for treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. In addition to clinical trials, several real-world studies have evaluated the effectiveness of palbociclib. With increased life expectancy in the general population, breast cancer in older women is also expected to increase., Objective: The aim was to systematically review evidence from both clinical trials and real-world studies for palbociclib treatment outcomes in older patients with HR+/HER2- advanced/metastatic breast cancer (a/mBC). Older patients are often underrepresented in clinical trials, and real-world evidence (RWE) will enrich the analysis of palbociclib outcomes in this subgroup of patients., Design: A systematic literature search in PubMed, EMBASE, and Cochrane Library through May 4, 2023, yielded 2355 unique articles. A total of 52 articles (13 and 39 articles reporting results from seven randomized controlled trials [RCTs] and 37 RWE studies, respectively) were included based on study eligibility criteria., Results: All RCTs used age cutoffs of ≥ 65 years to define older population (n = 722; 437 received palbociclib); all RWE studies, except one with an age cutoff of > 60 years, had age cutoffs of ≥ 65 years or higher to define older population (n = 9840; 7408 received palbociclib). Overall, in studies that compared efficacy (progression-free survival [seven RCTs, 20 RWE studies], overall survival [four RCTs, 11 RWE studies], tumor response [three RWE studies], and clinical benefit rate [one RCT, two RWE studies]) and safety outcomes (three RCTs, three RWE studies) between older and younger patients, palbociclib showed similar benefits, regardless of age. Results from two RCTs and two RWE studies showed that global quality of life (QoL) was maintained in older patients receiving palbociclib. Overall, palbociclib dose modifications (two RWE studies), dose reductions (one RCT, seven RWE studies), and treatment discontinuation rates (three RCTs, three RWE studies) were higher in older patients compared with younger patients; however, these differences did not appear to adversely impact efficacy outcomes., Conclusions: In this systematic review, data from RCTs showed that palbociclib was effective, well tolerated, and maintained QoL in older patients with HR+/HER2- a/mBC. Palbociclib treatment in older patients in real-world settings was associated with similar clinical benefit as in RCTs., Prospero Registration: CRD42023444195., (© 2024. The Author(s).)

Aim: Provide real-world data on palbociclib as evidence of effectiveness in patient populations from routine clinical practice. Methods: This was a retrospective, observational cohort study of patients with HR+/HER2- metastatic breast cancer treated with palbociclib plus aromatase inhibitor (AI) or AI alone as first-line therapy within the US Oncology Network. Results: Patients treated with palbociclib plus AI (n = 838) versus AI alone (n = 450) had a numerically longer median overall survival (42.1 vs 35.7 months; hazard ratio [HR] = 0.90 [95% CI: 0.75-1.07]; p = 0.117) and a significantly extended real-world progression-free survival (21.0 vs 15.7 months; HR = 0.75 [95% CI: 0.64-0.88]; p = 0.0002) after normalized inverse probability treatment weighting. Conclusion: These real-world results support the use of palbociclib plus AI as first-line treatment in routine clinical practice for patients with HR+/HER2- metastatic breast cancer.

There are limited real-world comparative effectiveness data for palbociclib plus an aromatase inhibitor (AI) as a first-line (1L) treatment examining endpoints that require long term follow-up and post 1L progression. The Flatiron Health Analytic Database was used to characterize treatment and dosing patterns in patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) receiving palbociclib plus an AI vs an AI alone in routine US clinical practice. In addition, time to chemotherapy (TTC) and real-world progression-free survival (rwPFS) when combining 1L and second-line of therapy (rwPFS2) were assessed. Of 1324 patients who received palbociclib plus an AI between February 3, 2015 and March 31, 2020, 1110 (83.8%) started palbociclib at the recommended 125 mg/day dose. After stabilized inverse probability treatment-weighting (sIPTW), median TTC in patients treated with palbociclib plus an AI and AI alone was 37.4 months (95% confidence interval [CI], 33.7-40.7) and 29.2 months (95% CI, 26.8-33.5), respectively (hazard ratio [HR] = 0.77 [95% CI, 0.69-0.86], P < .0001); median rwPFS2 was 32.6 months (95% CI, 29.4-35.2) and 20.7 months (95% CI, 18.9-22.6), respectively (HR = 0.62 [95% CI, 0.54-0.70], P < .0001). Sensitivity analyses with propensity score matching showed similar results to sIPTW analyses. Results from this large real-world study examining additional effectiveness outcomes beyond 1L rwPFS and overall survival support the use of palbociclib plus an AI as a 1L treatment for patients with HR+/HER2- mBC., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (HESI-DART) group held a hybrid in-person and virtual workshop in Washington, DC, in 2022. The workshop was entitled, "Interpretation of DART in Regulatory Contexts and Frameworks." There were 154 participants (37 in person and 117 virtual) across 9 countries. The purpose of the workshop was to capture key consensus approaches used to assess DART risks associated with chemical product exposure when a nonclinical finding is identified. The decision-making process for determining whether a DART endpoint is considered adverse is critical because the outcome may have downstream implications (e.g., increased animal usage, modifications to reproductive classification and pregnancy labeling, impact on enrollment in clinical trials and value chains). The workshop included a series of webinar modules to train and engage in discussions with federal and international regulators, clinicians, academic investigators, nongovernmental organizations, contract research organization scientists, and private sector scientists on the best practices and principles of interpreting DART and new approach methodologies in the context of regulatory requirements and processes. Despite the differences in regulatory frameworks between the chemical and pharmaceutical sectors, the same foundational principles for data interpretation should be applied. The discussions led to the categorization of principles, which offer guidance for the systematic interpretation of data. Step 1 entails identifying any hazard by closely analyzing the data at the study endpoint level, while Step 2 involves assessing risk using weight of evidence. These guiding principles were derived from the collective outcomes of the workshop deliberations., (© 2024 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

What Is This Summary About?: This summary is about a study that was published in the medical journal The Oncologist in July 2023. The combination of palbociclib with an aromatase inhibitor (AI) was approved by the FDA in 2015 as a treatment for people with hormone receptor -positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, the effectiveness of palbociclib in African-Americans with MBC is not well studied. The goal of this study was to find out whether adding palbociclib to an AI helped African-Americans with HR+/HER2- MBC live longer., What Are the Key Takeaways?: This study used de-identified medical information from the Flatiron Database. This database contains healthcare information on people with cancer treated by doctors in the United States but personal information is removed to maintain privacy. Medical information for people who received certain treatments in routine clinical practice or real-world setting was included in the study.This study showed that in the real-world setting, African-Americans with HR+/HER2- MBC lived longer when receiving palbociclib with an AI than with an AI alone. Also, the study showed that African-Americans treated with palbociclib plus an AI lived longer without their cancer getting worse than those treated with an AI alone., What Was the Main Conclusion Reported by the Researchers?: These results support the use of palbociclib with an AI as a first treatment for African-Americans with HR+/HER2- MBC. Clinical Trial Registration: NCT05361655 (ClinicalTrials.gov).

What Is This Summary About?: This summary describes an article published in the medical journal Frontiers in Oncology in September 2023. The article reports results from a study that looked at breast cancer treatments for older patients aged 75 years or older. The study focused on a type of cancer called HR+/HER2- metastatic breast cancer. HR+/HER2- stands for hormone receptorpositive/human epidermal growth factor receptor 2-negative. This study evaluated whether older patients with this type of cancer benefited from the combination of two medicines - palbociclib and an aromatase inhibitor - compared with taking an aromatase inhibitor alone., How Was the Study in This Summary Carried Out?: The Flatiron database contains medical records for people with cancer in the US. This study used deidentified health care information from this database. 'Deidentified' means that all information that could identify an individual was removed to protect individuals' privacy. People in this study received treatment in routine care and not in a clinical trial., What Do the Results Mean?: Older patients who took palbociclib plus an aromatase inhibitor lived longer than those who took an aromatase inhibitor alone. Older patients who took palbociclib plus an aromatase inhibitor also lived longer without their cancer getting worse and started chemotherapy later than those who took an aromatase inhibitor alone. These results support using palbociclib plus an aromatase inhibitor as the first treatment for patients aged 75 years or older with HR+/HER2- metastatic breast cancer.

Aim: Patients with metastatic breast cancer (MBC) may be vulnerable to changes in healthcare management, safety standards and protocols that occurred during the COVID-19 pandemic. Materials & methods: The REthink Access to Care & Treatment (REACT) survey assessed USA-based patient perspectives on COVID-19-related impacts to their MBC treatment experience between 27 April 2021 and 17 August 2021. Results: Participants (n = 341; 98.5% females, mean age 50.8 years) reported that overall oncology treatment quality was maintained during the pandemic. Delayed/canceled diagnostic imaging was reported by 44.9% of participants while telemedicine uptake was high among participants (80%). Conclusion: Overall, MBC care was minimally affected by the pandemic, possibly due to the expanded use of telemedicine, informing MBC management for future public health emergencies.

Background: Studies have reported positive outcomes of blended care therapy (BCT), which combines face-to-face care with internet modules. However, there is insufficient evidence of its effectiveness across racial and ethnic groups. This study evaluated outcomes of a BCT program, which combined video psychotherapy with internet cognitive-behavioral modules, across race and ethnicity., Methods: Participants were 6492 adults, with elevated anxiety (Generalized Anxiety Disorder-7 [GAD-7] ≥ 8) and/or depression (Patient Health Questionnaire-9 [PHQ-9] ≥ 10) symptoms, enrolled in employer-offered BCT. Changes in anxiety (GAD-7) and depression (PHQ-9) symptoms during treatment were evaluated using individual growth curve models. Interaction terms of time with race and ethnicity tested for between-group differences. Treatment satisfaction was assessed using a Net Promoter measure (range = 1 (lowest satisfaction) to 5 (greatest satisfaction))., Results: Participants' self-reported race and ethnicity included Asian or Pacific Islander (27.5%), Black or African American (5.4%), Hispanic or Latino (9.3%), and White (47.2%). Anxiety symptoms decreased during treatment (p < 0.01), with greater reductions among Hispanic or Latino participants compared to White participants (p < 0.05). Depressive symptoms decreased across treatment (p < 0.01), with significantly greater decreases among some racial and ethnic groups compared to White participants. Declines in anxiety and depressive symptoms slowed across treatment (p's < 0.01), with statistically significant differences in slowing rates of depressive symptoms across some racial and ethnic groups. Among participants with responses (28.45%), average treatment satisfaction ranged from 4.46 (SD = 0.73) to 4.67 (SD = 0.68) across race and ethnicity (p = 0.001). Racial and ethnic differences in outcomes were small in magnitude., Conclusions: BCT for anxiety and depression can be effective across diverse racial and ethnic groups., (© 2022. The Author(s).)

A cyclin-dependent kinase 4/6 inhibitor combined with endocrine therapy is the standard of care for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC), but real-world effectiveness data for patients with lung or liver metastases are limited. This retrospective study included data from the US Flatiron Health database of patients with HR+/HER2- mBC and lung or liver metastases treated with first-line palbociclib (PAL) plus an aromatase inhibitor (AI) or an AI alone in routine clinical practice. Overall survival (OS) and real-world progression-free survival (rwPFS) were assessed. A total of 891 patients were included (622 with lung metastasis, 376 with liver metastasis, and 107 with both lung and liver metastasis). After stabilized inverse probability of treatment weighting to balance patient characteristics, PAL + AI versus AI alone was associated with significantly prolonged OS (HR = 0.62; p < 0.001) and rwPFS (HR = 0.55; p < 0.001) in patients with lung metastases and numerically longer OS (HR = 0.73; p = 0.056) and significantly longer rwPFS (HR = 0.57, p < 0.001) for those with liver metastases. Overall, PAL + AI versus AI alone was associated with prolonged OS and rwPFS in routine clinical practice, supporting the use of first-line PAL + AI for patients with HR+/HER2- mBC with lung and/or liver metastases.

Background: Disparities in survival and clinical outcomes between African American and White patients with breast cancer (BC) are well documented, but African American patients have not been well represented in randomized clinical trials of CDK4/6 inhibitors. Real-world studies can provide evidence for effective treatment strategies for underreported patient populations., Patients and Methods: This retrospective analysis of African American patients with HR+/HER2- metastatic breast cancer (mBC) from the Flatiron Health longitudinal database evaluated treatments for patients with BC in routine clinical practice in the US. Patients initiated first-line therapy with palbociclib plus an aromatase inhibitor (AI) or AI alone between February 2015 and March 2020. Outcomes assessed included overall survival (OS) and real-world progression-free survival (rwPFS) until September 2020., Results: Of 270 eligible patients, 127 (median age 64 years) were treated with palbociclib + AI, and 143 (median age 68 years) were treated with an AI. Median follow-up was 24.0 months for palbociclib + AI and 18.2 months for AI-treated patients. Median OS was not reached (NR; 95% CI, 38.2-NR) in the palbociclib + AI group versus 28.2 months (95% CI, 19.2-52.8) in the AI group (adjusted HR, 0.56; 95% CI, 0.36-0.89; P = .013). Median rwPFS was 18.0 months (95% CI, 12.4-26.7) in the palbociclib + AI group and 10.5 months (95% CI, 7.0-13.4) in the AI group (adjusted HR, 0.74; 95% CI, 0.47-1.17; P = .199)., Conclusion: This comparative analysis of palbociclib + AI versus AI alone indicates that palbociclib combined with endocrine therapy in the first line is associated with improved effectiveness for African American patients with HR+/HER2- mBC in real-world settings., Trial Number: NCT05361655., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Elderly patients are generally underrepresented in oncology clinical trials; therefore, real-world data are needed to inform clinical management of elderly patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). This subanalysis of the P-REALITY X study (NCT05361655) evaluated palbociclib treatment patterns and comparative effectiveness of palbociclib plus an aromatase inhibitor (AI) versus an AI alone among patients with HR+/HER2- mBC aged ≥ 75 years treated in routine clinical practice in the United States., Methods: This retrospective observational cohort study used electronic health records from the Flatiron Health Analytic Database. Palbociclib treatment patterns, overall survival (OS), real-world progression-free survival (rwPFS), and time to chemotherapy (TTC) were evaluated. Three methods were used for comparative analyses: (1) an unadjusted analysis, (2) stabilized inverse probability treatment weighting (sIPTW; primary analysis), and (3) propensity score matching (PSM; sensitivity analysis)., Results: A total of 961 patients aged ≥ 75 years with HR+/HER2- mBC were identified who started palbociclib plus an AI (n = 313) or an AI alone (n = 648) as first-line (1L) therapy between February 2015 and March 2020 (data cut-off: September 30, 2020). Among patients in the palbociclib plus an AI group with a documented palbociclib starting dose (n = 306), approximately 75% started palbociclib at 125 mg/day, and approximately 40% experienced dose adjustment. After sIPTW, patients treated with palbociclib plus an AI versus an AI alone had significantly improved OS (median of 43.0 vs. 32.4 months; hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.51-0.84]; P = 0.0007), rwPFS (median of 20.0 vs. 15.0 months; HR, 0.72 (0.59-0.89); P = 0.0021), and TTC (median of 40.2 vs. 27.4 months; HR, 0.69 [0.55-0.87]; P = 0.0014). These significant improvements in OS, rwPFS, and TTC remained consistent in the unadjusted analysis and after PSM., Conclusion: This real-world comparative analysis demonstrated that 1L palbociclib plus an AI is associated with improved effectiveness compared with an AI alone among patients with HR+/HER2- mBC aged ≥ 75 years. These findings support palbociclib plus an AI as a standard-of-care 1L treatment for elderly patients with HR+/HER2- mBC., Competing Interests: AB has received grants from Agendia and AstraZeneca, and consulting fees or honoraria from AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, Seagen, Daiichi Sankyo, Merck, Agendia, Sanofi, and Puma. XL, BL, LM, and CC are employees of and stockholders in Pfizer. RL reports advisory/consultancy fees from Novartis, Eli Lilly, Pfizer, and Celcuity, and research/grant funding from Pfizer, Novartis, Eli Lilly, Zentalis, Puma, Celcuity, Accutar Biotechnology, and Arvinas. HR reports sponsored research to her institution from Pfizer, Merck, Novartis, Eli Lilly, Roche, Daiichi-Sankyo, Seagen, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Ayala, and Gilead, and honoraria from Puma, Samsung, and Mylan. The authors declare that this study received funding from Pfizer. The funder had the following involvement in the study: data acquisition, study design, data analysis, and co-authoring the paper., (Copyright © 2023 Brufsky, Liu, Li, McRoy, Chen, Layman and Rugo.)

The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Background: Limited real-world data exist regarding the efficacy of palbociclib in combination with endocrine therapy in pre/perimenopausal women with metastatic breast cancer., Objective: We aimed to compare real-world tumor responses among pre/perimenopausal women who initiated palbociclib plus an aromatase inhibitor (AI) or AI monotherapy as first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer., Methods: This retrospective observational cohort study (NCT05012644) used electronic health record data from The US Oncology Network. Tumor responses were determined based on treating clinicians' assessments of radiologic evidence for changes in disease burden. Normalized inverse probability treatment weighting was used to balance baseline characteristics between treatment cohorts., Results: Of 196 pre/perimenopausal women, 116 and 80 were in the palbociclib plus AI cohort and AI cohort, respectively. Real-world response rates (complete or partial response) were 52.1% and 46.2%, respectively (odds ratio, 1.27 [95% confidence interval 0.72‒2.24]). Among patients with one or more tumor assessments on treatment, real-world response rates were 60.0% in the palbociclib plus AI cohort (n = 103) and 49.9% in the AI cohort (n = 71; odds ratio, 1.51 [95% confidence interval 0.82‒2.77])., Conclusions: This real-world analysis suggests that pre/perimenopausal patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer appear more likely to respond to palbociclib plus AI versus AI alone as first-line therapy, which may support the combination as a standard-of-care treatment for this patient population., (© 2023. The Author(s).)

Error-corrected Next Generation Sequencing (ecNGS) is rapidly emerging as a valuable, highly sensitive and accurate method for detecting and characterizing mutations in any cell type, tissue or organism from which DNA can be isolated. Recent mutagenicity and carcinogenicity studies have used ecNGS to quantify drug-/chemical-induced mutations and mutational spectra associated with cancer risk. ecNGS has potential applications in genotoxicity assessment as a new readout for traditional models, for mutagenesis studies in 3D organotypic cultures, and for detecting off-target effects of gene editing tools. Additionally, early data suggest that ecNGS can measure clonal expansion of mutations as a mechanism-agnostic early marker of carcinogenic potential and can evaluate mutational load directly in human biomonitoring studies. In this review, we discuss promising applications, challenges, limitations, and key data initiatives needed to enable regulatory testing and adoption of ecNGS - including for advancing safety assessment, augmenting weight-of-evidence for mutagenicity and carcinogenicity mechanisms, identifying early biomarkers of cancer risk, and managing human health risk from chemical exposures., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.C., L.C., J.E., P.A.E, T.H. Jr, D.K., A.M.L., J.J.S., S.Z. and S.M. are employed by companies that may be engaged in using error-corrected sequencing. J.J.S is an employee and equity holder at TwinStrand Biosciences Inc. and is an author on one or more duplex sequencing-related patents., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Coronavirus disease 2019 (COVID-19) vaccines are associated with several ocular manifestations. Emerging evidence has been reported; however, the causality between the two is debatable. We aimed to investigate the risk of retinal vascular occlusion after COVID-19 vaccination. This retrospective cohort study used the TriNetX global network and included individuals vaccinated with COVID-19 vaccines between January 2020 and December 2022. We excluded individuals with a history of retinal vascular occlusion or those who used any systemic medication that could potentially affect blood coagulation prior to vaccination. To compare the risk of retinal vascular occlusion, we employed multivariable-adjusted Cox proportional hazards models after performing a 1:1 propensity score matching between the vaccinated and unvaccinated cohorts. Individuals with COVID-19 vaccination had a higher risk of all forms of retinal vascular occlusion in 2 years after vaccination, with an overall hazard ratio of 2.19 (95% confidence interval 2.00-2.39). The cumulative incidence of retinal vascular occlusion was significantly higher in the vaccinated cohort compared to the unvaccinated cohort, 2 years and 12 weeks after vaccination. The risk of retinal vascular occlusion significantly increased during the first 2 weeks after vaccination and persisted for 12 weeks. Additionally, individuals with first and second dose of BNT162b2 and mRNA-1273 had significantly increased risk of retinal vascular occlusion 2 years following vaccination, while no disparity was detected between brand and dose of vaccines. This large multicenter study strengthens the findings of previous cases. Retinal vascular occlusion may not be a coincidental finding after COVID-19 vaccination., (© 2023. The Author(s).)

Wnt signaling plays a major role in regulating cell proliferation and differentiation. The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either through β-catenin in the canonical pathway or through a series of other proteins in the noncanonical pathway. Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body, establishing the complex interplay between Wnt signaling and other signaling pathways. This crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ processes. Dysregulation of this system has been implicated in many diseases affecting a wide array of organ systems, including cancer and embryological defects, and can even cause embryonic lethality. The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments. However, both stimulatory and inhibitory treatments come with potential risks that need to be addressed. This review synthesized much of the current knowledge on the Wnt signaling pathway, beginning with the history of Wnt signaling. It thoroughly described the different variants of Wnt signaling, including canonical, noncanonical Wnt/PCP, and the noncanonical Wnt/Ca 2+ pathway. Further description involved each of its components and their involvement in other cellular processes. Finally, this review explained the various other pathways and processes that crosstalk with Wnt signaling., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Aim & methods: The Health and Environmental Sciences Institute Cell Therapy-TRAcking, Circulation & Safety Technical Committee launched an international, multisite study to evaluate the sensitivity and reproducibility of the highly efficient culture (HEC) assay, an in vitro assay to detect residual undifferentiated human pluripotent stem cells (hPSCs) in cell therapy products. Results: All facilities detected colonies of human induced pluripotent stem cells (hiPSCs) when five hiPSCs were spiked into 1 million hiPSC-derived cardiomyocytes. Spiking with a trace amount of hiPSCs revealed that repeatability accounts for the majority of reproducibility while the true positive rate was high. Conclusion: The results indicate that the HEC assay is highly sensitive and robust and can be generally applicable for tumorigenicity evaluation of hPSC-derived cell therapy products.

Background: Anxiety disorders are common and can be debilitating. In addition, various barriers exist that can hinder access to adequate care. Coaching that is grounded in evidence-based interventions and delivered via synchronous (ie, live) text-based messaging could potentially increase the reach of mental health services among populations who select this modality instead of other services (eg, face-to-face coaching and psychotherapy). In addition, the delivery of live messaging coaching within a blended care model has the potential to combine the benefits of coaching with those of evidence-based digital mental health tools., Objective: This real-world study evaluates the anxiety and satisfaction outcomes of live messaging coaching blended with digital tools (ie, digital exercises and activities)., Methods: This was a retrospective cohort study of 121 adults with moderate levels of anxiety symptoms at the beginning of coaching (Generalized Anxiety Disorder-7 [GAD-7] scores: range 8-14). Participants received an employer-offered blended messaging coaching (BMC) program, and those who opted to receive all live coaching sessions via text-based messaging were included. Anxiety symptom severity was regularly measured by using the GAD-7 scale. Using growth curve models, the change in GAD-7 scores over the course of BMC was evaluated, as were the effects of text-based coaching sessions on GAD-7 scores. The proportion of participants that had a reliable improvement in anxiety symptom severity (GAD-7 score reduction of ≥4) or subclinical symptom severity (GAD-7 score of <8) at the end of care was also estimated. Participants also self-reported their likelihood of recommending their live messaging coach to someone with similar needs., Results: At baseline, the average GAD-7 score was 9.88 (SD 1.80). Anxiety symptom severity significantly decreased with each week in the BMC program (week: b=-1.04; P<.001), and the rate of decline in anxiety symptom severity decreased over time (week 2 : b=0.06; P<.001). Each live messaging coaching session was associated with significantly lower anxiety symptom severity during the week of the coaching session (b=-1.56; P<.001) and the week immediately following the session (b=-1.03; P<.001). Overall, 86% (104/121) of participants had subclinical symptom severity or a reliable reduction in anxiety symptom severity by the end of care. Further, 33.1% (40/121) of participants reported coaching satisfaction levels; of the 40 participants in this subset, 37 (92.5%) were likely or extremely likely to recommend their live messaging coach., Conclusions: BMC that provides coaching sessions via live messaging can be beneficial for adults with moderate symptoms of anxiety who qualify for and self-select this care modality. Large-scale studies with longer follow-ups are needed., (©Jocelynn T Owusu, Pam Wang, Robert E Wickham, Sarah F Smith, Jennifer L Lee, Connie Chen, Anita Lungu. Originally published in JMIR Formative Research (https://formative.jmir.org), 01.02.2023.)

Genotoxicity assessment is a critical component in the development and evaluation of chemicals. Traditional genotoxicity assays (i.e., mutagenicity, clastogenicity, and aneugenicity) have been limited to dichotomous hazard classification, while other toxicity endpoints are assessed through quantitative determination of points-of-departures (PODs) for setting exposure limits. The more recent higher-throughput in vitro genotoxicity assays, many of which also provide mechanistic information, offer a powerful approach for determining defined PODs for potency ranking and risk assessment. In order to obtain relevant human dose context from the in vitro assays, in vitro to in vivo extrapolation (IVIVE) models are required to determine what dose would elicit a concentration in the body demonstrated to be genotoxic using in vitro assays. Previous work has demonstrated that application of IVIVE models to in vitro bioactivity data can provide PODs that are protective of human health, but there has been no evaluation of how these models perform with in vitro genotoxicity data. Thus, the Genetic Toxicology Technical Committee, under the Health and Environmental Sciences Institute, conducted a case study on 31 reference chemicals to evaluate the performance of IVIVE application to genotoxicity data. The results demonstrate that for most chemicals considered here (20/31), the PODs derived from in vitro data and IVIVE are health protective relative to in vivo PODs from animal studies. PODs were also protective by assay target: mutations (8/13 chemicals), micronuclei (9/12), and aneugenicity markers (4/4). It is envisioned that this novel testing strategy could enhance prioritization, rapid screening, and risk assessment of genotoxic chemicals., (© 2022 His Majesty the King in Right of Canada and The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagen Society. Reproduced with the permission of the Minister of Health Canada. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Mental health issues often result in significant impairment and financial challenges, both at home and in the workplace. Solutions vary widely in their usage and cost-effectiveness. This study presents an analysis of medical and prescription drug spending and utilization data for the employees of 4 companies who were eligible for an evidence-based workforce mental health program (WMHP). A variation of coarsened exact matching paired WMHP users to nonusers, based on demographics, location, and medical factors. Individuals included 2791 pairs of members whose medical claims were incurred in 2018 and 3883 pairs with claims in 2019. Using a cost efficiency measurement process, mean cost and utilization per person per year (PPPY) were compared. WMHP users had lower medical (-$2295 in 2018; -$2304 in 2019) and prescription drug spending (-$295 in 2018; -$312 in 2019). Over half of the cost reduction (-$1252 in 2018; -$1211 in 2019) resulted from shifting therapy services from the medical benefit to WMHP. WMHP users attended about 12 sessions PPPY, whereas the comparison group of nonusers attended about 7 mental health office visits PPPY under the medical benefit. WMHP users had more mental health-related visits in both years, but had fewer visits on the medical plan, and fewer emergency department visits for mental health than comparison group members. These results provide evidence that high-quality, evidence-based mental health services can reduce total expenditures and change utilization patterns. Evidence-based WMHP may represent a prudent investment for employers in providing mental health care to employees.

Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of early diagnosis. The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy, while several targeted therapies have recently been approved for maintenance treatment. The vast majority of OC patients relapse with chemoresistant tumors after an initial response. Thus, there is an unmet clinical need to develop new therapeutic agents to overcome the chemoresistance of OC. The anti-parasite agent niclosamide (NA) has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC. Here, we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant (CR) in human OC cells. To this end, we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer. We showed that NA inhibited cell proliferation, suppressed cell migration, and induced cell apoptosis in both CR lines at a low micromole range. Mechanistically, NA inhibited multiple cancer-related pathways including AP1, ELK/SRF, HIF1, and TCF/LEF, in SKOV3CR and OVCAR8CR cells. NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells. Collectively, our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant human OC, and further clinical trials are highly warranted., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Introduction: Hemoadsorption has emerged as an adjunctive therapy for sepsis, but its impact on antibiotic levels remains poorly defined. We conducted an in vivo experimental study to investigate the removal of vancomycin and gentamicin during hemoadsorption using the HA380 cartridge, a novel styrene-divinylbenzene copolymer cartridge., Methods: Six surgically prepared sheep were administered 2 g of vancomycin and 400 mg of gentamicin over 30 min, followed by a continuous infusion of vancomycin (20 mg/h). Hemoadsorption was implemented with a styrene-divinylbenzene copolymer HA380 cartridge at a blood flow of 120 mL/min. The removal ratio, sorbent-based clearance, and the mass removal rate were calculated for each time point., Results: The mean 10-min vancomycin removal ratio exceeded 90% and declined to 68.0% at 30 min; 52.8% at 60 min, and 28.0% by 4 h. Due to constant plasma flow, clearance varied proportionally with the removal ratio. Over 4 hours, the total mass removal was 556 mg (SD 106.3). For gentamicin, the mean 10-min removal ratio was 96.9% and the final ratio at 4 h remained 53.0%, with clearances changing proportionately. The total mass removal of gentamicin was 138 mg (SD 26.6) over 4 h. The sorbent-based clearance of vancomycin was significantly lower than that of gentamicin (Pgroup &lt; 0.0001)., Conclusion: The novel HA380 sorbent cartridge appears safe and achieves significant vancomycin and gentamicin removal over a four-hour period. This information can be used by clinicians to guide their prescription and consider the additional dosing of at least an extra 25-35% amount in patients receiving HA380 hemoadsorption therapy during sepsis., (© 2023 S. Karger AG, Basel.)

Objective: This study examines predictors of non-initiation of care and dropout in a blended care CBT intervention, with a focus on early digital engagement and sociodemographic and clinical factors., Methods: This retrospective cohort analysis included 3566 US-based individuals who presented with clinical levels of anxiety and depression and enrolled in a blended-care CBT (BC-CBT) program. The treatment program consisted of face-to-face therapy sessions via videoconference and provider-assigned digital activities that were personalized to the client's presentation. Multinomial logistic regression and Cox proportional hazard survival analysis were used to identify predictors of an increased likelihood of non-initiation of therapy and dropout., Results: Individuals were more likely to cancel and/or no-show to their first therapy session if they were female, did not disclose their ethnicity, reported poor financial status, did not have a college degree, endorsed more presenting issues during the onboarding triage assessment, reported taking antidepressants, and had a longer wait time to their first appointment. Of those who started care, clients were significantly more likely to drop out if they did not complete the digital activities assigned by their provider early in treatment, were female, reported more severe depressive symptoms at baseline, reported taking antidepressants, and did not disclose their ethnicity., Conclusions: Various sociodemographic and clinical predictors emerged for both non-initiation of care and for dropout, suggesting that clients with these characteristics may benefit from additional attention and support (especially those with poor early digital engagement). Future research areas include targeted mitigation efforts to improve initiation rates and curb dropout., Competing Interests: MW, SC, and AL are employed by Lyra Health, receive income from Lyra Health, and have been granted equity in Lyra Health. AV and CC are employed by Lyra Health and Lyra Clinical Associates, receive income from Lyra Health and Lyra Clinical Associates, and have been granted equity in Lyra Health. RW is a paid consultant for Lyra Health. YL has no conflicts of interest to declare., (© The Author(s) 2022.)

Sarcopenia, a pathologic deficiency of muscle mass and function, has emerged as an important secondary feature of many chronic disease states. For adults with end stage liver disease, there are multiple mechanisms which contribute to sarcopenia and its presence has proven to be an important predictor of morbidity and mortality. In children, there are only a limited number of reports which investigate the role of sarcopenia in liver disease. These studies, which are discussed and summarized in this review, report small, single-center analyses with dissimilar study cohorts and varying clinical definitions. Still, children meeting the study entry criteria have sarcopenia with a reported prevalence of 24-70%. When assessed, sarcopenia appears to be associated with more severe disease but is independent of the Pediatric End-Stage Liver Disease (PELD) score and does not correlate with age, gender, or traditional anthropometric measures such as weight, height, weight-for-height, or body mass index (BMI). While individual studies may identify sarcopenia as a statistically significant risk factor for certain post-transplant outcomes such as longer ICU stay, longer duration of intubation, repeat operation, development of serious infection, longer hospital stay, death, or long-term growth failure, such associations are not consistently replicated across studies. Finally, although various methods of muscle mass quantification are utilized, the most reported is the total psoas muscle surface area (tPMSA) on computed tomography. This method, along with others such as skeletal muscle area and skeletal muscle index, have had normative values recently defined and these collective efforts should enable researchers a common basis of comparison when delineating sarcopenia, and its impact, across various study populations in future investigations - including in children with liver disease., Competing Interests: Dr Connie Chen reports grants from Cystic Fibrosis Foundation, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Chen et al.)

Data on real-world effectiveness of cyclin-dependent kinase 4/6 inhibitor combination therapy versus endocrine therapy alone are limited. The Flatiron Health Analytic Database was used to assess overall survival (OS) in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC) treated with first-line palbociclib plus an aromatase inhibitor (AI) versus an AI alone in routine US clinical practice. In total, 2888 patients initiated treatment during February 3, 2015-March 31, 2020, with a potential ≥6-month follow-up (cutoff date, September 30, 2020). After stabilized inverse probability treatment weighting, median OS (95% CI) is significantly longer among palbociclib versus AI recipients (49.1 [45.2-57.7] versus 43.2 [37.6-48.0] months; hazard ratio, 0.76 [95% CI, 0.65-0.87]; P < 0.0001). Progression-free survival (95% CI) is 19.3 (17.5-20.7) versus 13.9 (12.5-15.2) months, respectively (hazard ratio, 0.70 [95% CI, 0.62-0.78]; P < 0.0001). These data support first-line palbociclib plus an AI treatment for HR+/HER2- MBC.(Trial number NCT05361655)., (© 2022. Pfizer Inc.)

Background: Both the gut microbiota and chronic viral infections have profound effects on host immunity, but interactions between these influences have been only superficially explored. Cytomegalovirus (CMV), for example, infects approximately 80% of people globally and drives significant changes in immune cells. Similarly, certain gut-resident bacteria affect T-cell development in mice and nonhuman primates. It is unknown if changes imposed by CMV on the intestinal microbiome contribute to immunologic effects of the infection., Results: We show that rhesus cytomegalovirus (RhCMV) infection is associated with specific differences in gut microbiota composition, including decreased abundance of Firmicutes, and that the extent of microbial change was associated with immunologic changes including the proliferation, differentiation, and cytokine production of CD8 + T cells. Furthermore, RhCMV infection disrupted the relationship between short-chain fatty acid producers and Treg/Th17 balance observed in seronegative animals, showing that some immunologic effects of CMV are due to disruption of previously existing host-microbe relationships., Conclusions: Gut microbes have an important influence on health and disease. Diet is known to shape the microbiota, but the influence of concomitant chronic viral infections is unclear. We found that CMV influences gut microbiota composition to an extent that is correlated with immunologic changes in the host. Additionally, pre-existing correlations between immunophenotypes and gut microbes can be subverted by CMV infection. Immunologic effects of CMV infection on the host may therefore be mediated by two different mechanisms involving gut microbiota. Video Abstract., (© 2022. The Author(s).)

Introduction: Prior studies have supported the effectiveness of blended interventions for anxiety and depression; however, outcomes research of large-scale blended interventions for these conditions is limited. Objective : To investigate the outcomes of scaled-up blended care (BC) cognitive behavioral therapy (CBT), a program that combined video-based psychotherapy with internet CBT, for symptoms of anxiety and depression. Materials and Methods : Participants were 6,738 U.S.-based adults with elevated symptoms of anxiety (Generalized Anxiety Disorder-7 [GAD-7] ≥ 8) and/or depression (Patient Health Questionnaire-9 [PHQ-9] ≥ 10) at baseline who received BC-CBT as an employer-offered mental health benefit. The primary outcomes, anxiety (GAD-7) and depression (PHQ-9) symptoms, were routinely measured in the program. Recovery and reliable improvement in outcomes were calculated, and growth curve models evaluated change in outcomes during treatment and the effects of engaging in psychotherapy sessions on outcomes. Results : On average, participants received treatment for 7.6 (standard deviation = 6.2) weeks. By the end of care, 5,491 (81.5%) participants had reliable improvement in either anxiety or depression symptoms; in addition, 5,535 (82.1%) fell below the clinical threshold for either anxiety or depression symptoms (i.e., recovered). Declines in anxiety and depression symptoms were statistically significant over the course of BC-CBT (both p 's < 0.01), with the rate of decline significantly decreasing for each outcome as treatment progressed (both p 's < 0.01). Each psychotherapy session completed was significantly associated with lower anxiety and depression symptoms during the week of the session and the subsequent week (all p 's < 0.01). Conclusions : This real-world study provides evidence that scaled-up BC-CBT can be effective in the treatment of symptoms of anxiety and depression.

Environmental epidemiology has proven critical to study various associations between environmental exposures and adverse human health effects. However, there is a perception that it often does not sufficiently inform quantitative risk assessment. To help address this concern, in 2017, the Health and Environmental Sciences Institute initiated a project engaging the epidemiology, exposure science, and risk assessment communities with tripartite representation from government agencies, industry, and academia, in a dialogue on the use of environmental epidemiology for quantitative risk assessment and public health decision making. As part of this project, four meetings attended by experts in epidemiology, exposure science, toxicology, statistics, and risk assessment, as well as one additional meeting engaging funding agencies, were organized to explore incentives and barriers to realizing the full potential of epidemiological data in quantitative risk assessment. A set of questions was shared with workshop participants prior to the meetings, and two case studies were used to support the discussion. Five key ideas emerged from these meetings as areas of desired improvement to ensure that human data can more consistently become an integral part of quantitative risk assessment: 1) reducing confirmation and publication bias, 2) increasing communication with funding agencies to raise awareness of research needs, 3) developing alternative funding channels targeted to support quantitative risk assessment, 4) making data available for reuse and analysis, and 5) developing cross-disciplinary and cross-sectoral interactions, collaborations, and training. We explored and integrated these themes into a roadmap illustrating the need for a multi-stakeholder effort to ensure that epidemiological data can fully contribute to the quantitative evaluation of human health risks, and to build confidence in a reliable decision-making process that leverages the totality of scientific evidence., (© 2022 The Authors.)

Introduction: Access to quality mental health medication management (MM) in the United States is limited, even among those with employment-based health insurance. This implementation, feasibility, and outcome study sought to design and evaluate an evidence-based telemental health MM service using a collaborative care model (CoCM). Materials and Methods: CoCM MM was available to adult employees/dependents through their employer benefits, in addition to therapy. Outcomes included Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7) collected at baseline and throughout participation. This analysis was not deemed to be human subjects research by the Western Institutional Review Board. Results: Over 17 months, 212 people enrolled and completed >2 assessments; the enrollees were 58.96% female with average age of 32.00 years (standard deviation [SD] = 7.38). In people with moderate to severe depression or anxiety, PHQ-9 and GAD-7 scores reduced by an average of 7.27 (SD = 4.80) and 6.71 (SD = 5.18) points after at least 12 ± 4 weeks in the program. At 24 ± 4 weeks, the PHQ-9 and GAD-7 reductions were on average 7.17 (SD = 5.00) and 6.03 (SD = 5.37), respectively. Approximately 65.88% of participants with either baseline depression or anxiety had a response on either the PHQ-9 or GAD-7 at 12 ± 4 weeks and 44.71% of participants experienced remission; at 24 ± 4 weeks, 56.41% had response and 41.03% experienced remission. Conclusions: An evidence-based CoCM telemedicine service within an employee behavioral health benefit is feasible and effective in reducing anxiety and depression symptoms when using measurement-based care. Widespread implementation of a benefit like this could expand access to evidence-based mental health MM.

Genotoxicity testing is performed to determine potential hazard of a chemical or agent for direct or indirect DNA interaction. Testing may be a surrogate for assessment of heritable genetic risk or carcinogenic risk. Testing of nanomaterials (NM) for hazard identification is generally understood to require a departure from normal testing procedures found in international standards and guidelines. A critique of the genotoxicity literature in Elespuru et al., 2018, reinforced evidence of problems with genotoxicity assessment of nanomaterials (NM) noted by many previously. A follow-up to the critique of problems (what is wrong) is a series of methods papers in this journal designed to provide practical information on what is appropriate (right) in the performance of genotoxicity assays altered for NM assessment. In this "Common Considerations" paper, general considerations are addressed, including NM characterization, sample preparation, dosing choice, exposure assessment (uptake) and data analysis that are applicable to any NM genotoxicity assessment. Recommended methods for specific assays are presented in a series of additional papers in this special issue of the journal devoted to toxicology methods for assessment of nanomaterials: the In vitro Micronucleus Assay, TK Mutagenicity assays, and the In vivo Comet Assay. In this context, NM are considered generally as insoluble particles or test articles in the nanometer size range that present difficulties in assessment using techniques described in standards such as OECD guidelines., Competing Interests: Author RC is employed by the company Millipore Sigma The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elespuru, Doak, Collins, Dusinska, Pfuhler, Manjanatha, Cardoso and Chen.)

Background: Depression and anxiety are leading causes of disability worldwide. Though effective treatments exist, depression and anxiety remain undertreated. Blended care psychotherapy, combining the scalability of online interventions with the personalization and engagement of a live therapist, is a promising approach for increasing access to evidence-based care., Objectives: To evaluate the effectiveness and individual contribution of two components - i) digital tools and ii) video-based therapist-led sessions - in a blended care CBT-based intervention under real world conditions., Methods: A retrospective cohort design was used to analyze N = 1372 US-based individuals who enrolled in blended care psychotherapy. Of these, at baseline, 761 participants had depression symptoms in the clinical range (based on PHQ-9), and 1254 had anxiety symptoms in the clinical range (based on GAD-7). Participants had access to the program as a mental health benefit offered by their employer. The CBT-based blended care psychotherapy program consisted of regular video sessions with therapists, complemented by digital lessons and digital exercises assigned by the clinician and completed in between sessions. Depression and anxiety levels and clients' treatment engagement were tracked throughout treatment. A 3-level individual growth curve model incorporating time-varying covariates was utilized to examine symptom trajectories of PHQ-9 scores (for those with clinical range of depression at baseline) and GAD-7 scores (for those with clinical range of anxiety at baseline)., Results: On average, individuals exhibited a significant decline in depression and anxiety symptoms during the initial weeks of treatment ( P  < .001), and a continued decline over subsequent weeks at a slower rate ( P  < .001). Engaging in a therapy session in a week was associated with lower GAD-7 (b = -0.81) and PHQ-9 (b = -1.01) scores in the same week, as well as lower GAD-7 (b = -0.58) and PHQ-9 (b = -0.58) scores the following week (all P  < .01). Similarly, engaging with digital lessons was independently associated with lower GAD-7 (b = -0.19) and PHQ-9 (b = -0.18) scores during the same week, and lower GAD-7 (b = -0.25) and PHQ-9 (b = -0.27) the following week (all P  < .01)., Conclusions: Therapist-led video sessions and digital lessons had separate contributions to improvements in symptoms of depression and anxiety over the course of treatment. Future research should investigate whether clients' characteristics are related to differential effects of therapist-led and digital components of care., Competing Interests: AL and SYC are employed by Lyra Health, receive income from Lyra Health, and have been granted equity in Lyra Health. JJ and CC are employed by Lyra Health and Lyra Clinical Associates, receive income from Lyra Health and Lyra Clinical Associates, and have been granted equity in Lyra Health. RW is a paid consultant for Lyra Health. YL has nothing to disclose., (© 2022 The Authors. Published by Elsevier B.V.)