Development Timelines Research Articles

Adaptive Evolution of Marine Organisms: A Bibliometric Analysis Based on CiteSpace

(1) Background: The increasing complexity of marine organism habitats and the impact of climate change on the marine environment have garnered global attention towards the adaptive evolution of marine organisms. However, there still remains a lack of understanding regarding the historical development and research trends of adaptive evolution in marine organisms. (2) Methods: We conducted an analysis on the adaptive evolution of marine organisms published in the Web of Science (WOS) over the past two decades. Through a visualization of publications, authors, institutional affiliations, and keywords based on CiteSpace, this review examines research contributions, identifies research hotspots, and outlines future development trends in this field. (3) Results: The findings indicate a surge in the advancement of the adaptive evolution of marine organisms, particularly since 2017, with tight collaboration among European nations. Additionally, Chinese research institutions and scholars have emerged as some of the most significant contributors in this field. (4) Conclusions: This review provides an overview of the main research hotspots and frontiers in the field pertaining to adaptive evolution of marine organisms, as well as the historical timeline of research and development. This review has offered scientific guidance to scholars and institutions concerned with conducting research on marine organisms and adaptive evolution.

Immune checkpoint inhibitors in breast cancer: development, mechanisms of resistance and potential management strategies.

The use of immune checkpoint inhibitors (ICIs) has increased exponentially in the past decade, although its progress specifically for breast cancer has been modest. The first U.S. Food and Drug Administration approval for ICI in breast cancer came in 2019, eight years after the first-ever approval of an ICI. At present, current indications for ICIs are relevant only to a subset of patients with triple-negative breast cancer, or those displaying high microsatellite instability or deficiency in the mismatch repair protein pathway. With an increasing understanding of the limitations of using ICIs, which stem from breast cancer being innately poorly immunogenic, as well as the presence of various intrinsic and acquired resistance pathways, ongoing trials are evaluating different combination therapies to overcome these barriers. In this review, we aim to describe the development timeline of ICIs and resistance mechanisms limiting their utility, and summarise the available approaches and ongoing trials relevant to overcoming each resistance mechanism.

A Review: Development of Plant Protection Methods and Advances in Pesticide Application Technology in Agro-Forestry Production

In this review, through reviewing the history of the struggle between human beings and plant diseases, insects and weeds, more specifically thoughts on plant protection in ancient Chinese agricultural books, the recognition of plant pests as a target and six types of plant protection methods and 36 subdivision measures are summarized. Then, we focus on the development overview of pesticide application technology and conduct a systematic review by combining the development timeline of pesticide application and key technologies including performance measurement and the simulation and modeling of pesticide-spraying systems. Finally, three suggestions for further research are proposed from the perspectives of human beings’ and environmental health, sustainable and eco-friendly application media and efficient application equipment systems in plant protection.

Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy

BackgroundOver the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.ObjectivesThis study reviews the FDA’s five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price.MethodsWe conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview.ResultsExpedited approval reduces new drugs’ time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as “breakthroughs”, are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US.ConclusionSpecial FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices.

Reduction in metabolic noise reveals rejuvenation following transient severe caloric restriction.

Among land vertebrates, the laying hen stands out due to its great reproductive efficiency: producing an egg daily all year long. This production rate makes the laying hen a special model animal to study the general process of reproduction and aging. One unique aspect of hens is their ability to undergo reproductive plasticity and to rejuvenate their reproductive tract during molting, a standard industrial feed restriction protocol for transiently pausing reproduction, followed by improved laying efficiency almost to peak production. Here we use longitudinal metabolomics, immunology, and physiological assays to show that molting promotes reproduction, compresses morbidity, and restores youthfulness when applied to old hens. We identified circulating metabolic biomarkers that quantitatively predict the reproduction and age of individuals. Lastly, we introduce metabolic noise, a robust, unitless, and quantifiable measure for heterogeneity of the complete metabolome as a general marker that can indicate the rate of aging of a population. Indeed, metabolic noise increased with age in control hens, whereas molted hens exhibited reduced noise following molting, indicating systemic rejuvenation. Our results suggest that metabolic noise can be used as a quick and universal proxy for assessing successful aging treatments, accelerating the timeline for drug development.

Application of platform process development approaches to the manufacturing of Mabcalin™ bispecifics.

Bispecific biotherapeutics offer potent and highly specific treatment options in oncology and immuno-oncology. However, many bispecific formats are prone to high levels of aggregation and instability, leading to prolonged development timelines, inefficient manufacturing, and high costs. The novel class of Mabcalin™ molecules consist of Anticalin® proteins fused to an IgG and are currently being evaluated in pre-clinical and clinical studies. Here, we describe a robust high-yield manufacturing platform for these therapeutic fusion proteins providing data up to commercially relevant scales. A platform upstream process was established for one of the Mabcalin bispecifics and then applied to other clinically relevant drug candidates with different IgG target specificities. Process performance was compared in 3L bioreactors and production was scaled-up to up to 1000L for confirmation. The Mabcalin proteins' structural and biophysical similarities enabled a downstream platform approach consisting of initial protein A capture, viral inactivation, mixed-mode anion exchange polishing, second polishing by cation exchange or hydrophobic interaction chromatography, viral filtration, buffer exchange and concentration by ultrafiltration/diafiltration. All three processes met their target specifications and achieved comparable clearance of impurities and product yields across scales. The described platform approach provides a fast and economic path to process confirmation and is well comparable to classical monoclonal antibody approaches in terms of costs and time to clinic.

Design of experiments for the automated development of a multicellular cardiac model for high-throughput screening

Cardiovascular toxicity remains a major cause of drug attrition in early drug development, clinical trials, and post-market surveillance. In vitro assessment of cardiovascular liabilities often relies on single cell type-based model systems coupled with functional assays, like calcium flux and multielectrode arrays. Although these models offer high-throughput capabilities and demonstrate good predictivity for functional cardiotoxicities, they fail to consider the vital contribution of non-myocyte cells, thus limiting the potential for integrated risk assessment. Complex 3D hPSC-derived multicellular cardiac model systems have been growing in popularity; however, many of these models are limited to low-throughput with lengthy development timelines and high costs, which hampers their suitability to drug discovery.To optimize the development of an in vitro multicellular model system containing human-induced pluripotent stem-cell derived cardiomyocytes, endothelial cells and cardiac fibroblasts, we employed the Synthace platform, which enables scientists to express complex experimental intent in a simple format (e.g. Design of Experiments) and to translate this to automation protocols using no-code. Utilizing this approach, we systematically screened the impact of multiple cell culture parameters, including the co-culture of three cell types, on cardiac contractility, with minimal hands-on time. Our platform accelerates the assay development process, providing users with an efficient means to explore and optimize the experimental space for the development of multicellular models. This is particularly valuable in scenarios involving variable biological responses and limited understanding of underling mechanisms. Moreover, users can make better use of resources, streamline their workflows, and drive data-driven decision-making throughout the assay development journey.

Accelerating Biocatalysis Discovery with Machine Learning: A Paradigm Shift in Enzyme Engineering, Discovery, and Design.

Emerging computational tools promise to revolutionize protein engineering for biocatalytic applications and accelerate the development timelines previously needed to optimize an enzyme to its more efficient variant. For over a decade, the benefits of predictive algorithms have helped scientists and engineers navigate the complexity of functional protein sequence space. More recently, spurred by dramatic advances in underlying computational tools, the promise of faster, cheaper, and more accurate enzyme identification, characterization, and engineering has catapulted terms such as artificial intelligence and machine learning to the must-have vocabulary in the field. This Perspective aims to showcase the current status of applications in pharmaceutical industry and also to discuss and celebrate the innovative approaches in protein science by highlighting their potential in selected recent developments and offering thoughts on future opportunities for biocatalysis. It also critically assesses the technology's limitations, unanswered questions, and unmet challenges.

A rapid synthesis of evidence on whole systems approaches to obesity prevention to inform policy

Abstract Background The Department of Health in Northern Ireland is developing a new obesity prevention strategy. To support policy development, the Institute of Public Health commissioned a rapid synthesis of evidence on whole systems approaches to obesity prevention. Objectives were to present evidence from existing reviews on whole systems approach effectiveness, describe case studies where a whole systems approach has been applied and propose key policy considerations. Methods A rapid synthesis of evidence on whole systems approaches, rather than a full systematic evidence review, was conducted to meet policy development timelines. Review articles were included, as were national and international case studies that described whole systems approach implementation and/or evaluation. The Methodological Index for Non-Randomised Studies Framework was used to assess the methodological quality of the case studies. Results Five review articles and five case studies (majority moderate-borderline strong quality) were included. Results showed whole systems approaches can be associated with improvements in Body Mass Index, physical activity environment and improved community wellbeing, with a school component being particularly effective. Facilitators to implementation included leadership, community involvement, consistent language, adequate resources and evaluation/systems science knowledge. Conclusions Whole systems approaches can be effective in enhancing the capacity of communities to create healthier environments and deliver measurable reductions in Body Mass Index. Key messages • Whole systems approaches to obesity prevention can be effective in creating healthier environments. • Findings from this research could support any future pilot of this approach in Northern Ireland.

High power NVPF/HC-based sodium-ion batteries

The Na-ion battery consisting of Na3V2(PO4)2F3 (NVPF) cathode and hard carbon (HC) anode has been developed and commercialized by Tiamat. This study focuses on the assessments of NVPF/HC-based prototype cells in a cylindrical cell format. The specific cell for this investigation has a capacity of 0.61 Ah, a specific energy of 68 Wh/kg, and an energy density of 135 Wh/L at 1C. The cycle life of this specific cell generation (2020) shows 1600 cycles at 5C charge and 5C discharge, but more recent cell generations show improved cycle stability: a trend of enhancement in cell cycle life is presented in the development timeline, and the latest version cell achieves a cycle life of 3200 cycles at 2C charge and 5C discharge. The cell shows excellent power rate capabilities up to 20C discharge and 10C charge. It is highlighted that >90 % of capacity and >80 % of energy (compared to 1C) can still be accessed at 20C discharge. Safety tests with different abuse conditions (overcharge, external heating, short circuit, and nail penetration) were performed. For all these abuse conditions, the specific cell version showed no thermal runaway. Thus, the NVPF/HC-based Na-ion technology seems to develop towards a well-suited candidate for high-power energy storage applications.

Transcriptomic and morphological maturation of human astrocytes in cerebral organoids.

Cerebral organoids (CerOrgs) derived from human induced pluripotent stem cells (iPSCs) are a valuable tool to study human astrocytes and their interaction with neurons and microglia. The timeline of astrocyte development and maturation in this model is currently unknown and this limits the value and applicability of the model. Therefore, we generated CerOrgs from three healthy individuals and assessed astrocyte maturation after 5, 11, 19, and 37 weeks in culture. At these four time points, the astrocyte lineage was isolated based on the expression of integrin subunit alpha 6 (ITGA6). Based on the transcriptome of the isolated ITGA6-positive cells, astrocyte development started between 5 and 11 weeks in culture and astrocyte maturation commenced after 11 weeks in culture. After 19 weeks in culture, the ITGA6-positive astrocytes had the highest expression of human mature astrocyte genes, and the predicted functional properties were related to brain homeostasis. After 37 weeks in culture, a subpopulation of ITGA6-negative astrocytes appeared, highlighting the heterogeneity within the astrocytes. The morphology shifted from an elongated progenitor-like morphology to the typical bushy astrocyte morphology. Based on the morphological properties, predicted functional properties, and the similarities with the human mature astrocyte transcriptome, we concluded that ITGA6-positive astrocytes have developed optimally in 19-week-old CerOrgs.

Neocortex neurogenesis and maturation in the African greater cane rat

BackgroundNeocortex development has been extensively studied in altricial rodents such as mouse and rat. Identification of alternative animal models along the “altricial-precocial” spectrum in order to better model and understand neocortex development is warranted. The Greater cane rat (GCR, Thyronomys swinderianus) is an indigenous precocial African rodent. Although basic aspects of brain development in the GCR have been documented, detailed information on neocortex development including the occurrence and abundance of the distinct types of neural progenitor cells (NPCs) in the GCR are lacking.MethodsGCR embryos and fetuses were obtained from timed pregnant dams between gestation days 50–140 and their neocortex was analyzed by immunofluorescence staining using characteristic marker proteins for NPCs, neurons and glia cells. Data were compared with existing data on closely related precocial and altricial species, i.e. guinea pig and dwarf rabbit.ResultsThe primary sequence of neuro- and gliogenesis, and neuronal maturation is preserved in the prenatal GCR neocortex. We show that the GCR exhibits a relatively long period of cortical neurogenesis of 70 days. The subventricular zone becomes the major NPC pool during mid-end stages of neurogenesis with Pax6 + NPCs constituting the major basal progenitor subtype in the GCR neocortex. Whereas dendrite formation in the GCR cortical plate appears to initiate immediately after the onset of neurogenesis, major aspects of axon formation and maturation, and astrogenesis do not begin until mid-neurogenesis. Similar to the guinea pig, the GCR neocortex exhibits a high maturation status, containing neurons with well-developed dendrites and myelinated axons and astrocytes at birth, thus providing further evidence for the notion that a great proportion of neocortex growth and maturation in precocial mammals occurs before birth.ConclusionsTogether, this work has deepened our understanding of neocortex development of the GCR, of the timing and the cellular differences that regulate brain growth and development within the altricial–precocial spectrum and its suitability as a research model for neurodevelopmental studies. The timelines of brain development provided by this study may serve as empirical reference data and foundation in future studies in order to model and better understand neurodevelopment and associated alterations.

Perception of the McGurk effect in people with one eye depends on whether the eye is removed during infancy or adulthood.

The visual system is not fully mature at birth and continues to develop throughout infancy until it reaches adult levels through late childhood and adolescence. Disruption of vision during this postnatal period and prior to visual maturation results in deficits of visual processing and in turn may affect the development of complementary senses. Studying people who have had one eye surgically removed during early postnatal development is a useful model for understanding timelines of sensory development and the role of binocularity in visual system maturation. Adaptive auditory and audiovisual plasticity following the loss of one eye early in life has been observed for both low-and high-level visual stimuli. Notably, people who have had one eye removed early in life perceive the McGurk effect much less than binocular controls. The current study investigates whether multisensory compensatory mechanisms are also present in people who had one eye removed late in life, after postnatal visual system maturation, by measuring whether they perceive the McGurk effect compared to binocular controls and people who have had one eye removed early in life. People who had one eye removed late in life perceived the McGurk effect similar to binocular viewing controls, unlike those who had one eye removed early in life. This suggests differences in multisensory compensatory mechanisms based on age at surgical eye removal. These results indicate that cross-modal adaptations for the loss of binocularity may be dependent on plasticity levels during cortical development.

Bring memristive in-memory computing into general-purpose machine learning: A perspective

In-memory computing (IMC) using emerging nonvolatile devices has received considerable attention due to its great potential for accelerating artificial neural networks and machine learning tasks. As the basic concept and operation modes of IMC are now well established, there is growing interest in employing its wide and general application. In this perspective, the path that leads memristive IMC to general-purpose machine learning is discussed in detail. First, we reviewed the development timeline of machine learning algorithms that employ memristive devices, such as resistive random-access memory and phase-change memory. Then we summarized two typical aspects of realizing IMC-based general-purpose machine learning. One involves a heterogeneous computing system for algorithmic completeness. The other is to obtain the configurable precision techniques for the compromise of the precision-efficiency dilemma. Finally, the major directions and challenges of memristive IMC-based general-purpose machine learning are proposed from a cross-level design perspective.

Addressing Veteran Health-Related Social Needs: How Joint Commission Standards Accelerated Integration and Expansion of Tools and Services in the Veterans Health Administration

The Joint Commission recently named reduction of health care disparities and improvement of health care equity as quality and safety priorities (Leadership [LD] Standard LD.04.03.08 and National Patient Safety Goal [NPSG] Standard NPSG.16.01.01). As the largest integrated health system, the Veterans Health Administration (VHA) sought to leverage these new accreditation standards to further integrate and expand existing tools and initiatives to reduce health care disparities and address health-related social needs (HRSNs). A combination of existing data tools (for example, Primary Care Equity Dashboard), resource tools (for example, Assessing Circumstances and Offering Resources for Needs tool), and a care delivery approach (for example, Whole Health) are discussed as quality improvement opportunities to further integrate and expand how VHA addresses health care disparities and HRSNs. The authors detail the development timeline, building, limitations, and future plans for these tools and initiatives. Responding to new health care equity Joint Commission standards led to new implementation strategies and deeper partnerships across VHA that facilitated expanded dissemination, technical assistance activities, and additional resources for VHA facilities to meet new standards and improve health care equity for veterans. Health care systems may learn from VHA's experiences, which include building actionable data platforms, employing user-centered design for initiative development and iteration, designing wide-reaching dissemination strategies for tools, and recognizing the importance of providing technical assistance for stakeholders. VHA continues to expand implementation of a diverse set of tools and resources to reduce health care disparities and identify and address unmet individual veteran HRSNs more widely and effectively.

Adaptation of an rVSV Ebola vaccine purification process for rapid development of a viral vaccine candidate for SARS-CoV-2.

During the COVID-19 pandemic, long development timelines typically associated with vaccines were challenged. The urgent need for a vaccine provided a strong driver to reevaluate existing vaccine development approaches. Innovative approaches to regulatory approval were realized, including the use of platform-based technology. In collaboration with the International AIDS Vaccine Initiative, Inc. (IAVI), Merck & Co., Inc., Rahway, NJ, USA rapidly advanced an investigational SARS-CoV-2 vaccine based on the recombinant vesicular stomatitis virus (rVSV) platform used for the Ebola vaccine ERVEBO (rVSV∆G-ZEBOV-GP). An rVSV∆G-SARS-CoV-2 vaccine candidate was generated using the SARS-CoV-2 spike protein to replace the VSV G protein. The purification process development for this vaccine candidate was detailed in this paper. Areas were highlighted where the ERVEBO platform process was successfully adopted and where additional measures were needed for the SARS-CoV-2 vaccine candidate. These included: (i) endonuclease addition directly into the bioreactor prior to harvest, (ii) inclusion of a core-shell chromatography step for improved purification, and (iii) incorporation of a terminal, sterile filtration step to eliminate the need for aseptic, closed processing. High infectious virus titers were achieved in Phase 3 clinical drug substance (>108 PFUmL-1 ), and process consistency was demonstrated across four large scale batches that were completed in 6 months from clone selection.

SCDM eSource Playbook 2: Taking a sites’-eye view

Clinical research is in the midst of a digital transformation, with the emergence of eSource data promising to accelerate drug development timelines, enhance patient centricity, and unlock previously unseen insights.  While much has been written on the rationale for eSource approaches, practical advice on their implementation has been less widely available.   As the world's leading advocate for the discipline of clinical data management, the Society For Clinical Data Management (SCDM) is in a unique position to fill this knowledge gap.   To achieve this aim, the group has produced a series of podcasts in which leading experts from across the clinical research ecosystem share their case studies and practical advice on moving eSource from theory into practice.  We then distilled their learnings into four playbooks, each from the standpoint of one of the main stakeholder groups: CROs and vendors, pharma, regulators, and academia/sites.  This paper focuses on the academia/site's perspective.

Meningeal origins and dynamics of perivascular fibroblast development on the mouse cerebral vasculature.

Perivascular fibroblasts (PVFs) are a fibroblast-like cell type that reside on large-diameter blood vessels in the adult meninges and central nervous system (CNS). PVFs contribute to fibrosis following injury but their homeostatic functions are not defined. PVFs were previously shown to be absent from most brain regions at birth and are only detected postnatally within the cerebral cortex. However, the origin, timing and cellular mechanisms of PVF development are not known. We used Col1a1-GFP and Col1a2-CreERT2 transgenic mice to track PVF development postnatally. Using lineage tracing and in vivo imaging we show that brain PVFs originate from the meninges and are first seen on parenchymal cerebrovasculature at postnatal day (P) 5. After P5, PVF coverage of the cerebrovasculature expands via local cell proliferation and migration from the meninges. Finally, we show that PVFs and perivascular macrophages develop concurrently. These findings provide the first complete timeline for PVF development in the brain, enabling future work into how PVF development is coordinated with cell types and structures in and around the perivascular spaces to support normal CNS vascular function.

Mapping oto-pharyngeal development in a human inner ear organoid model.

Inner ear development requires the coordination of cell types from distinct epithelial, mesenchymal and neuronal lineages. Although we have learned much from animal models, many details about human inner ear development remain elusive. We recently developed an in vitro model of human inner ear organogenesis using pluripotent stem cells in a 3D culture, fostering the growth of a sensorineural circuit, including hair cells and neurons. Despite previously characterizing some cell types, many remain undefined. This study aimed to chart the in vitro development timeline of the inner ear organoid to understand the mechanisms at play. Using single-cell RNA sequencing at ten stages during the first 36 days of differentiation, we tracked the evolution from pluripotency to various ear cell types after exposure to specific signaling modulators. Our findings showcase gene expression that influences differentiation, identifying a plethora of ectodermal and mesenchymal cell types. We also discern aspects of the organoid model consistent with in vivo development, while highlighting potential discrepancies. Our study establishes the Inner Ear Organoid Developmental Atlas (IODA), offering deeper insights into human biology and improving inner ear tissue differentiation.

Quantifying Radiation Induced Vaginal Stenosis for the Development of a Novel Dilator Device: A Prospective Cohort Study of Patients with Cervical Cancer Treated with Definitive Chemoradiation Therapy

Chemoradiation therapy (CRT) is the standard of care for the treatment of locally advanced cervical cancer (LACC). Vaginal stenosis (VS) is a common side effect of CRT and leads to sexual dysfunction, pain, and difficulty with vaginal intercourse, resulting in decreasing quality-of-life (QOL). However, there is scant data on the timeline of VS development, and patient use and satisfaction with a standard vaginal dilator (VD). In this study, we plan to develop a standardized technique to assess VS using physical exam measurements at specified timepoints after CRT. Secondarily, we will assess patient preferences and use of available VDs with the goal of developing a novel VD device with our multidisciplinary engineering team. We report the rationale, methods, and objectives of this clinical study. Patients with LACC treated with CRT and brachytherapy are eligible. CT-based imaging pre-CRT and 3-months post-CRT to assess radiographic changes in the vaginal length and width will be collected. Vaginal measurements and physical exam will be recorded at baseline and 3-, 6-, and 12-months following CRT. Patients will also be given a set of VDs that range in diameter and length. Patient vaginal capacity, defined as the largest VD that can be comfortably accommodated in the vagina during pelvic exam, and compliance with VD use will be recorded at each visit. Patients will be given the EORTC Sexual Health Questionnaire (EORTC SHQ-22). Toxicity grading will use the CTCAE v5. We plan to assess patient preference using a VD-specific questionnaire to help guide the development of a personalized VD. For the primary analysis, we will examine the VS CTCAE v5 toxicity at baseline vs 1 year for 20 patients. The sample size we propose is sufficient to achieve at least 80% power at 5% significance level for detecting a significant non-zero proportion with a margin of 20%. For the secondary analysis, we will test the Spearman's coefficient and Kendall's tau between VS CTCAE and EORTC questions: "has the treatment affected your sexual activity?"; "have you felt pain during/after sexual activity?"; "have you been sexually active?" We will use permutation tests in which the ID will be permuted for vaginal stricture but kept as original for the EORTC questions. We will test the null hypothesis of no correlation by comparing the observed Spearman's coefficient and Kendall's tau to the permutation distributions. We plan to incorporate the specific VD questionnaire responses into the development of a novel device using qualitative measures. This clinical trial is an observational cohort study that aims to quantify CRT-induced VS, obtain patient reported sexual health, and understand specific preferences and compliance with VD use for the development of a novel engineered device.