Advancing Research on Chronic Conditions in Women (2024)

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9 Improving Prevention and Care for Chronic Conditions in Women In previous chapters, the committee described evidence and research gaps regarding what is known about the biological mechanisms involved in chronic conditions and on research aiming to improve their diagnosis, treatment, prevention, and management in women. The chapters described the evidence from and gaps in research in various fields along the research continuum, including basic sciences and preclinical, clinical, and population health research. This chapter examines in more detail the barriers to enhancing the translation of research findings that this report describes and explores the potential application of other research areas to the study of chronic conditions in women. Translational research offers a useful framework for reducing the time to go from basic science discovery to application in clinical practice and health care delivery by keeping a focus on accomplishing the goal of improving health and well-being for women experiencing one or more chronic conditions. Translating research to the clinical setting may take years. Moreover, chronic conditions may begin with ambiguous, episodic symptoms that may change over the life course, shaped by variations across reproductive milestones and socioeconomic and cultural factors. Therefore, this chapter will also highlight additional perspectives that should be considered as strategies to facilitate progress beyond the hallways of research laboratories and hospitals. For example, a focus on patient-centered outcomes, which begins with the lived experience of affected women, could create a customized, interdisciplinary approach to care for those with complex conditions, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia, and depression. Evolving clinical guidelines will need to be tested in the clinical environment, which is open to constant review and adaptation to innovative, interdisciplinary interventions. The model of the learning health system provides the necessary platform to address these complex diseases. Moreover, continued scrutiny and evaluation of health services and engagement with the communities served by health systems is important to consider, as chronic conditions may require new long-term strategies, which may be facilitated by using technology and engaging community partners. Thus, this chapter also includes discussions regarding patient-centered outcomes, health services and policy, learning health system, and community engagement, as women with chronic conditions seek and require ongoing care over their life course. PREPUBLICATION COPY: UNCORRECTED PROOFS 

2 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN TRANSLATING RESEARCH: OPPORTUNITIES AND CHALLENGES Interest has been growing among researchers in the biomedical and clinical sciences about translational research, an approach that aims to put basic science findings into practice and serves as a learning system that moves research from the laboratory to bedside and then feeds real-world data back to the laboratory to inform research projects (Marincola, 2003). Translational research has been characterized as harnessing discoveries from basic science to develop new diagnostic tests, therapies, and prevention devices, which translational scientists call “T1 translation,” and implementing research findings into practice to improve care (T2 translation) (Fontanarosa, 2002; Woolf, 2008). A 2013 Institute of Medicine 1 report outlined the continuum of translational research: T0 refers to basic science research, T1 to translation to humans, T2 to translation to patients, T3 to translation to practice, and T4 to translation to community (see Figure 9-1). 1 As of March 2016, the Health and Medicine Division of the National Academies of Sciences, Engineering and Medicine (NASEM) continues the consensus studies and convening activities previously carried out by the Institute of Medicine (IOM). The IOM name is used to refer to reports issued prior to July 2015. PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPROVING PREVENTION AND CARE FOR CHRONIC CONDITIONS IN WOMEN 3 FIGURE 9-1 The operational phase of translational research SOURCE: IOM (2013) In the context of health services research, translating research into practice involves implementation science, closing the gap between optimal and actual care, and promoting the uptake of evidence-based practices and policies in the healthcare system. Implementation science in population health research involves behavioral science research, such as studying factors that lead to the uptake of clinical preventive services and health behaviors in the community and among certain groups (Woolf et al., 2015). Improving the understanding of sex and gender differences for chronic conditions that affect women across the research continuum, from basic and preclinical sciences to clinical research is essential for developing evidence-based guidelines. Next are examples of challenges faced in translation of research in these areas. Challenges in the Translation of Basic Science Research Basic science research has large biases related to the lack of assessment of sex differences, which lead to poor translation. Promoting sex as a biological variable in research has resulted in including more females in animal studies, but comparison of both sexes in basic research is still lacking (see Chapter 6). The cellular and molecular mechanisms underlying the differences between men and women regarding prevalence, risk factors, and therapeutic response for several chronic conditions are still incompletely understood, which has significant translational implications (Perrino et al., 2021). Several fields have taken steps to increase the rigor of research findings by including sex as a biological variable, such as the Stroke Therapy PREPUBLICATION COPY: UNCORRECTED PROOFS 

4 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Academic Industry Roundtable 2 (STAIR) guidelines for clinical trials and the Animal Research: Reporting on In Vivo Experiments guidelines, 3 but this practice needs to become universal in cell and animal models of chronic conditions. Such efforts will promote scientific rigor, and reproducibility, leading to better efficacy and suitability of clinical treatment in women (Clayton and Collins, 2014). In vitro and ex vivo models are simplistic tools used to evaluate how disease agents affect cells. Early evidence of sex differences tied to the sex chromosomes was first discovered using in vitro models (Beyer et al., 1991, 1992; De Vries et al., 2002; Shamir and Ewald, 2014). These studies demonstrated that the early development of cells in the midbrain, located below the cerebral cortex and the topmost part of the brainstem, reflect a sex difference induced by sex chromosome complement—XX or XY—not hormones. Over the last decade, investigators have developed three-dimensional (3D) cell culture models to overcome the physiological limitations of traditional two-dimensional models, and employed them to study multiple disease pathologies, including gastrointestinal, cardiac, and reproductive tissues. The increased complexity of 3D model systems, including stem cell-based systems, 3D cultures, organoids, and organ-on-a-chip technologies, better capture the nature of human biology, allowing researchers to model disease pathologies that do not have an animal model available (Loewa et al., 2023; Shamir and Ewald, 2014). Although the use of 3D models has improved the understanding of sex differences, consistency and transparency of cell sources is vital for creating a robust tissue model, particularly given the male bias that is still widespread in cell experiments. The American Type Culture Collection (ATCC) recommends cell authentication when acquiring a cell line after 10 passages, after preparing a cell bank, or when in doubt (ATCC, 2022, 2024). ATCC and other cell line repositories, such as the European Collection of Authenticated Cell Cultures 4 and Japanese Collection of Research Bioresources Cell Bank, 5 mandate reporting the sex of human cell lines by using the sex of the isolate subject or evaluating short tandem repeats of genes expressed on the X or Y chromosome. Authentication of the sex in human cell lines has become widely available and more routine as a result of their commercialization. However, the sex of animal cell lines remains underreported, even by cell repositories, often requiring additional effort on the part of investigators. The informed use of cells, including obtaining the donor’s sex and verifying any comorbid conditions, represents a translational challenge goal that will improve downstream effects in the research pipeline and health outcomes, including decisions related to designing preclinical and clinical studies. Despite advances in cell-based technology, 3D and organoid systems typically lack tissue-resident immune populations, hampering investigations of inflammation (Loewa et al., 2023), which is a key component of many chronic conditions that impact women. The main limitations are the sources of immune cells, successful incorporation, and maintenance of their phenotype and longevity. For example, primary isolated immune cells typically are not long-lived and do not remain within the system for long (Zhang et al., 2007). Combining these 3D models with a microfluidic system would offer an opportunity for immune cells to perfuse through the tissue mimicking the pathological response to disease (Yip et al., 2023). This would be even more important when the human condition and an animal model do not completely mirror each other. 2 Available at https://www.thestair.com/ 3 Available at https://arriveguidelines.org/ 4 Available at https://www.ukbrcn.org/ 5 Available at https://cellbank.nibiohn.go.jp/english PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPROVING PREVENTION AND CARE FOR CHRONIC CONDITIONS IN WOMEN 5 In Type 2 diabetes, which underlies many chronic conditions (see Chapter 6), the conventional human criteria that define it would ensure that almost all animal models would be considered diabetic. Moreover, susceptibility to complex diseases such as Type 2 diabetes shows a low contribution of genes when considered individually but collectively contributes substantially to population risk. Thus, using human-derived cell types from susceptible versus low-risk individuals would provide an important avenue for understanding chronic disease. In several conditions referenced in this report, much remains to be done to improve the health of women. Basic science or preclinical studies are essential in understanding the pathophysiology of diseases and developing therapies or biomarkers. However, in many cases, basic science research has not been effectively translated. Several factors influence poor translation into clinical outcomes; a few critical ones are described next. Lack of Female-Specific Models In some cases, as in endometriosis, poor translation may be associated with the lack of a good animal model. Endometriosis (see Chapter 5) is defined by endometrium-like tissue thriving outside the uterus. However, women present with varied and complex symptomatic and multisystemic sequelae with potentially distinct pathophysiology (Horne and Missmer, 2022; Zondervan et al., 2020). Endometriosis lesions are complex, multicellular tissue deposits comprising endometrium-like stromal cells, epithelial glands, and extracellular matrix deposition including fibrosis, scarring, and sometimes evidence of hemorrhage (Clement, 2007; Vigano, 2018). Estrogens regulate the local cellular niche of a lesion, affecting endometrium-like cell types (Saunders and Horne, 2021) and processes such as neuroangiogenesis and neuroinflammation (Greaves et al., 2014a, 2015). Surgical visualization and histologic appearance of lesions varies, with different contributions of extracellular matrix and fibrosis (Li et al., 2022; Liu et al., 2018), the presence of endometrium-like cells (Clement, 2007), their synchronicity with the menstrual cycle (Colgrave et al., 2020), and the extent of immune and nerve infiltration (Tran et al., 2008). Associated genomic loci vary by macro lesion phenotype, with most of the 42 loci identified associated with endometriomas (Rahmioglu et al., 2023). Researchers have reported that spontaneous endometriosis occurs in several primate species, leading them to evaluate nonhuman primate models (Hastings and Fazleabas, 2006). Researchers have experimentally enhanced endometriosis in female baboons and Rhesus macaques (Hastings and Fazleabas, 2006). These models, however, are time intensive to develop, expensive to maintain, and limited in sample size and scope of experimentation. Rodent models are more common for in vivo studies. They are an attractive choice because of their short generation time, relatively low husbandry costs and space requirements, genetically modified strains, and ability to provide large experimental groups (Burns et al., 2022). Homologous rodent models used to study endometriosis range from the surgical engraftment of uterine tissue to injection of “menses”-like endometrial tissue (Cummings and Metcalf, 1995; Greaves et al., 2014b; Hogg et al., 2021; Pelch et al., 2010, 2012; Wilson et al., 2020). Human translation has been limited, however, as no rodent model directly reproduces the human hallmarks of subphenotypes of lesions and symptoms. In addition, as most rodents do not menstruate, the artificial lesions do not undergo repeated tissue injury and repair as in humans, a process known to facilitate lesion survival and fibrogenesis (Guo, 2018; Zhang et al., 2016a, 2016b). To add to the challenge, the many variations of rodent models use different measures of PREPUBLICATION COPY: UNCORRECTED PROOFS 

6 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN pain and well-being (Nunez-Badinez et al., 2021). The World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (Becker et al., 2014; Fassbender et al., 2014; Rahmioglu et al., 2014; Vitonis et al., 2014) is leading efforts to create rodent model standardization tools for informative discovery, but none yet adequately reflect the human heterogeneous presentation and physiologic milieu that investigators could use to rapidly and robustly advance etiologic, diagnostic, and novel treatment discovery. Lack of Understanding of Sex Differences Chapter 6 discussed that women are likely to be misdiagnosed and/or undertreated for many chronic conditions, which is partially attributed to a lack of understanding of sex differences in pathophysiology and therapies. Two examples that illustrate this point are knee replacement surgery and stroke therapies. Considering knee replacement surgery, sex-specific approaches have gained interest due to the well documented anatomic differences between the knees observed in males and females. However, there is insufficient evidence to support gender-specific knee replacement surgery (Bellemans et al., 2010). Although there is limited evidence for the use of gender specific implants that may reduce the potential of overhang of tissue in women, no long-term studies affirm the benefits of this intervention (Bellemans et al., 2010; Rankin et al., 2008). As osteoarthritis is the leading contributor to decreased mobility among older adults and considering that predominance of osteoarthritis of the knees (Kolasinski et al., 2020), a greater understanding on the appropriate use of gender-specific knee surgery is needed. Pertinent to the lived experience of the patient highlighted in the Preface to this report, gender differences have also been documented with regard to the decision making-process when knee replacement surgery is recommended. Notably, women exhibited less knowledge about the benefits of knee replacement surgery and were more likely to seek strategies to avoid surgery compared to men. This study was conducted in a cohort of 193 individuals, of which 72 percent were women. Thus, not only are there opportunities that explore surgical interventions (e.g., knee replacement surgery) but also strategies that enhance sex-related shared decision making between the provider and the patient (Torrente-Jimenez et al., 2022). In stroke, basic science research has focused on sex differences in pathophysiology and therapies. In this context, disproportionate and/or exclusive use of male animals has hindered therapeutic development for women. A major success regarding experimental stroke models is that middle cerebral artery occlusion models can replicate sex and age differences in severity. For example, comorbid conditions, such as Type 2 diabetes and metabolic disease, have been combined in these models and shown to impair recovery (Ward et al., 2018). Researchers have used the spontaneously hypertensive rat, a model of primary hypertension, the most significant risk factor for stroke, in middle cerebral artery occlusion models, although sex differences have not been well studied (Yao and Nabika, 2012). Experimental stroke models have also been used to evaluate the effect of gonadal hormones on stroke outcomes and provided an explanation for the decreased incidence and severity of stroke among younger women. Depletion of endogenous ovarian hormones by removing the ovaries worsens stroke outcomes in young female mice and rats, and providing estrogen to young female mice and rats without ovaries is neuroprotective (Dubal et al., 1998; Hawk et al., 1998; Rusa et al., 1999; Simpkins et al., 1997). Consistent with the Women’s Health Initiative findings which demonstrated higher stroke risk in postmenopausal PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPROVING PREVENTION AND CARE FOR CHRONIC CONDITIONS IN WOMEN 7 women (Demel et al., 2018; Wassertheil-Smoller et al., 2003), hormone treatment given to reproductively senescent rats increases the risk for stroke (Selvamani and Sohrabji, 2010). The most critical realization to emerge from basic science stroke studies is that therapies may be effective in only one sex. Minocycline, a microglial inhibitor, is neuroprotective in males but not females (Li and McCullough, 2009). Sex-specific pathways mediate the cell death effectors that are central to stroke injury—for example, caspase inhibition is protective in females but not males (Liu et al., 2009), but inhibiting the enzyme poly(ADP-ribose) polymerase is protective for males but not females (Liu et al., 2011). A series of studies have shown that epigenetic modifiers, such as small noncoding RNA, are effective in one sex or age group (Sampath et al., 2023; Selvamani et al., 2014; Selvamani and Sohrabji, 2017). These data provide a strong justification for including both sexes when designing stroke therapies. A pertinent example of the importance of preclinical sex differences and how neglecting them can be catastrophic is illustrated by the research and eventual clinical trials of tirilazad mesylate, which in experimental studies showed antioxidant and neuroprotective properties for traumatic brain injury and bleeding in the space between the brain and surrounding membrane (Cahill and Hall, 2017). It was tested in several small clinical trials but never received Food and Drug Administration approval. From the first trial, it was apparent that the treatment group had reduced mortality and showed better scores on the Glasgow Outcome Scale than the placebo group (Kassell et al., 1996), but these beneficial effects were only seen in male patients. Several more trials tested this drug but failed to show significant effects. Despite the intriguing sex difference seen in the first trial, subsequent studies did not stratify the results by sex. As a result, a promising drug was permanently shelved (Cahill and Hall, 2017; Galea et al., 2020). These examples make a compelling case for including both male and female animals in preclinical studies. Although a 10-year analysis indicates that more studies incorporate both sexes, doing so has met with resistance from researchers, mainly because of the concern it will double the cost of the studies. This is a legitimate concern given the costs of conducting research in general has increased substantially over the past 25 years as the National Institutes of Health (NIH) budget has stagnated. Without an overall increase in the budget, a recommendation to increase the cost of a single R01 would have the unintended consequence of reducing the number of funded grants. Additional exploration regarding more targeted strategies to support research focused on chronic diseases impacting women is needed. For example, given the interdisciplinary approaches that are required and the need to support relevant animal models, mechanisms such as program project/center grants may need to be used. These grants have the advantage of supporting central core grants such as the P30 and specialized center grants such as the P50, the latter of which will provide the necessary resources regionally to support male and female animals in preclinical studies and facilitate the advancement of chronic conditions in women across the clinical spectrum under a common theme (Mehrotra et al., 2008). While there may be further exploration at the systems level, fundamentally there needs to be continued education of the researcher, specifically related to experimental design. Most researchers have trained in labs where the model has only included one sex, mostly male, and considerations pertaining to including both sexes may lead to design flaws. This includes group housing; estrus cycle determination; and evaluation of the role of gonadal hormones using surgical or chemical ovariectomy. Mandatory responsible conduct of research courses could be used to train students on not only the importance of sex as a biological variable, but also design elements. The NIH Office of Research on Women’s Health has already initiated some of these PREPUBLICATION COPY: UNCORRECTED PROOFS 

8 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN learning tools, but they need to be widely known and applied at the institutional level and among professional societies. In addition to enhanced learning opportunities, Institutional Review Boards (IRB) may consider additional reviews when protocols are submitted for approval. The potential benefits of this approach were highlighted in an analysis that assessed the inclusion of either sex as a biological variable or gender in protocols submitted by researchers at a single institution (Freeman et al., 2017). The investigators noted that of the 68.8 percent of the 240 protocols which included either sex or gender in their submissions only 14.5 percent of these protocols provided justification for the proposed population targeted in their study. Moreover, of the 63 percent of protocols for which the peer-reviewed literature indicated that sex and gender were important in the pathophysiology of the condition under study, only 2 percent proposed the inclusion of either sex or gender as a contributor to their primary outcomes. These findings suggest that an intervention at the level of IRB submission may reaffirm the importance of considering sex and gender in research (Freeman et al., 2017). Lack of Diverse Animal Models Most preclinical studies involve either rats or mice, with the most common choices being Sprague-Dawley rats, an outbred strain, and C57Bl/6 mice, an inbred strain. Mice are used overwhelmingly in preclinical research because of their well characterized genetics, relatively stable and predictable phenotype across labs, and availability of genetic modifications, however, data from genetically homogenous animal models are unlikely to translate to a genetically diverse human population. Recent efforts have addressed the need for greater diversity of mouse models, such as the Hybrid Mouse Diversity Panel and Collaborative Cross model (Threadgill et al., 2011) that could lead to studies that aim to provide insights into how strain-specific behaviors are regulated by genetic and epigenetic variability, for example, or identify susceptibility loci linked to variations in chronic condition outcomes. These models may increase robustness and lead to more informed clinical trials. A broader use of genetically diverse models would increase translational validity of animal studies, in both disease processes and therapies. Understanding Chromosomal Versus Gonadal Sex Differences in Disease Etiology Most sex differences are attributed to gonadal hormones rather than sex chromosomal factors. In part, this is the result of a lack of animal models that compare chromosomal versus gonadal contributions. Over the last 20-plus years, the Four Core Genotypes mouse model has provided a unique opportunity to test the relative contributions of gonadal and chromosomal sex. Investigators have used it in many studies to demonstrate that sex chromosome complement contributes to sex differences in a wide variety of tissues and disease models, including autoimmune diseases, Alzheimer disease (AD), metabolic diseases, neural tube closure defects, bladder cancer, and cardiovascular disease (CVD) (Arnold, 2020, 2022). In stroke, for example, research has shown that gonadal sex, specifically the presence of ovaries, leads to better recovery in young animals (Manwani et al., 2015), but chromosomal sex is a better determinant of recovery in aging animals (McCullough et al., 2016). In mouse models of multiple sclerosis (MS) and systemic lupus erythematosus (SLE), both autoimmune diseases, chromosomal sex also contributes to sex differences (Dou et al., 2024; Fazazi et al., 2023; Itoh et al., 2019; Smith- Bouvier et al., 2008), although estrogens and androgens are also protective (Lasrado et al., 2020). Therefore, in addition to including both sexes in research models, understanding the interacting PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPROVING PREVENTION AND CARE FOR CHRONIC CONDITIONS IN WOMEN 9 contributions of sex chromosomes and gonadal hormones in the etiology of chronic conditions is critical. A good example of this is diabetes, which occurs at approximately similar rates in men and women, but women are at an increased risk of serious health outcomes, including heart disease, heart attack, stroke, and depression (Pan et al., 2011). Although gonadal hormones have been implicated in this process, the role of sex chromosomes is less well understood. Models to Assess Complex Chronic Conditions As described with endometriosis and pain, the ability to assess specific human symptoms and traits in animal models can be challenging. This is also true for other conditions, including mental health disorders and cognitive impairment. Mental health disorders, such as depression and anxiety, may occur independently or co-occur with other chronic conditions, such as vulvodynia, CVD, and stroke. Poststroke depression is more common in females in human and animal studies. Although evidence is limited regarding the efficacy of conventional antidepressants for trauma- or stroke-induced depression in women, preclinical findings have suggested antidepressant treatment improves postischemic depressive behaviors in animal models (Kronenberg et al., 2014). Stroke-induced depression has largely been studied in males (Kato et al., 2000; Kronenberg et al., 2012, 2014; O’Keefe et al., 2014; Verma et al., 2014), although recent studies have incorporated both sexes (Panta et al., 2019). Most tests of depression-like behaviors take advantage of a species’ natural behaviors, such as the degree of social interaction (Becker et al., 2021), burrowing (Mallien et al., 2022), and sucrose preference (Pitzer et al., 2022). Male and female animals respond differently to these tests (Eltokhi et al., 2021; Pitzer et al., 2022). For example, in the social interaction test, the duration and type of interaction with the test subject differs, with males more likely showing territorial behaviors and females showing more affiliative, prosocial behaviors (Kondrakiewicz et al., 2019; Misiołek et al., 2023). Hormones also influence these tests, with animals that have had their gonads removed surgically differing in their depressive responses from gonadally intact animals (Boivin et al., 2017; de Chaves et al., 2009) and young females differing from older acyclic females in chronic stress models (Lotan et al., 2018). However, the translational value of these tests to the human condition has limitations (Becker et al., 2021). Depression in humans is complex and multifactorial; although simple assessment, such as a lack of interest or enjoyment from life experiences in animals, as measured by sucrose preference, may have uses in predicting the efficacy of antidepressant treatments, tests with better predictive validity and construct validity for both sexes are needed (Becker et al., 2021). Models to Assess Cognitive Impairment and Dementia Similar to tests of depressive behaviors, advancement is also needed in tests of cognitive impairment, so that rodent-based tests can better model human cognitive domains (Vitek et al., 2020). Rodent assessments typically involve spatial learning (Ghafarimoghadam et al., 2022), associative learning such as cued fear conditioning (Webster et al., 2014), or episodic memory, such as novel object recognition (Ghafarimoghadam et al., 2022), in which rodents use similar neural circuits as humans (Chen et al., 2013). Although neuropsychological testing in humans assesses these visuospatial skills, memory, and recall (Battista et al., 2017), a complete assessment will also include structured interview-based tools to assess memory, orientation, judgment, problem solving, and knowledge of recent community affairs and national events (Battista et al., 2017; Weakley et al., 2015), which is not possible in rodent or nonhuman primate PREPUBLICATION COPY: UNCORRECTED PROOFS 

10 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN models. This is not to imply that rodent models should be discarded for cognitive testing, but they should be studied in context (Vitek et al., 2020). Thus, data from humanized AD models where AD-related genes are expressed in mice and rats have been valuable in showing that cognitive performance is impaired in these animals, strengthening the hypothesis that these genes are related to specific cognitive domains (Sanchez-Varo et al., 2022; Vitek et al., 2020). This is also seen in preclinical studies of ischemic stroke, a leading cause of vascular dementia and AD (Mellon et al., 2015). The increased risk and severity of cognitive impairment is strongly associated with female sex, which in turn is strongly associated with poststroke cognitive impairment (Pendlebury and Rothwell, 2009). A high fat diet worsened features of vascular dementia in females compared to males (Gannon et al., 2022). Poststroke cognitive impairment is replicated in experimental stroke models in males and females (Mani et al., 2023; Sampath et al., 2023; Ward et al., 2018), and aging females (Panta et al., 2020). The challenge is to focus on other indicators of cognition, including biomarkers that indicate impairment or dementia. Another strategy would be to study brain neural circuits related to cognition. In rodents, cognitive performance has been inferred from an observable behavior, such as a preference for a particular reward. A more nuanced understanding of choice, preference, and motivation may be obtained by adding in vivo electrophysiological recordings of specific circuits, using technology such as head-mounted cameras and optogenetics. Rigor of Preclinical Studies Preclinical research focuses on identifying and developing models to understand the basis of a disease or disorder and identify potential therapeutics. Bridging preclinical and clinical studies can facilitate understanding how early disease events can predict progression. Often, when testing preclinical hypotheses, researchers use cell or animal models; samples of human or animal tissues; or computer-assisted simulations of drug, device, or diagnostic interactions within living systems (Seyhan, 2019). For a biomarker to be considered a surrogate endpoint, scientific evidence, such as epidemiological, therapeutic, and pathophysiological data, must demonstrate that it consistently and accurately predicts a clinical outcome (Batis et al., 2021). Preclinical studies typically only include young and healthy male animals or tissues obtained from them, omitting the possible effects of sex-related variables (Perrino et al., 2021). For some biomarkers, a major obstacle to clinical translation is the high cost and invasiveness of the measure (Batis et al., 2021; DeLouize et al., 2022; Seyhan, 2019). Most clinical trials consist of double-blind, placebo-controlled, multicenter studies. Preclinical studies have variation in housing of the animals (temperature, light/dark cycle, food source etc.) by institutes, resulting in potential discrepancy of findings between labs especially when evaluating effects or circadian rhythm or similar behaviors (Russell et al., 2021; Seyhan, 2019). Mimicking study analysis and rigor of clinical studies, there is a huge push for more preclinical researchers to analyze data in a blinded manner to ensure lack of bias. One example where researchers have taken a multicenter preclinical approach is the quest to identify agents that extend life-span and healthspan in mice. The National Institute of Aging- sponsored Interventions Testing Program is a peer-reviewed program where investigators can recommend drugs for testing. It is carried out at three sites—the Jackson Laboratory, University of Michigan, and University of Texas Health Science Center at San Antonio—and uses genetically heterogeneous mice. Over the last 20 years, this study has identified nine agents that PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPROVING PREVENTION AND CARE FOR CHRONIC CONDITIONS IN WOMEN 11 significantly increase median life-span (Harrison et al., 2009, 2014, 2019; Miller et al., 2011, 2014, 2019; Strong et al., 2008, 2016, 2022). As a result of appropriate stratification, this program reported major benefits from treatment with rapamycin in both males and females, albeit with greater efficacy in males; acarbose, which was more effective in males, and 17α- estradiol, which only increased longevity in males. The lack of translational success is evident in stroke research, where hundreds of preclinical studies and dozens of drugs tested in animal models have not produced effective, novel therapies. A concerted effort to improve preclinical studies resulted led to the STAIR guidelines (Fisher et al., 2009; Thomas et al., 2017), which recommend using more than one stroke model, including animal models with comorbid factors; including both males and females and young and aging animals; applying multiple behavioral tests; studying acute and chronic outcomes; and selecting anesthesia protocols to minimize bias (Thomas et al., 2017). More recently, NIH instituted a funding mechanism, the Stroke Pre-Clinical-Clinical Assessment Network (SPAN), to replicate the rigor of clinical trials in a preclinical setting. Each approved project proposed a drug for which every participating lab would use blinded testing (Morais et al., 2023). All labs would perform the same tests and generate video recordings that a central coordinating center would assess, similar to the way human multicenter trials are run. The SPAN methodology has identified one promising drug, uric acid (Lyden et al., 2023). Recently, researchers used a similar approach, albeit on a smaller scale, to test the efficacy of an interleukin-17A inhibitor as a stroke therapy (Gelderblom et al., 2023). Researchers have integrated machine learning into all stages of drug discovery and development, including clinical trials. They have developed software to identify novel targets, provide stronger evidence for target–disease associations, improve small-molecule compound design and optimization and increase understanding of disease mechanisms and disease and non- disease phenotypes. Investigators are also using machine learning to develop new biomarkers for prognosis, progression and drug efficacy; improve analysis of biometric and other data from patient monitoring and wearable devices; and enhance extraction of high-content information from pathology images. ADDITIONAL OPPORTUNITIES TO ENHANCE THE TRANSLATION OF RESEARCH TO CLINICAL PRACTICE Although the translational research T0 to T4 continuum provides a long-standing pathway for taking research from basic science through implementation and health policy, several critically important approaches do not fit cleanly within that rubric. These often reflect a different positionality than conventional research, which is shaped almost exclusively by the lens of the researcher, and broaden that lens to include the individual patient, family unit, community, and other key stakeholders. When considering women who present with chronic conditions, particularly those with multiple chronic conditions (MCC), the approach to diagnosis and management should not merely take into account the perspective of the researcher but must also take into consideration the perspective of the individual patient. Given potentially vague symptoms that may require an interdisciplinary team to address the complexity of the presentation, the patient’s perspective needs to be central. This ongoing research perspective is important and must include patient-centered approaches and community-engaged research, as many of these conditions required long-term services. PREPUBLICATION COPY: UNCORRECTED PROOFS 

12 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN The perspective of the patient must also be considered when sex-specific state and federal policies intersect with health care access and patient care. As an example, there is insufficient research to support the sexual and reproductive health requirements of women, particularly in those 18 to 25 years of age. Considering that women in early adulthood are at greater risk for poorer sexual and reproductive health outcomes compared to men in this age group, there is a need for age-specific policies and practice guidelines to inform care for these individuals (Schlegel and Smith, 2021). Only recently has there been sufficient data disaggregation to assess age-specific outcomes for young women (CDC, 2019). This period in a woman’s life course corresponds to the highest occurrence of unintended pregnancies. In addition, women of color and women identifying as lesbian, gay, bisexual, transgender, queer, intersex, or asexual (LGBTQIA+) are at higher risk for experiencing poorer health outcomes due to bias, discrimination, and social determinants which negatively impact access and continuity of care. During this stage, there is increased risk associated with substance use and situational uncertainty that can further exacerbate underlying conditions which may negatively impact the health of mother and their unborn child. State policies will dictate access and health care options available to this vulnerable population (CDC, 2019). Moreover, restrictions to gender-affirming care at the state-level further complicates accessibility to care and assurance of quality care for transgender youth aged 13 years and older. (Redfield et al., 2023. A more tailored, culturally-relevant, age- specific, sexually-driven approach to care is needed for these specific groups that considers how the confluence of sociopolitical contributors to health, uncertainties of access and support, and vulnerability to poor health outcomes influence optimal well-being over the life course (Schlegel and Smith, 2021). Patient Centeredness and Patient-Centered Outcomes Research “I would include the human experience [when considering treatment and care]. I think that is the biggest thing… having a true understanding by prioritizing the lived experience and collaborating with patients to find the best outcomes for them.” –Presenter at Committee Open Session The concept of patient centeredness or patient-centered care was elevated in 2001 by IOM when it identified patient-centered care as one of six areas of focus required to improve U.S. health care quality. Crossing the Quality Chasm: A New Health System for the 21st Century, defined patient-centered care as “…providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions” (IOM, 2001). Research focusing on patient centeredness is critical to improving experiences of care and care quality. This is particularly true in conditions where the voice of the individual patient is unintentionally but all too easily silenced or lost in population- based studies or evidence-based medicine and among groups that society and health care have marginalized. PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPROVING PREVENTION AND CARE FOR CHRONIC CONDITIONS IN WOMEN 13 Patient-Reported Outcomes Patient-reported outcomes (PROs) are self-reports “of the status of a patient’s health condition, health behavior or experience with health care.” They are used to improve clinical research, health care quality and patient care (Gregory et al., 2018). Researchers use PRO measures (PROMs) to collect information about general health, health behaviors, quality of life, functional status, or preferences associated with health care or a specific treatment (Cella et al., 2015). In women’s health, studies have validated PROMs for several female-specific and gynecologic conditions, including endometriosis (Gater et al., 2020), pelvic floor disorders (Fitzgerald et al., 2020; Ralphsmith et al., 2022), uterine fibroids (Arlene et al., 2020; Laughlin- Tommaso et al., 2020; Neumann et al., 2024), and SLE (Strand et al., 2020). However, some of the PROMs for gynecologic conditions, such as endometriosis are specifically focused on outcomes, such as infertility, rather than important outcomes that are centered on well-being and quality of life. PROMs are not available for all chronic conditions, and some tools may lack measures for specific symptoms associated with a condition. For example, a systematic review reported a lack of appropriate pain-specific measures for women who have pelvic organ prolapse and urinary incontinence (Ralphsmith et al., 2022). PROMs can provide important information for clinical practice. A review of studies on the effect of a uterine fibroids diagnosis on mental health found that PRO related to quality of life were the most important management outcomes (Arlene et al., 2020). The Menopause- Specific Quality of Life Questionnaire, another PRO tool, has shown utility in assessing quality of life and associations with depression in the menopausal transition, though a scoping review from 2016 showed that it has not yet been used in clinical practice (Sydora et al., 2016). Researchers have noted that sex and gender differences are not adequately represented in the development and use of PROMs (Hertler et al., 2020). For example, PROs reported by patients with atherosclerotic CVD showed that women had poorer satisfaction with health care providers, lower quality of life, and poorer perceived health in comparison to men (Okunrintemi et al., 2018). In a review of studies focused on sex differences in long-term outcomes after stroke, female patients tended to experience a worse outcome with regard to health-related quality of life, primarily the result of age, disability, and depression, compared with male patients (Gall et al., 2012). In another study using PROMs, women scored a significantly lower quality of life at 3 and 12 months poststroke (Bushnell et al., 2014). The development and use of sex and gender-specific questionnaires that address patient-centered outcomes is an important research gap to address, given that men and women report differences in physical symptoms such as pain, quality of life, and other outcomes (Hertler et al., 2020). Comparative Clinical Effectiveness Research Patient-centered research is a lens more than a single methodology and can take on a wide variety of forms, such as patient-centered comparative clinical effectiveness research (CCER). In CCER, investigators compare patient-centered or -valued outcomes of treatments in diverse populations to provide patients with the information they need to determine which ones work best for them. Although the use of CCER is increasing, particularly since the establishment of the Patient-Centered Outcomes Research Institute 6 (PCORI) in 2010, a relative dearth of data remains on chronic conditions and particularly on MCC. 6 Found at https://www.pcori.org/ PREPUBLICATION COPY: UNCORRECTED PROOFS 

14 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN The significance of having, or not having, these data is undeniable. As detailed in Chapter 5, uterine fibroids are a major source of chronic morbidity for reproductive-aged women, affecting 70 percent by the age of 50 and causing chronic abnormal uterine bleeding, dysmenorrhea, infertility, and chronic pelvic pain. They are the leading cause of hysterectomy in the United States, with limited number of other procedural interventions available. In addition, significant racial disparities in prevalence exist (Katon et al., 2023). Until recently, no CCER data existed to help inform patient decision making. Comparative effectiveness data regarding short- and long-term quality of life when having fibroids removed using the three most common surgical approaches largely did not exist. Part of the challenge is the substantial variability in disease presentation, such as in the symptoms and number and size of fibroids. Treatment availability also has variability and disparity across institutions. The Comparing Options for Management: Patient-Centered Results for Uterine Fibroids (COMPARE-UF) registry was a longitudinal PCORI-funded study designed to ascertain the clinical effectiveness of procedural interventions for uterine fibroids. Data generated from it provided much needed information for not only patients but providers (Stewart et al., 2018). COMPARE-UF found that when comparing approaches to remove fibroids, all of them had significant improvement in health-related quality of life, but the time to return to work after hysterectomy was faster compared to laparoscopic and abdominal fibroid removal that left the uterus intact (Laughlin-Tommaso et al., 2020). COMPARE-UF also provided insights into long- term comparative effectiveness, comparing the various approaches to abdominal removal of fibroids, hysterectomy, and uterine artery embolization (UAE). It found that although all approaches were associated with a significant increase in health-related quality of life at the end of the first year, differences between the uterine-sparing approaches—surgical removal and UAE—and hysterectomy in terms of the durability of symptom relief were seen by the third year after surgery (Anchan et al., 2023). Given the recurrence rate of fibroids, longer-term CCER studies are needed to better inform women about when to expect return of symptoms after a given procedure and enable them to weigh the risks and benefits accordingly. Incorporating the Patient Lived Experience While conducting this study, the committee invited several women living with select chronic conditions to share their lived experience and perspectives at workshops held on May 31 and August 9, 2023. Given the breadth of chronic conditions that this study covered, it was not feasible to include patient perspectives on all conditions. The committee’s selection of chronic conditions featured in the panels was based on committee members’ interest in learning more about specific conditions: CVD, migraine, endometriosis, uterine fibroids, and autoimmune conditions including psoriasis, MS, and Sjogren’s syndrome. The committee invited the panelists to share their experiences with navigating the health care system and their reflections on how to improve facets of scientific research and clinical care—from diagnosis, treatment, and management. Several crosscutting themes emerged from the panel discussions. When discussing the most significant barriers they faced as patients or patient advocates, the most frequent responses were the following: 1. a lack of knowledge and understanding related to the diagnosis of the condition; 2. biases, stigma, and cultural insensitivity encountered in the health system that is rooted in this lack of understanding; 3. access to health care, including affordability of medications and procedures; and PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPROVING PREVENTION AND CARE FOR CHRONIC CONDITIONS IN WOMEN 15 4. challenges posed by the day-to-day management of symptoms and risk factors associated with the condition. Appendix C includes a full summary of the panelists’ remarks. The panelists’ perspectives were invaluable to the committee’s understanding of the effect these chronic conditions have on their lives. Systematically obtaining the perspectives and lived experiences of patients and their communities in research can contribute to more meaningful, relevant, and patient-centered health care practices and outcomes. Community-Engaged Research Patient-centered research focuses on the individual patient and their experiences with the health care system; community-engaged research focuses on the community as the unit of identity. It represents a spectrum of approaches where community members and organizations and researchers work together to answer specific questions (Han et al., 2021). The nature of working “together” can vary significantly, from community-placed or -based research, where researchers but do not seek community input or buy-in in any aspect of the research, to community-led research, where the research question, design, and data interpretation are initiated and conducted by community members exclusively, with minimal if any role for the researcher. A key benefit of community-engaged research is that it centers research in spaces that significantly affect health outcomes: physical community, social community, geographies of shared and common social and health-related behaviors, and geographies of trusted organizations and individuals. It has become a key lever in health disparities and equity research, as it goes beyond spaces that traditional translational research has been able to reach. One of the most recognized approaches is community-based participatory research (CBPR), which involves shared responsibility and accountability and shared control between the community and researchers. Although a given team ideally determines and agrees upon its principles, common principles highlighted in CBPR include equity in the partnership in responsibility and resources, mutual respect, bidirectional learning, mutual benefit, and the sustainability of the work (Israel et al., 2018). CBPR has been used in various settings, including to enhance participation of racial and ethnic groups in clinical trials (McFarlane et al., 2022) and in academic-led research that focuses on preventing and improving outcomes for chronic conditions in women. Although it remains underused, community-engaged research is uniquely positioned to address the intersections of social determinants of health and health disparities in chronic conditions of women. One example is the MONARCAS Community and Academic Collaborative Program in Chicago (Mancera-Cuevas et al., 2018). It sought to increase awareness of SLE in predominantly Latino/a communities in Chicago. Using the Center for Disease Control and Prevention’s Popular Opinion Leader (POL) model, high school students, community health workers, and parents who were identified as POLs were recruited and trained on the symptoms and self-management of SLE and sent throughout the community to share what they had learned. Over the course of the study, screenings, access to health care, and patient engagement in disease management improved (Leatherwood et al., 2021). In addition to SLE, researchers have leveraged CBPR to address posttraumatic stress disorder, human immunodeficiency virus (HIV), and substance use disorder (SUD) in women from historically marginalized communities (Pearson et al., 2019). Investigators have also applied CBPR to health promotion interventions related to chronic conditions such as cardiometabolic conditions. Researchers worked with community PREPUBLICATION COPY: UNCORRECTED PROOFS 

16 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN partners that recruit and implement research in certain settings within communities. For example, in the Black and African American community, faith-based settings, such as churches, and other settings, such as hair salons, have served to promote greater participation in research from women and incorporate cultural aspects in the intervention and its delivery (Palmer et al., 2021). Cultural tailoring of interventions to a particular group is also an important component of efforts to reduce health disparities and improve health outcomes. Health Services and Policy Research As mentioned in the prior chapters, research focused on screening for and diagnosing chronic conditions affecting women is essential for improving quality life and decreasing mortality and morbidity. Federal health policies, such as the 2010 Affordable Care Act (ACA), made great strides to improve women’s health outcomes on a population health scale. Overall, ACA improved health care access, expanded coverage, and helped decrease health care cost. The percentage of uninsured women and costs for health care coverage decreased, and health care for women in poverty improved (Sugar et al., 2022). ACA also expanded women’s preventive health services and eliminated cost sharing for services. More specifically, that included screenings, such as for cervical cancer, depression, HIV and other sexually transmitted infections, mammograms, osteoporosis, and domestic violence (HRSA, 2024). It eliminated cost sharing for well visits, testing and preventive medications for breast cancer, contraception, and breastfeeding support and supplies. Despite these improvements, disparities among women of racial and ethnic groups and by lower socioeconomic status remain. Researchers note that studies of ACA have focused more on proximal outcomes related to coverage, access, and affordability, and few studies have addressed the effect on downstream health outcomes. More research focusing on gender is needed to understand how such initiatives improve health care outcomes specific to women (Lee et al., 2020). The Learning Health System Model In 2007, an IOM workshop introduced the concept of the learning health system as a strategy to improve access and care, among other challenges faced in health care (IOM, 2007). This model incorporates continuous learning through the process of care delivery, focusing on PROs, clinical informatics, and organizational culture. It allows for continually improving quality of care by leveraging the information needed at the point of care. The juxtaposition of relevant knowledge and patient interaction contributes to optimal clinical decision making. The infusion of clinical practice guidelines, continually informed with new insights from patient interactions, provides an opportunity to mitigate possible provider–patient bias. Research has demonstrated the benefits of applying clear clinical guidelines across a health system (Yehia et al., 2020). One study, for example, noted equivalent mortality rates among self-reported African American and White patients who were admitted across a system of 92 hospitals with a diagnosis of Coronavirus disease 2019 (COVID-19). Consensus-driven clinical guidelines informed by newly observed findings in the clinical setting can be effective strategies to deliver quality care. One group of researchers described a tripartite construct of population health, learning health systems, and measurement-based care that can improve access, care, outcomes, and equity by providing a framework for systematic measurement of PROs (Tepper et al., 2022). This framework can also promote shared decision making, team-based models of care, and equity. PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPROVING PREVENTION AND CARE FOR CHRONIC CONDITIONS IN WOMEN 17 Investigators have applied a health equity framework for learning health systems to various case studies. One program, the Community Engagement for Early Recognition and Immediate Action in Stroke, incorporated community engagement and education with racial and ethnic groups (Brooks et al., 2017). Exploring Telehealth with a Learning Health Systems Approach to Improve Access to Care for Women with Chronic Conditions An example of an area that may transform access to care is the emergence of digital and telehealth. The latter expanded rapidly during the onset of the COVID-19 pandemic to reduce exposure (CCHP, 2024b) and continues to be a critical access point (Lee et al., 2023). This model of care is defined as “a collection of means or methods for enhancing the health care, public health, and health education delivery and support using telecommunications technologies” (CCHP, 2024a). Traditionally, it has focused on diagnosis and monitoring, augmented by additional modes of telecommunication. However, the recent inclusion of wearable devices, mobile applications, and virtual communication has expanded its potential effect on the health of populations, particularly rural populations that do not have access to specialty care (Kruse et al., 2021). The COVID-19 pandemic revealed significant inequities in care. For example, one study found that 38 percent of women compared to 26 percent of men failed to adhere to scheduled preventive care visits (Frederiksen et al., 2021). These differences were affected by income and well-being and were particularly common among women of color. Promising evidence shows that telehealth may positively contribute to optimizing women’s health. Related to access to mental health services and SUD interventions, the Medical University of South Carolina Reproductive Behavioral Health Program reported an increase in use of services associated with telehealth. A consequence of this initial success was the ability to reduce barriers to screening and treatment that many women who were pregnant and postpartum or challenged with SUD often face, such as the lack of transportation, time, child care, and stigma, referral, and service (Moreland et al., 2021). Although it is promising that mental health services can be delivered effectively to women in the reproductive stage, availability varies across states and counties. Facilities in urban areas were more likely to offer support for medical therapy and less likely to offer diagnostic services. Most facilities offered telehealth that included virtual counseling, medication management, and diagnostic services; however, services can still improve since about one in four facilities did not provide virtual medication management while one in three did not offer virtual diagnostic services (Cantor et al., 2024). The median time for an appointment was 14 days, with a range of 4–75 days, with no difference found in appointment availability when considering either the patient’s demographic profile or diagnosis. The availability of telehealth varied by state, with fewer facilities in Mississippi and South Carolina offering it compared to other states (Cantor et al., 2024). It may be important in addressing outreach in rural settings where it is difficult to access health services, but the evidence of variation across states makes this difficult to envision. This is important given the high prevalence of depression associated with chronic diseases affecting women, such as ME/CFS, fibromyalgia, and endometriosis. A review of the literature regarding the effectiveness of preventive services for reproductive health and interpersonal violence found limited evidence that telemedicine has equivalent efficacy for intervening for contraception and intimate partner violence compared to PREPUBLICATION COPY: UNCORRECTED PROOFS 

18 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN in-person care. The authors expressed uncertainty regarding the best strategies to deliver these services, given the inequities in access to care (Cantor et al., 2022). Pertinent to this report, the motivating factors that would drive women with chronic conditions to engage in care are critically important. Important insight can be gained by a review of patients with chronic conditions during the COVID-19 pandemic in May 2020. In one survey of 2,210 participants, 49 percent used telemedicine, including 50 percent of women compared to 43 percent of men. Individuals from homes with income levels greater than $100,000 were more likely to use telehealth compared to those with income levels less than $30,000. Only 45 percent of individuals over 56 years were likely to participate. Individuals reporting a diagnosis of SLE, cystic fibrosis, and ankylosing spondylitis were more likely to use the service. Other chronic conditions represented included endometriosis, macular degeneration, chronic obstructive pulmonary disease, asthma, MS, migraine, hypertension, and diabetes. Of those who did have a telehealth visit, 68 percent were satisfied with it (Horrell et al., 2021). These data suggest additional focus on research using a learning health system approach is needed to enhance telehealth use in patients with chronic conditions. Finally, as telemedicine continues to be explored by health systems in the future, it will be important to address the barriers that currently exist within the United States. As noted by Lopez and colleagues, “internet connectivity, digital literacy, and the digital divide remain the first and foremost challenge for older adults” (Lopez et al., 2021). SUMMARY This chapter highlighted challenges and research strategies related to improving health outcomes of women with chronic conditions. Some of the most pressing concerns related to translating basic science research to the clinical setting include limited experimental models that fail to capture all aspects of human disease, particularly female-specific and gynecologic conditions and MCC; a continuing lack of representation of females and a lack of sexual minorities in studies; and a lack of disaggregation of data according to sex. Research approaches that involve the researcher and the patients, family, and community members are essential for centering women’s needs. These strategies that incorporate patient engagement and community- based participation more directly address the social and structural drivers of the development of certain chronic conditions in women and may thus be more effective in improving health outcomes. Health services and policy research and learning health system models can accelerate the optimization of clinical care delivery according to patient experience and feedback. REFERENCES Anchan, R. M., J. B. Spies, S. Zhang, D. Wojdyla, P. Bortoletto, K. Terry, E. Disler, A. Milne, A. Gargiulo, J. Petrozza, O. Brook, S. Srouji, C. C. Morton, J. Greenberg, G. Wegienka, E. A. Stewart, W. K. Nicholson, L. Thomas, S. Venable, S. Laughlin-Tommaso, M. P. Diamond, G. L. Maxwell, E. E. Marsh, E. R. Myers, A. I. Vines, L. A. Wise, K. Wallace, and V. L. Jacoby. 2023. Long-term health- related quality of life and symptom severity following hysterectomy, myomectomy, or uterine artery embolization for the treatment of symptomatic uterine fibroids. American Journal of Obstetrics and Gynecology 229(3):275.e271 –275.e217. PREPUBLICATION COPY: UNCORRECTED PROOFS 

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