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P2Y12 Inhibitors Refill Gap Predicts Death in Medicare Beneficiaries on Chronic Dialysis
Get PDFINTRODUCTION: Oral P2Y(12) inhibitors (P2Y12-I) are commonly used antiplatelet drugs in patients with end-stage kidney disease (ESKD) on chronic dialysis. Although gaps in prescription refills are quite common in patients with ESKD, it remains unclear whether P2Y12-I prescription refill patterns are associated with adverse clinical outcomes. METHODS: We used the United States Renal Data System (USRDS) registry for patients with ESKD to capture new P2Y12-I prescriptions from 2011 to 2015. The primary exposure was prescription refill patterns and the primary outcome was all-cause death. RESULTS: Among the 31,243 patients with new P2Y12-I prescription, median age was 64 years; 54% were male; and 39% were Caucasian, 37% African American, and 18% Hispanic. We observed 3 P2Y12-I refill patterns as follows: continuous users (45.1%), noncontinuous users (3.6%), and users with >/=30 days refill gap (51.4%). Prescription refill pattern with >/=30 days refill gap (vs. continuous use) was associated with all-cause death (adjusted hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 1.13-1.23). Age and race were the most important risk factors associated with prescription refill pattern. African Americans (vs. Caucasians) were more likely to demonstrate >/=30 days refill gap, (adjusted odds ratio [OR]: 1.43; 95% CI: 1.36-1.51). In addition, younger patients (vs. older) were more likely to demonstrate >/=30 day refill gap (adjusted OR/decade: 0.9; 95% CI: 0.89-0.92). CONCLUSION: Nonadherence to P2Y12-I prescriptions is quite common, and disproportionately affects minorities. Younger individuals with ESKD are independently associated with a higher risk of death. The odds of having a refill gap are decreasing for older patients who are more compliant than younger patients. Future studies should investigate whether phenotyping subgroups of patients with ESKD based on prescription refill patterns can help in improving adverse clinical outcomes.This study was supported by the American Heart Association (AHA) Scientist Development Grant 16SDG31000045 (NJ) and the American Society of Nephrology (ASN) Foundation for Kidney Research (NJ). Institutional support for the project was provided using the Data Scholar award by the Translational Research Institute (TRI), grant [KL2 TR003108 and UL1 TR003107] through the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHA, ASN and the NIH. A data-use agreement was signed and approved by the USRDS Program Director (DUA 2016-50). The University of Kansas Medical Center was the primary site for data collection, processing, and analysis. The manuscript was approved for publication by the USRDS Coordinating Center (approval # MS2021-27)
Effects of Osteopathic Manipulative Treatment on Breastfeeding LATCH Assessments in Infants
No full textImportance: Effective suckling is crucial for infants to gain nutrition, grow, and bond with their mothers. Suckling difficulties within the first month can put infants at a higher risk of early weaning. Successful suckling involves coordinated movements of the lips, tongue, and jaw which rely on input from cranial nerves. Half of mothers who stop breastfeeding in the first month report biomechanical issues, highlighting the need to address these challenges for successful breastfeeding. Osteopathic Manipulative Treatments (OMT) have been utilized to treat the infant population for a variety of somatic dysfunctions and may be effective for suckling difficulties. Objective: To evaluate infants’ LATCH assessment scores before and after OMT sessions in the term infant population with feeding difficulties. Design, Settings, and Participants: This was a longitudinal prospective study conducted between October 2022 and July 2023 of 40 term infants <6 months of age with at least one of the following conditions: feeding difficulty, ankyloglossia (tongue tie), difficulty gaining and/or maintaining weight. After completing an initial eligibility screening, patients and their parents attended two clinic visits one week apart. Parents completed a LATCH questionnaire to evaluate infant latching at the beginning of each visit (visits 1-2). A phone follow up was conducted two weeks after the second visit to collect the LATCH survey over the phone (visit 3). Interventions: Participants received two full body OMT treatments one week apart, done by two different osteopathic physicians. Main Outcomes and Measures: LATCH assessment tool assigns a score of 0, 1, or 2 for five components (Latch, Audible swallowing, Type of nipple, Comfort, Hold) of feeding for a possible total score of 10 points, with higher scores indicating better outcomes. LATCH numerical scores were compared between the two visits to gauge improvement of the infant’s feeding abilities following OMT. LATCH scores were compared between the first and second visit, the second and third visit, and from visit 1 to visit 3 using independent samples t-tests. Results: Infants in the study were an average of 7.1 weeks old (standard deviation (SD)=4.4), an average weight of 3.6kg (SD=0.4) and an average length of 20.4 inches (SD=0.9). The majority were of white ethnicity (80%), possessed medical insurance coverage (92%), and had insurance covering lactation consultants (61%). Statistical analyses revealed a significant improvement in the LATCH scores between Visit 1 (8.01) and 2 (8.47; p=0.012); a significant improvement in LATCH scores between Visit 2 (8.47) and Visit 3 (9.11; p=.005); and an overall significant improvement from Visit 1 to Visit 3 (p<.001). The improvement at Visit 2 compared to Visit 1 was significantly larger among those who were bottle-fed (change=1.35) compared to those who were breastfed (change=0.21; p=.004). Conclusions and Relevance: In term infant populations with feeding difficulties, OMT significantly improved the LATCH scores over the course of the study. There are specific subpopulations, such as infants who were bottle-fed, who may have greater improvement in LATCH scores following OMT. OMT remains strongly recommended in this patient population to help with difficulties pertaining to latching.American Academy of Osteopath
Demographic disparities in the limited awareness of alcohol use as a breast cancer risk factor: empirical findings from a cross-sectional study of U.S. women
Get PDFBACKGROUND: Alcohol use is an established yet modifiable risk factor for breast cancer. However, recent research indicates that the vast majority of U.S. women are unaware that alcohol use is a risk factor for breast cancer. There is limited information about the sociodemographic characteristics and alcohol use correlates of awareness of the alcohol use and breast cancer link, and this is critically important for health promotion and intervention efforts. In this study, we assessed prevalence of the awareness of alcohol use as a risk factor for breast cancer among U.S. women and examined sociodemographic and alcohol use correlates of awareness of this link. METHODS: We conducted a 20-minute online cross-sectional survey, called the ABLE (Alcohol and Breast Cancer Link Awareness) survey, among U.S. women aged 18 years and older (N = 5,027) in the fall of 2021. Survey questions assessed awareness that alcohol use increases breast cancer risk (yes, no, don't know/unsure); past-year alcohol use and harmful drinking via the Alcohol Use Disorders Identification Test (AUDIT); and family, health, and sociodemographic characteristics. We conducted multivariate multinomial regression analysis to identify correlates of awareness that alcohol use increases breast cancer risk. RESULTS: Overall, 24.4% reported that alcohol use increased breast cancer risk, 40.2% reported they were unsure, and 35.4% reported that there was no link between alcohol use and breast cancer. In adjusted analysis, awareness of alcohol use as a breast cancer risk factor, compared to not being aware or unsure, was associated with being younger (18-25 years old), having a college degree, and having alcohol use disorder symptoms. Black women were less likely than white women to report awareness of the alcohol use and breast cancer link. CONCLUSIONS: Overall, only a quarter of U.S. women were aware that alcohol use increases breast cancer risk, although 40% expressed uncertainty. Differences in awareness by age, level of education, race and ethnicity and level of alcohol use offer opportunities for tailored prevention interventions, while the overall low level of awareness calls for widespread efforts to increase awareness of the breast cancer risk from alcohol use among U.S. women.The authors declare that no funds, grants, or other support were received during the preparation of this manuscript
Addressing the Impact of COVID-19 Restrictions on Depression and Eating Disorders in Pediatric Populations
No full textPurpose:
The mental health of global youth populations has been a serious topic of concern, especially following the onset of the COVID-19 pandemic. Early research has shown that the global prevalence of adolescent and pediatric mental health episodes has increased following the pandemic; with a 25% increase in depressive symptoms and a 20% increase in anxiety symptoms. It is also known that there is a strong correlation between depression and eating disorders; with each diagnosis increasing the risk of the other. Prior to the pandemic, it was estimated that the lifetime prevalence of eating disorders in adolescents was 2.7%, which was more prevalent among females (3.8%) vs. males (1.5%). Despite these known statistics, minimal research has been performed in the U.S. evaluating eating disorders among pediatric populations following the pandemic. Therefore, given the declining mental health of our youth following COVID-19, it is imperative to consider the development of eating disorders and/or depression in these vulnerable populations.
The purpose of the present study is to explore the presence of eating disorders and depression in pediatric populations following the COVID-19 pandemic, and how these rates differ between males and females.
Methods:
A literature review was conducted using PubMed and Google Scholar electronic databases. Relevant articles were screened using the following keywords found in either the title or abstract: depression, major depressive disorder, eating disorders, anorexia nervosa, bulimia nervosa, binge eating, adolescence, pediatrics, children, COVID-19, pandemic.
This search was limited to articles with the following criteria: written in English (i) inclusion of adolescents or children as research participants (ii), and research conducted after 2018 (iii). Studies selected based on the above criteria included longitudinal studies, comparative studies, and systematic reviews.
Results:
Recent studies have shown an increase in the prevalence of both depression and eating disorders in global youth populations following the COVID-19 pandemic. As a result of the mandated COVID-19 lockdown, many pediatric populations were isolated from their friends, classmates, and family members. A cross-sectional study in China found that children who were left alone throughout the day without a companion during COVID-19 had higher levels of depressive symptoms (22%) and anxiety (27%) as compared to those who had company throughout the day. The mandated COVID-19 lockdowns have differing affects across gender identity. A longitudinal study of children in Australia found that when compared to their male cohort, females experienced higher levels of generalized anxiety and depressive symptoms as well as lower life satisfaction during the pandemic.
Conclusion:
These findings indicate that children, especially females, are at increased risk for depression and eating disorders both during and following the COVID-19 pandemic. Increased rates of depression and other psychological conditions leaves the pediatric and adolescent populations vulnerable to future health and developmental complications later in life and across the life course. At the public policy level, safeguards need to be put in place to ensure that the mental health of children remains protected and a public health priority during future pandemics
Psychosocial Factors Associated with Non-Suicidal Self Injury Among Youth
No full textPurpose
Suicide ranks third in adolescent mortality (CDC), necessitating intervention. Healthy People 2030 noted 14.1 suicides and 146.6 self-harm injuries per 100,000. Nonsuicidal self-injury (NSSI) can precede suicide, involving deliberate harm without suicidal intent by cutting, burning, scratching, and various atypical behaviors. Previous studies indicate NSSI is most common in the adolescent and young adult populations. Further, previous studies suggest peer socialization and emotion regulation as explanations for NSSI behavior. The purpose of this study is to explore the potential risk factors associated with NSSI among youth.
Methods
A secondary analysis of the PRIDE (Parents’ Resource Institute for Drug Education) was conducted on a large sample of youth participating in 133 local schools in Cincinnati. The response rate for the survey was 85.9%.Our outcome, past month NSSI, was assessed by the following question: “Did you engage in NSSI in the past 30 days?” Options were binary (1 = “Yes”, 0 = “No”). Past thirty day depression, stress, bullying, and anxiety were used as psychosocial risk factors. Participants’ age, biological sex (female/male), race/ethnicity (Non-Hispanic White, Non-Hispanic African American, Hispanic, and other) were used as covariates. Here, “other” is a combination of Pacific Islander, Native American, and Mixed race; we created this category given the small sample sizes. Frequencies and bivariate statistics were estimated to capture relationships between independent variables and our outcome of interest. Logistic regression models were built to determine conditional associations. Analyses took place in SAS v.9.4, and the level of significance was set at p <.05.
Results
The final analytic sample was 34,410 youth 12-17 years old. An estimated 6.1% (n= 2,249) of youth reported past-month NSSI. Girls were less likely to engage in NSSI when compared to boys (aOR: 0.69, 95% CI 0.62, 0.76). Compared to 12-13 year olds, 16-17 year olds were at higher risk for NSSI (aOR: 1.44, 95% CI 1.27, 1.64). Compared to White youth, every racial group was less likely to engage in NSSI. Youth who experienced past-30 day anxiety (aOR: 2.00), depression (aOR: 14.2), bullying (aOR: 3.92), and/or stress (aOR: 1.70) were all at higher risk for engaging in NSSI.
Conclusion
The present study indicated that NSSI was found to occur more frequently in males than females. Moreover, older adolescents (16-17 years old) exhibited higher NSSI rates than younger peers (12-13 years old). Importantly, NSSI was strongly associated with depression, anxiety, stress, and bullying experiences. Given the perilous link between NSSI and suicide, the study underscores the urgency of comprehensive prevention methods. This research prompts a collaborative effort from medical professionals, parents, and school to screen risk factors, tailor mental health programs, and increase access to counseling services
Assessment of digit skin temperatures via infrared thermography under different climatic conditions.
No full textThe responsiveness of the manual/pedal digits (i.e., finger/toes) to temperature changes makes them valuable indicators of thermoregulatory function. Further, while infrared thermography is used in many medical settings, its utility in assessing acute changes in digit skin temperatures remains poorly established. Accordingly, this research investigated the use of forward-looking infrared (FLIR) imaging as a methodological tool for analyzing digital skin temperatures across varying climatic conditions. A Teledyne FLIR E76 camera and associated FLIR Studio software were used to assess peripheral digit skin temperatures in a sample of 25 living human subjects (12 female, 13 male). Images of each hand and foot were captured every 5 minutes over a 45-minute period during exposure to four controlled climatic conditions in an environmental chamber. These experimental conditions included a control (22°C and 50% humidity), hot-humid (37°C and 85% humidity), hot-dry (44°C and 15% humidity), and cold-dry (5°C and 80% humidity) exposures. All images were taken at a perpendicular angle from the skin surface at a distance of 0.45 mm, as measured using the camera’s laser-guided range finder function. Baseline images were similarly taken during a preliminary rest period prior to each experimental exposure. This resulted in a total of 2,200 images collected from the left hand and left foot of the 25 participants. Following theoretical expectations, preliminary findings indicate peripheral digit temperatures predictably decrease during the cold-dry exposure, while the hot-dry and hot-humid exposures induce increases in digit temperatures. These preliminary results suggest that infrared thermography likely provides an expedient mechanism for accurately assessing peripheral skin temperatures in humans under different climatic conditions. Infrared thermography may thus have valuable applications for assessing thermoregulatory function in both clinical and research settings.National Science Foundation #2020506 (Cowgill), #2020096 (Ocobock), #2203808 (Cho), #2020715 (Maddux
Experimental ischemic stroke induces secondary white matter degeneration and long-term cognitive impairment
No full textClinical investigations have detected extensive white matter degeneration in individuals affected by ischemic stroke. Nonetheless, current stroke research has primarily concentrated on the infarct and periinfarct penumbra regions. The exploration of white matter degeneration's role after ischemic stroke and its contribution to post-stroke cognitive impairment and dementia (PSCID) has been limited in experimental models. Understanding the impact of white matter degeneration on PSCID in these models could offer valuable insights into potential therapeutic targets and interventions for alleviating cognitive decline following ischemic stroke. In this study, we analyzed the progression of locomotor and cognitive function up to 4 months after inducing ischemic stroke by middle cerebral artery occlusion in young adult rats. Despite evident ongoing locomotor recovery, long-term cognitive and affective impairment persisted after ischemic stroke, as indicated by Morris water maze, elevated plus maze, and open field performance. At 4-month after stroke, multimodal MRI was conducted to assess white matter degeneration. T2-weighted MRI (T2WI) unveiled bilateral cerebroventricular enlargement after ischemic stroke. Fluid Attenuated Inversion Recovery MRI (FLAIR) revealed white matter hyperintensities in the corpus callosum and fornix across bilateral hemispheres. A positive association between the volume of white matter hyperintensities and total cerebroventricular volume was noted in stroke rats. Further evidence of bilateral white matter degeneration was indicated by the reduction of fractional anisotropy (FA) and quantitative anisotropy (QA) in diffusion-weighted MRI (DWI) analysis. FA measures water diffusion directionality; reduced FA implies decreased white matter tract coherence. QA, linked to diffusion directionality, indicates microstructural white matter changes with decreased QA. Reduced FA and QA in DWI MRI suggest brain microstructural integrity changes, involving myelin sheath disruption, axonal damage, or overall white matter deterioration. Additionally, microglia and astrocyte activation were identified in the bilateral corpus callosum after stroke. This inflammatory response indicates the involvement of glial cells in the post-stroke environment, suggesting a complex interplay between structural alterations and neuroinflammatory processes that may contribute to the observed changes in white matter integrity. Understanding these multifaceted mechanisms is crucial for developing targeted interventions aimed at promoting recovery and minimizing long-term neurological consequences following ischemic stroke. The importance of these results is underscored by their potential connection to neurological or neurodegenerative conditions, given that white matter degeneration is commonly noted in diverse neurological disorders, including Alzheimer's disease, multiple sclerosis, and other related conditions. Our study suggests that experimental ischemic stroke induced by MCAO in young rats replicates long-term cognitive impairment and pervasive white matter degeneration observed in ischemic stroke patients. This model provides an invaluable tool for unraveling the mechanisms underlying post-stroke secondary white matter degeneration and its contribution to PSCID. Researchers and clinicians use these metrics to understand and monitor the progression of neurological diseases, potentially aiding in early diagnosis and treatment planning. This research may pave the way for a more comprehensive understanding of the mechanisms underlying post-stroke cognitive impairment and dementia, ultimately leading to improved strategies for patient care and rehabilitation.National Institutes of Health grants NS109583 (S.Y.) and Cancer Prevention and Research Institute of Texas #RP210046 (R.B.
Randomized trial promoting cancer genetic risk assessment when genetic counseling cost removed: 1-year follow-up
Get PDFPURPOSE: Cancer genetic risk assessment (CGRA) is recommended for women with ovarian and high-risk breast cancer. However, the underutilization of CGRA has long been documented, and cost has been a major barrier. In this randomized controlled trial, a tailored counseling and navigation (TCN) intervention significantly improved CGRA uptake at 6-month follow-up, compared with targeted print (TP) and usual care (UC). We aimed to examine the effect of removing genetic counseling costs on CGRA uptake by 12 months. METHODS: We recruited racially and geographically diverse women with breast and ovarian cancer from cancer registries in Colorado, New Jersey, and New Mexico. Participants assigned to TCN received telephone-based psychoeducation and navigation. After 6 months, the trial provided free genetic counseling to participants in all arms. RESULTS: At 12 months, more women in TCN obtained CGRA (26.6%) than those in TP (11.0%; odds ratio [OR] = 2.77, 95% confidence interval [CI] = 1.56 to 4.89) and UC (12.2%; OR = 2.46, 95% CI = 1.41 to 4.29). There were no significant differences in CGRA uptake between TP and UC. The Kaplan-Meier curve shows that the divergence of cumulative incidence slopes (TCN vs UC, TCN vs TP) appears primarily within the initial 6 months. CONCLUSION: TCN significantly increased CGRA uptake at the 12-month follow-up. Directly removing the costs of genetic counseling attenuated the effects of TCN, highlighting the critical enabling role played by cost coverage. Future policies and interventions should address multilevel cost-related barriers to expand patients' access to CGRA. TRIAL REGISTRATION: This trial was registered with the NIH clinical trial registry, clinicaltrials.gov, NCT03326713. https://clinicaltrials.gov/ct2/show/NCT03326713.This work was supported by the National Cancer Institute of the National Institutes of Health (R01CA211625 to AYK), the Rutgers Cancer Institute of New Jersey Comprehensive Cancer Center core grant from the National Cancer Institute (NIH/NCI, 3P30CA072720) including the use of the Biostatistics Shared Resource and the University of New Mexico Comprehensive Cancer Center core grant from the National Cancer Institute (NIH/NCI P30CA118100) including use of the services provided by the Behavioral Measurement and Population Sciences (BMPS) and Biostatistics Shared Resources. Support is also provided by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey Department of Health, funded by the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program (#75N91021D00009), Centers for Disease Control and Prevention's National Program of Cancer Registries (#5NU58DP006279) with additional support from the State of New Jersey and the Rutgers Cancer Institute of New Jersey; New Mexico Tumor Registry, contract number HHSN261201800014I; Task Order HHSN26100001 from the National Cancer Institute; and the Colorado Cancer Registry, cooperative agreement NU58DP006347-02 from the CDC, with data collected and provided, in part, by the Colorado Central Cancer Registry (CCCR), a participating registry in the National Program of Cancer Registries (NPCR), CDC, cooperative agreement number 5 NU58DP006347. Study data were collected and managed using REDCap electronic data capture tools hosted at the University of New Mexico and the Rutgers Cancer Institute of New Jersey
The Importance of Investigative Primary Care Physicians in Managing Complex Genetic Disorders: A Case Study of Ehlers Danlos Syndrome and Its Vascular Complications
No full textINTRODUCTION:
Ehlers Danlos Syndrome (EDS) is commonly thought of in relation to joint hypermobility, its most common feature, yet by no means its most concerning. EDS has several subtypes, some of which do not even present with hypermobility. Despite this seemingly simple and obvious symptom, EDS often presents with symptoms that are mistaken for other diseases, thereby prolonging the diagnosis of EDS for patients. Recent studies have identified life-threatening abnormalities common among patients presenting with EDS, inviting an investigation into whether this collagen disorder could be the underlying cause. This case study aims to review one instance of the associations found with this disease, contributing to the current literature regarding this investigation, improving diagnostic probability of this disease to minimize patient suffering, and furthering the research about uncommon genetic disorders.
BACKGROUND:
This case study surveys a 42-year-old female with EDS, Postural Orthopedic Tachycardia Syndrome (POTS), May Thurner Syndrome, Nutcracker Syndrome, Median Arcuate Ligament Syndrome (MALS), Polycystic Ovary Syndrome, and a host of other diagnoses. She reported a history of doctor visits starting at age 13, initially for abnormal uterine bleeding and then for gastrointestinal issues, prompting a diagnosis of Irritable Bowel Syndrome. She started having seizures and migraines in her twenties, and at age 39, she began to have spells of dizziness and collapsing that led to the diagnosis of POTS. Additionally during this time, she had severe right upper quadrant pain that led to her refusal to eat, causing subsequent weight loss. She obtained abdominal computed tomography angiography at age 41 that finally showed the following findings: Nutcracker Syndrome, May Thurner Syndrome, MALS, and an enlarged duodenum, all of which were missed on the reported nine computed tomography (CT) scans in the preceding two years. A friend with similar symptoms encouraged her to meet with a geneticist, who made encompassing diagnoses of Classical-like and Spondylodysplastic EDS. Experiencing difficulties finding a surgeon willing to perform external vascular grafting, the patient traveled overseas for her abdominal vascular compressions. Throughout her surgeries in life, she experienced complications due to her collagen disorder in which the sutures were not retained or her organs did not stay in place after positioning. The patient expressed frustration with the healthcare system in regards to her delayed EDS diagnosis. Currently, the patient is relieved that her primary care physician (PCP) closely follows her disease progression and responds to her concerns.
CONCLUSION:
Given the various symptoms associated with EDS, it can be challenging for PCPs to make this diagnosis, often leading them to refer patients to specialists for their various symptoms. Unfortunately, this can result in patients not receiving the proper treatment and preventive care, as specialists may only focus on specific aspects of the disease process, potentially worsening the patient's overall condition. Our case study aims to add to the pool of cases related to conditions associated with EDS. Additionally, it highlights the crucial role that PCPs play in diagnosing and managing patients with EDS, given the complex set of symptoms that require close follow-up
The impact of 17beta-estradiol on the estrogen-deficient female brain: from mechanisms to therapy with hot flushes as target symptoms
No full textSex steroids are essential for whole body development and functions. Among these steroids, 17beta-estradiol (E2) has been known as the principal female" hormone. However, E2's actions are not restricted to reproduction, as it plays a myriad of important roles throughout the body including the brain. In fact, this hormone also has profound effects on the female brain throughout the life span. The brain receives this gonadal hormone from the circulation, and local formation of E2 from testosterone via aromatase has been shown. Therefore, the brain appears to be not only a target but also a producer of this steroid. The beneficial broad actions of the hormone in the brain are the end result of well-orchestrated delayed genomic and rapid non-genomic responses. A drastic and steady decline in circulating E2 in a female occurs naturally over an extended period of time starting with the perimenopausal transition, as ovarian functions are gradually declining until the complete cessation of the menstrual cycle. The waning of endogenous E2 in the blood leads to an estrogen-deficient brain. This adversely impacts neural and behavioral functions and may lead to a constellation of maladies such as vasomotor symptoms with varying severity among women and, also, over time within an individual. Vasomotor symptoms triggered apparently by estrogen deficiency are related to abnormal changes in the hypothalamus particularly involving its preoptic and anterior areas. However, conventional hormone therapies to "re-estrogenize" the brain carry risks due to multiple confounding factors including unwanted hormonal exposure of the periphery. In this review, we focus on hot flushes as the archetypic manifestation of estrogen deprivation in the brain. Beyond our current mechanistic understanding of the symptoms, we highlight the arduous process and various obstacles of developing effective and safe therapies for hot flushes using E2. We discuss our preclinical efforts to constrain E2's beneficial actions to the brain by the DHED prodrug our laboratory developed to treat maladies associated with the hypoestrogenic brain."The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The National Eye Institute, the Office of Research on Women's Health, and the National Cancer Institute (National Institutes of Health, Bethesda, MD, USA, grant numbers EY027005 to KP-T, and CA215550 to LP) and from the Robert A. Welch Foundation (endowment BK-0031 to LP)