Publications

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) leads to faltering growth and psychosocial impairment. Three phenotypes can co-occur: fear of aversive consequences of eating (ARFID-fear phenotype), sensory sensitivity, and lack of interest in eating/food. We hypothesized that youth with ARFID, especially ARFID-fear phenotype, would show hyperactivation of fear-related regions in response to ARFID-specific fear images, compared to healthy controls (HC), and activation of these regions would positively correlate with ARFID fear severity.

METHODS: Youth (N=103: 76 ARFID, including 20 ARFID-fear phenotype; 27 HC) underwent functional MRI scanning while viewing ARFID-specific fear (e.g. vomiting, choking) versus neutral images. We compared blood-oxygen-level-dependent (BOLD) response in fear-related region of interests (ROI; e.g. amygdala, hippocampus, insula) between ARFID and ARFID-fear phenotype versus HC. We evaluated the association between brain response and ARFID fear severity in ARFID-fear phenotype.

RESULTS: Across individuals, there was a robust bilateral amygdala response to ARFID-specific fear versus neutral images. Compared to HC, ARFID-fear phenotype showed a greater insula response to ARFID-specific fear versus neutral images (p=0.049). There were no other group differences and no significant relationships between BOLD response and ARFID fear severity in ARFID-fear phenotype.

CONCLUSIONS: ARFID-specific fear images elicit amygdala responses across individuals, with greater activation in the insula only in ARFID-fear phenotype versus HC. These findings validate the ARFID-specific fear paradigm and highlight the intriguing possibility that, in the ARFID-fear phenotype, universally feared experiences such as choking and vomiting serve as the unconditioned stimulus in developing ARFID and may partially be mediated by the insular cortex.

OBJECTIVE: For women with pathogenic variants in BRCA1 and BRCA2, risk-reducing salpingo-oophorectomy (RRSO) at the recommended age causes surgical menopause. We previously reported elevated depressive symptoms at 6 and 12 months and elevated anxiety symptoms at 6 months after RRSO. We now report these outcomes at 24 months, their baseline and 12-month predictors and the effect of Menopausal Hormone Therapy (MHT).

METHODS: Prospective controlled study of 59 premenopausal women planning RRSO and 91 comparisons who retained their ovaries. Depressive (CESD) and anxiety symptoms (GAD-7) were measured at baseline (before RRSO) and at 12 and 24 months. We used ordinary and logistic multivariable regression to estimate differences between and within groups at 24 months, before and after conditioning on baseline and 12 month measures.

RESULTS: Overall, depressive and anxiety symptoms were not elevated above baseline at 24 months and did not differ between RRSO and comparisons, before or after adjusting for previous measures (P > 0.05). Elevated depressive symptoms at 12 months (OR = 24, P < 0.001), and elevated anxiety symptoms at 12 months (OR = 13, P < 0.001), strongly predicted 24 month measures. Elevated depressive symptoms at baseline no longer predicted 24 month symptoms once 12 month symptoms were considered, but elevated baseline anxiety still predicted anxiety at 24 months, even when 12 month anxiety was considered. No association between MHT use and depressive or anxiety symptoms was observed.

CONCLUSIONS: Depressive and anxiety symptoms are not elevated 24 months after RRSO. However, depressive symptoms at 12 months after RRSO are likely to persist at 24 months.

STUDY OBJECTIVES: This study examined whether sleep timing and its regularity are associated with cognitive performance in older women and whether associations vary based on cardiometabolic risk factors.

METHODS: The cross-sectional analysis included 1177 community-dwelling females (mean age 65 years) from the observational Study of Women's Health Across the Nation (SWAN) annual visit 15. Sleep timing (mean midpoint from sleep onset to wake-up) and its regularity (standard deviation of midpoint) were assessed using actigraphy. Cognitive measures included immediate and delayed verbal memory, working memory, and processing speed. Cardiometabolic risk measures included central obesity, hypertension, diabetes, and the Atherosclerotic Cardiovascular Disease (ASCVD) risk score. Linear regression models, adjusted for covariates, tested associations between sleep and cognitive measures.

RESULTS: After covariate adjustment, early sleep timing was associated with worse delayed verbal memory (β = -0.37; p = .047) and late sleep timing was associated with worse processing speed (β = -1.80; p = .008). Irregular sleep timing was associated with worse immediate (β = -0.29; p = .020) and delayed verbal memory (β = -0.36; p = .006), and better working memory (β = 0.50; p = .004). Associations between early sleep timing and delayed verbal memory strengthened as ASCVD risk increased (interaction β = -8.83, p = .026), and sleep timing irregularity's effect on working memory was stronger among women with hypertension (interaction β = -3.35, p = .039).

CONCLUSIONS: Sleep timing and its regularity are concurrently associated with cognitive performance in older women. Cardiovascular disease risk may modify some of these associations. Future longitudinal studies are needed to clarify these relationships.

It is now recognized that there are significant differences between the sexes affecting prevalence, incidence, and severity over a broad range of diseases, although the extent of the differences is not fully elucidated. Until the early 1990s, women were excluded from most clinical trials and the limited research including women focused primarily on diseases affecting fertility and reproduction. For these reasons, the prevention, diagnosis, and treatment of chronic diseases in women continue to be based primarily on historical findings in men, and sex-specific clinical guidelines are often lacking. Many illnesses, ranging from cardiovascular disease to cancer to mental health issues, for example, differ by sex in terms of prevalence and adverse effects. Research is needed to understand how medically relevant biological sex differences optimally inform sex-specific prevention, diagnosis, and treatment strategies for women and men. In this way, sex-specific clinical guidelines can be developed where warranted, using evidence-based data.

Surgical menopause, the removal of both ovaries prior to natural menopause, may impact short-and long-term physical and emotional health. An increasingly common cause of surgical menopause is risk-reducing salpingo-oophorectomy (RRSO) in those at high inherited risk of ovarian cancer. The WHAM (What Happens After Menopause?) study is the largest prospective controlled study of RRSO. It measured the effect of RRSO compared to controls on physical and mental health over 2 years, and the potential modifying effects of menopausal hormone therapy (MHT). WHAM consists of 104 premenopausal women with BRCA1/2 pathogenic variants undergoing RRSO and 102 age-matched comparators who retained their ovaries. Outcomes including sexual function, vasomotor symptoms, cognition, mood, cardiometabolic health and bone health were measured between baseline and 24 months. MHT uptake after RRSO and the impact of MHT on these outcomes were assessed. Findings of WHAM have been published in more than ten manuscripts. Key findings include that RRSO adversely affects sexual function, sleep, and mood compared to comparison women. After RRSO, vasomotor symptoms (VMS) are generally mild, peak at 3 months, and do not worsen by 24 months. MHT reduces but does not resolve VMS. Loss of bone density was observed at 24 months and was partially mitigated by MHT. Cardiometabolic health and cognition were largely maintained at 24 months. This manuscript summarises the published findings of WHAM. These unique data will enhance evidence-based care in surgical menopause and will support shared decision-making around RRSO, ensuring rapid translation of new evidence into clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: registration no: ACTRN12615000082505; anzctr.org.au.

OBJECTIVE: Migraine and vasomotor symptoms (VMS) are prevalent brain conditions linked to female sex hormones and negatively impact the quality of life for middle-aged women. We aimed to quantify the association between migraine phenotype and VMS severity and duration across the final menstrual period.

METHODS: We analyzed data from 21,468 participants in Nurses' Health Study II, an ongoing prospective cohort study of female registered nurses aged 25-42 at baseline in 1989. We included naturally menopausal individuals who reported a final menstrual period from 2007 through 2015. We analyzed the cross-sectional association between self-reported migraine headaches (with and without self-reported clinician diagnosis) and migraine phenotype (with and without aura) and VMS in midlife using logistic regression, adjusting for demographic, lifestyle, and reproductive health factors.

RESULTS: Overall, 64% of the cohort reported VMS in the past 4 weeks. Of those experiencing VMS, 7% reported severe VMS and 31% reported VMS lasting ≥5 years. Individuals with recent (past 2 y) migraine in midlife (29%) had 30% (21%-40%) greater odds of reporting VMS than those without migraine (68% of women vs 63%). Among women reporting VMS, recent midlife migraine (vs no recent migraine) was also associated with severe (8% vs 6%, OR = 1.53, 95% CI = 1.30-1.81) and prolonged (35% vs 30% ≥5 years; OR = 1.24, 95% CI = 1.12-1.36) VMS. Although migraine phenotype was unassociated with VMS frequency or duration, migraine with aura and self-reported clinician-diagnosed migraine were more strongly associated with severe VMS than were migraine without aura or self-reported migraine.

CONCLUSION: While the nature of the association remains unclear, our findings highlight the importance of risk assessment and screening for VMS among women with migraine.

Evidence exists for the daily rhythmicity of bone metabolism that may be influenced by melatonin production, reproductive hormones, the light/dark cycle, or all three, but the ability to determine their independent contributions is confounded by the synchrony of the sleep/wake and dark/light cycles with the endogenous circadian system in sighted individuals. Blind participants, who often have no circadian light perception and may exhibit desynchrony between their sleep/wake cycle and circadian system, provide an opportunity to study the independent contribution of melatonin and light on bone metabolism in a field-based setting. In this exploratory study, 35 pre-, peri-, and postmenopausal blind women (N = 13, 8, and 14, respectively) both with (N = 17) and without (N = 18) visual light perception (LP and NPL, respectively) who were either normally entrained (N = 19) or abnormally entrained or non-entrained (N = 16) to the 24-h day were randomly selected from a cohort of 130 visually impaired women. Levels of 6-sulfatoxymelatonin (aMT6s; ng/h) and the bone resorption marker amino-terminal cross-linked telopeptide of collagen I (NTx; BCE nM/h) were assayed from serial urine samples collected over 48 h and fit by a cosinor model to determine the presence of significant 24-h rhythms. Most blind women (N = 32/35, 91%) had a significant 24-h aMT6s rhythm (mean ± SD, 03:44 ± 4:27 hh:mm), but fewer women had a significant 24-h NTx rhythm (N = 20/35, 57%; 21:01 ± 5:50 hh:mm). There was no significant difference in the proportion of women with significant NTx rhythms by visual light perception status (LP: N = 10/17, 59% vs. NPL, N = 10/18, 56%), entrainment status (Entrained: N = 11/19, 58% vs. Abnormal or Not entrained: N = 9/16, 56%) or reproductive status (Premenopausal: N = 7/13, 54% vs. Perimenopausal: 5/8, 63% vs. Postmenopausal: 8/14, 57%). There was no correlation between the peak timings of aMT6s and NTx among the 17 participants with significant rhythms in both metabolites (r = 0.07, p = 0.80). NTx area under the curve was significantly higher among perimenopausal women with LP (p = 0.04). Our results do not support a direct influence of light, melatonin, or reproductive status on NTx rhythms, but the apparent increase of NTx in the perimenopausal period warrants further investigation.

OBJECTIVES: The EQ-5D-5L may not adequately capture the health-related quality of life in patients with sleep disturbances. We examined the psychometric properties of a hybrid PROM comprising a module of four sleep-related bolt-ons and EQ-5D-5L.

METHODS: We employed a sequential exploratory mixed method by first qualitatively testing the face validity of "sleep", "cognition", "tiredness" and "relationship" and refining these bolt-ons through in-depth interviews with 23 patients and clinicians. We then quantitatively assessed their performance by administering the four bolt-ons, appended to EQ-5D-5L, and three condition-specific patient-reported outcome measures (cPROMs) during two clinical visits of patients with respiratory-related sleep disorders. We compared ceiling effects and construct validity of EQ-5D-5L with and without the bolt-ons by testing a priori hypotheses about the cPROMs and polysomnographic characteristics via correlation and areas under the curves (AUC) analyses, respectively. We examined their responsiveness among "treated/improved" participants using standardized response means (SRM) and AUC analysis, and reliability among "untreated/no change" participants using intra-class correlation coefficient (ICC) or Cohen's Kappa (k).

RESULTS: 110 participants (mean [SD] age: 47[13]) were recruited and 90 returned for their review assessments (mean [SD] interval: 2.2 [2.1] months). The bolt-ons led to a reduction of 42.7% in ceiling effects. The bolt-ons were better correlated with cPROMs and exhibited higher discriminatory power and responsiveness, with comparable reliability to EQ-5D-5L. A combined module of the four bolt-ons provided better results than individual bolt-ons.

CONCLUSIONS: A "hybrid" PROM of sleep bolt-ons module added to EQ-5D-5L improved its psychometric properties among patients with sleep disturbances.

OBJECTIVES: Fatigue is a common nonhematologic toxicity of the CDK4/6 inhibitor palbociclib in metastatic breast cancer (MBC) patients with prevalence rates of clinician-rated all-grade and grade 3/4 fatigue of 39.2% and 2.5%, respectively. We prospectively assessed the incidence of fatigue emerging on palbociclib using patient-reported measures and explored potential predictors.

METHODS: Eighty-eight patients with HR+ HER2- MBC without fatigue initiating palbociclib with endocrine therapy were assessed before and monthly across the initial 6 cycles. Clinically meaningful levels of patient-reported fatigue (Functional Assessment of Chronic Illness Therapy Fatigue Scale, FACIT-F < 34), severity of, and functional interference due to fatigue (NCI Patient-Reported Outcomes for CTCAE, PRO-CTCAE) were assessed. Hematologic and nonhematologic predictors were examined pretreatment and concurrent with fatigue assessments.

RESULTS: Patient-reported fatigue emerged in 21/88 patients [incidence rate 23.9% (95%CI, 15.4%-34.1%)] within 2.8 ± 1.7 treatment cycles. PRO-CTCAE-rated incidence rate of severe fatigue and fatigue interference was 14.8% (95%CI, 8.1%-23.9%) and 10.2% (95%CI, 4.8%-18.5%), respectively. Lower pretreatment absolute neutrophil count (ANC) levels predicted treatment-emergent fatigue (P =.01), but ANC levels on treatment did not (P =.78). Other pretreatment predictors were long sleep duration (P =.02) and low physical activity (trend, P =.07). Treatment-emergent fatigue was associated with objectively measured long sleep duration on treatment (P =.02), but not other measures (P ≥.35).

CONCLUSIONS: One-quarter of patients with HR+ HER2- MBC initiating palbociclib report rapidly emergent clinically meaningful fatigue, often with severe symptoms and functional interference. Treatment-emergent fatigue is associated with both pretreatment (lower ANC levels, longer sleep duration) and on-treatment (long sleep duration) hematologic and nonhematologic profiles.