Internal Delensing of Cosmic Microwave Background Polarization B-Modes with the POLARBEAR Experiment.

Using only cosmic microwave background polarization data from the polarbear experiment, we measure B-mode polarization delensing on subdegree scales at more than 5σ significance. We achieve a 14% B-mode power variance reduction, the highest to date for internal delensing, and improve this result to 22% by applying for the first time an iterative maximum a posteriori delensing method. Our analysis demonstrates the capability of internal delensing as a means of improving constraints on inflationary models, paving the way for the optimal analysis of next-generation primordial B-mode experiments.

Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials.

BACKGROUND: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. PATIENTS AND METHODS: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. RESULTS: A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95-5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). CONCLUSIONS: In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.

The critical period hypothesis: can it explain discrepancies in the oestrogen-cognition literature?

Although there is compelling evidence from small randomised controlled trials and cross-sectional studies indicating that oestrogen helps to protect against cognitive ageing in women, the findings of the large, Women's Health Initiative Memory Study failed to support the earlier findings. The attempt to resolve these discrepancies led to the formulation of the Critical Period Hypothesis which holds that oestrogen has maximal protective benefits on cognition in women when it is initiated closely in time to a natural or surgical menopause but not when treatment is begun decades after the menopause. This article reviews the evidence from basic neuroendocrinology, from animal behavioural studies and from human studies that supports the critical period hypothesis. In view of the promise of this hypothesis and its considerable clinical implications, a direct test of its validity is warranted.

No differences in performance on test of working memory and executive functioning between healthy elderly postmenopausal women using or not using hormone therapy.

BACKGROUND: On average, ovarian function ceases at the age of 52 years so that estrogen (E) levels are chronically low following the menopause. Numerous studies have found that hormone therapy (HT) helps to protect verbal memory, a hippocampal function. Estrogen receptors are also found in the prefrontal cortex (PFC), suggesting that estrogen may modulate executive and working memory functions, both mediated by the PFC. The possible role of progesterone (P) on executive functions and working memory is unknown. OBJECTIVE: To examine the relationship between neuropsychological performance, age of initiation of HT, and duration of HT use. METHOD: In this cross-sectional study, the neuropsychological performance of 37 postmenopausal women (mean age, 65 years) who used either estrogen-only or sequential E + P (E-alone group)(n = 22) or E + P continuously (n = 15) was compared to that of 28 healthy postmenopausal women matched for age and education who had never used HT. It was hypothesized that the E-only users would perform better then the E + P and the never-users on neuropsychological tests of verbal memory, executive function and working memory. RESULTS: Results showed only minor between-group differences on working memory scores such that the E + P users were slowest to generate a response on the N-Back test of working memory. No group differences on tests of executive functions were found. CONCLUSION: There was no relationship between neuropsychological performance, age of initiation of HT, or duration of HT use.

Estrogen and cognitive aging in women.

Although several randomized controlled trials of surgically menopausal women have provided evidence that estrogen protects aspects of memory, many cross-sectional and longitudinal studies, including those from the Women's Health Initiative Memory Study, have failed to confirm these findings. One critical difference between studies that found a protective effect of estrogen on memory and those that did not is that, in the former studies, treatment with estrogen began at the time of menopause and in the latter studies, it was first administered many years after the menopause had occurred. Recent evidence from rodent, nonhuman primate, and human studies consistently suggests that the timing of the initiation of estrogen treatment with regard to the menopause may be critical to our understanding of the estrogenic effect on memory. Results of these animal and human studies indicate that the initiation of estrogen treatment at the time of menopause, or soon after ovariectomy, provides a window of opportunity for the protection of memory in females whereas the administration of the hormone following a considerable delay in time after ovariectomy or following a natural menopause has little or no beneficial effect on cognition.

Oestrogen and cognitive function throughout the female lifespan.

Evidence that oestrogen helps to maintain verbal memory in women comes from several sources. Studies that have tested cognitive functioning at different phases of the menstrual cycle have found few differences, perhaps because oestrogen levels are sufficiently high, albeit variable, during all cycle phases. Experimental studies in postmenopausal women have generally found a protective effect of oestrogen, specifically on verbal memory. Results of several large, longitudinal studies that have become available recently have also demonstrated that women who were oestrogen users performed better on certain tests of cognitive function than non-users of similar age. On the basis of this body of evidence, it is possible to conclude that oestrogen may attenuate or prevent the decline in aspects of memory that occur with normal ageing in women.

Mild cognitive impairment: potential pharmacological treatment options.

Both mild cognitive impairment and age-associated memory impairment are terms used to describe memory decline in otherwise healthy, intellectually intact individuals aged older than 50 years. It is estimated that up to 38% of the middle-aged and older population fulfill diagnostic criteria for this condition. Although the memory deficits observed in these individuals are fairly mild, they can interfere with day-to-day functioning. This article presents a review of the types of memory decline observed in older people, the diagnostic criteria used to define memory decline, the physiological and morphological brain changes that accompany aging, and the potential pharmacological treatment options, focusing on agents that have been evaluated in mildly cognitively impaired or normal older populations.

Higher levels of plasma estradiol and testosterone in healthy elderly men compared with age-matched women may protect aspects of explicit memory.

OBJECTIVE: To assess longitudinally the relationships between plasma levels of estradiol (E2) and free testosterone (T) and cognitive functioning in elderly men, women who use estrogen, and women who do not use estrogen. DESIGN: At two test times 18 months apart (time 1 and time 2), men (time 1, n = 31; time 2, n = 23), women who were using estrogen (time 1, n = 14; time 2, n = 10), and women who were not using estrogen (time 1, n = 41; time 2, n = 27), whose average age was 72.1 and 73.4 years at time 1 and time 2, respectively, were administered a battery of neuropsychological tests that measured verbal memory, visual memory, concentration and attention, language fluency, and semantic memory. Plasma levels of E2 and free T were assessed by radioimmunoassay. RESULTS: The men had higher free T levels than both groups of women at both test times. Although women who were using estrogen had higher E2 levels than those of the men and of the women who were not using estrogen, the men's E2 levels were also significantly higher than those of the women who were not using estrogen. Moreover, the women who were using estrogen and the men had higher Forward Digit Span scores compared with the women who were not using estrogen at both test times, and women who were using estrogen had higher Backward Digit Span scores than those who were not using estrogen. Both groups of women performed better than the men on the Category Retrieval Test (verbal fluency). The performance of women who were using estrogen on the Delayed Selective Reminding Test (long-term rote memory) improved over time compared with that of the men and of the women who were not using estrogen. CONCLUSIONS: These findings raise the possibility that higher E2 levels in elderly men and in women who use estrogen may protect against some declines in explicit memory with normal aging.

Relationships between mood and estradiol (E2) levels in Alzheimer's disease (AD) patients.

This study investigates the relationship between mood and estradiol (E2) levels and assesses the prevalence of mood symptoms in Alzheimer's disease (AD) patients compared to healthy elderly controls. Fifty-two AD patients (26 men, 23 estrogen non-using women and three estrogen-using women), mean age 76.2 years, were recruited and assessed with the Geriatric Depression Scale (GDS), a test of mood, and a radioimmunoassay measure of E2 levels at the time of testing. The AD patients were compared to a control group of age and gender-matched healthy elderly men and women estrogen-users and non-users. No differences were found between the AD patients and the controls in overall E2 levels, but, as expected, the women estrogen-users in both the AD and control groups had higher E2 levels than the men and the female estrogen non-users. Both groups of men had higher E2 levels than the estrogen non-using women. There was a significant negative correlation between E2 levels and GDS scores in the full sample, which was particularly strong in the estrogen-using women. This indicates that those subjects with higher E2 levels had less mood symptomatology. Overall, mood scores in the AD patients were higher than in the healthy controls, indicating higher levels of depressive symptomatology; the highest depression scores occurred in the AD women who were estrogen non-users. This suggests that depressive symptoms are common in AD patients, and that women with AD who are not taking estrogen replacement may be especially vulnerable to depression.

Relationships among cortisol (CRT), dehydroepiandrosterone-sulfate (DHEAS), and memory in a longitudinal study of healthy elderly men and women.

At test times 18 months apart (Time 1 and Time 2), men (n Time 1 = 31, Time 2 = 23), women estrogen-users (n Time 1 = 14, Time 2 = 10), and women estrogen non-users (n Time 1 = 41, Time 2 = 27), whose average age was 72.1 and 73.4 years at Time 1 and Time 2, respectively, were tested with a battery of neuropsychological tests measuring verbal memory, visual memory, concentration/attention, language fluency and semantic memory. Plasma levels of CRT and DHEAS were assayed by radioimmunoassay at both test times. The men had higher DHEAS levels than both groups of women at both test times (p < 0.001) and also had a higher DHEAS/CRT ratio compared to the estrogen non-users (p < 0.05). Although there were no group differences in CRT levels at either time, CRT levels increased in the estrogen non-using women from Time 1 to Time 2 (p < 0.001). Subjects with lower CRT levels performed better than those with higher levels on several tests of declarative memory (p < 0.05). Men and estrogen-users had higher Digit Span scores compared to female estrogen non-users at both test times (p < 0.01), and women estrogen-users also had higher Backward Digit Span scores than non-users (p < 0.05). Both groups of women performed better than men on Category Retrieval (p < 0.01). These findings suggest that higher CRT levels in elderly men and women are associated with poorer explicit memory functioning; however, these results failed to provide any evidence that DHEAS is protective against declarative memory decline with aging.

Can estrogen keep you smart? Evidence from clinical studies.

OBJECTIVE: To review and critically analyze the biological plausibility of and the clinical empirical evidence concerning a link between estrogen levels and memory in women. DATA SOURCES: MEDLINE search of the literature published from 1980 to 1998. Studies published between 1952 and 1980 that were known to the author were also included. STUDY SELECTION: Sixteen prospective, placebo-controlled studies in humans. DATA SYNTHESIS: Most of the studies that used neuropsychological tests with known reliability and validity found that estrogen maintained aspects of memory in women. CONCLUSIONS: Estrogen specifically maintains verbal memory in women and may prevent or forestall the deterioration in short- and long-term memory that occurs with normal aging. There is also evidence that estrogen decreases the incidence of Alzheimer disease or retards its onset or both.

Relationships between dehydroepiandrosterone sulfate (DHEAS) and cortisol (CRT) plasma levels and everyday memory in Alzheimer's disease patients compared to healthy controls.

Fifty-two age-matched Alzheimer's disease (AD) patients (26 men, 26 women), mean age 76.2 years, were assessed with the Rivermead Behavioural Memory Test, a test of everyday memory, coincident with the measurement of plasma cortisol (CRT) and dehydroepiandrosterone sulfate (DHEAS) via radioimmunoassay. The AD patients were compared to a control group of age- and gender-matched healthy elderly men and women. No differences were found between the AD patients and the controls in DHEAS or CRT levels, or in the DHEAS/CRT ratio. There were no gender differences in DHEAS or CRT levels, or in the DHEAS/CRT ratio in subjects with AD. However, AD patients with higher levels of DHEAS scored better than those with lower levels on the subtests of Remembering a Name associated with a picture, Digit Span Total and Forward, and the Mini Mental Status Exam. AD patients with higher CRT levels performed worse on Delayed Route Recall than those with lower levels. These findings suggest that AD patients with higher endogenous levels of DHEAS may perform better on some memory tasks than those with lower levels, while AD patients with lower levels of CRT may perform better than those with higher CRT.

Progestogens used in menopause. Side effects, mood and quality of life.

Progesterone receptors are found in many of the same brain areas as estrogen receptors, including the hypothalamus and limbic system. The limbic system, particularly the amygdala, plays a prominent role in regulating emotion and mood. Progestogens decrease brain excitability, whereas estrogens increase it. This explains, in part, why women with epilepsy have a higher frequency of seizures during the late follicular and ovulatory phases of the menstrual cycle than during the luteal phase. In addition, progesterone has been shown to have profound anesthetic properties and to increase the concentration of monoamine oxidase (MAO), the enzyme that catabolizes serotonin in the brain), whereas estrogen decreases MAO, thereby increasing the concentration of serotonin. The purpose of this paper is to review the extant research regarding these biologic effects of progestogens on brain function.

Cognitive assessment for postmenopausal women and general assessment of their mental health.

Mechanisms of action of estrogen on brain structure and function provide biological plausibility for the purported effects of this steroid hormone on aspects of cognition in women. Prospective experimental studies and observational studies indicate that estrogen helps maintain verbal and, possibly, visual memory in women. A suggested battery of neuropsychological tests is presented while caveats concerning possible experimental confounds in studies of estrogen and memory such as depression and the concomitant administration of progestins are discussed. The use of hormone replacement therapy (HRT) in postmenopausal women must also consider the risks and benefits of such treatment for each individual woman.

Steroid hormones, memory and mood in a healthy elderly population.

Men (n = 31), women estrogen-users (n = 14), and women estrogen non-users (n = 41), whose average age was 72.1 +/- 5.6 years, were tested with a battery of psychological tests measuring verbal memory, visual memory, concentration and attention, language fluency and semantic memory, and mood. Plasma levels of testosterone (T), estradiol (E2), cortisol (CRT) and dehydroepiandrosterone-sulfate (DHEAS) were assessed by radioimmunoassay. The ratio of DHEAS to CRT was calculated to determine it's relationship to memory functioning. The men had higher T and DHEAS levels than both groups of women. Women estrogen-users had higher E2 levels than both men and estrogen non-users and the men had higher E2 levels and a higher DHEAS/CRT ratio than the estrogen non-users. There were no group differences in CRT levels. Men and estrogen-users had higher total (p < .01) and forward (p < .001) digit span scores compared with non-users. Women estrogen-users also had higher backward digit span scores than non-users (p < .05), while both groups of women performed better than men on category retrieval (p < .01). The implications of these findings with respect to hormonal influences on memory in elderly men and women are discussed.

Use of combined estrogen-androgen preparations in the postmenopause: evidence from clinical studies.

This article reviews the effects, on clinical symptoms, such as energy level and aspects of sexual functioning in postmenopausal women, of adding testosterone to an estrogen replacement regimen. The efficacy of combined estrogen-androgen preparations on bone density and lipoprotein lipid metabolism is also reviewed. Clinical recommendations for use of combined therapy are described with respect to specific symptoms.