Resilience to Early Life Adversity Effects on Stress Reactivity by Postnatal Knockdown of 5-HT 1A Autoreceptors.

Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that can protect from long-lasting effects of ELA are poorly understood. Serotonin 1A (5HT 1A ) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but if 5HT 1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT 1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10. We then tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In ELA-exposed females, adult swim stress exposure increased passive coping and despair-like behavior, corticosterone levels at baseline and after stress, and neuronal activity and corticotropin releasing hormone levels in the paraventricular nucleus of the hypothalamus. ELA also reduced neurogenesis and increased microglia activation in the ventral dentate gyrus (DG) of the hippocampus - an important mediator of individual differences in stress susceptibility. These effects of ELA were specific to females, but not males, and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal 5HT 1A autoreceptor knockdown prevented ELA effects on stress reactivity and on neurogenesis and neuroinflammation in the DG, indicating that reducing 5HT 1A autoreceptors confers resilience to ELA. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in stress reactivity and ventral DG function across development, and identify 5HT 1A autoreceptors as potential targets to prevent these persistent effects of ELA.

TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding.

OBJECTIVE: Metabolic Syndrome, which can be induced or exacerbated by current antipsychotic drugs (APDs), is highly prevalent in schizophrenia patients. Recent preclinical and clinical evidence suggest that agonists at trace amine-associated receptor 1 (TAAR1) have potential as a new treatment option for schizophrenia. Intriguingly, preclinical tudies have also identified TAAR1 as a novel regulator of metabolic control. Here we evaluated the effects of three TAAR1 agonists, including the clinical development candidate ulotaront, on body weight, metabolic parameters and modulation of neurocircuits implicated in homeostatic and hedonic feeding. METHODS: Effects of TAAR1 agonists (ulotaront, RO5166017 and/or RO5263397) on body weight, food intake and/or metabolic parameters were investigated in rats fed a high-fat diet (HFD) and in a mouse model of diet-induced obesity (DIO). Body weight effects were also determined in a rat and mouse model of olanzapine-, and corticosterone-induced body weight gain, respectively. Glucose tolerance was assessed in lean and diabetic db/db mice and fasting plasma glucose and insulin examined in DIO mice. Effects on gastric emptying were evaluated in lean mice and rats. Drug-induced neurocircuit modulation was evaluated in mice using whole-brain imaging of c-fos protein expression. RESULTS: TAAR1 agonists improved oral glucose tolerance by inhibiting gastric emptying. Sub-chronic administration of ulotaront in rats fed a HFD produced a dose-dependent reduction in body weight, food intake and liver triglycerides compared to vehicle controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in HFD rats switched to ulotaront or RO5263397 treatment compared to those switched to vehicle. Chronic ulotaront administration also reduced body weight and improved glycemic control in DIO mice, and normalized corticosterone-induced body weight gain in mice. TAAR1 activation increased neuronal activity in discrete homeostatic and hedonic feeding centers located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures. CONCLUSION: The current data demonstrate that TAAR1 agonists, as a class, not only lack APD-induced metabolic liabilities but can reduce body weight and improve glycemic control in rodent models. The underlying mechanisms likely include TAAR1-mediated peripheral effects on glucose homeostasis and gastric emptying as well as central regulation of energy balance and food intake.

5-HT1A Receptors on Dentate Gyrus Granule Cells Confer Stress Resilience.

BACKGROUND: Hyperactivity of granule cells in the ventral dentate gyrus (vDG) promotes vulnerability to chronic stress. However, which receptors in the vDG could be targeted to inhibit this hyperactivity and confer stress resilience is not known. The serotonin 1A receptor (5-HT1AR) is a Gi protein-coupled inhibitory receptor that has been implicated in stress adaptation, anxiety, depression, and antidepressant responses. 5-HT1ARs are highly expressed in the DG, but their potential to promote stress resilience by regulating granule cell activity has never been examined. METHODS: We exposed male and female mice expressing 5-HT1ARs only in DG granule cells to 10 days of chronic social defeat stress (CSDS) and treated them with the 5-HT1AR agonist 8-OH-DPAT every day 30 minutes before each defeat throughout the CSDS paradigm. We then used whole-cell current clamp recordings, immunohistochemistry for the immediate early gene cFos, corticosterone immunoassays, and behavioral testing to determine how activating 5-HT1ARs on granule cells affects DG activity, neuroendocrine stress responses, and avoidance behavior. RESULTS: We found that activating 5-HT1ARs hyperpolarized DG granule cells and reduced cFos+ granule cells in the vDG following CSDS, indicating that 5-HT1AR activation rescued stress-induced vDG hyperactivity. Moreover, 5-HT1AR activation dampened corticosterone responses to CSDS and prevented the development of stress-induced avoidance in the social interaction test and in the open field test. CONCLUSIONS: Our findings show that activating 5-HT1ARs on DG granule cells can prevent stress-induced neuronal hyperactivity of the vDG and confer resilience to chronic stress.

A survey of Canadian radiation therapists' perspectives on caring for LGBTQ2SPIA+ cancer patients.

PURPOSE: The lesbian, gay, bisexual, trans, queer, two-spirit, pansexual, intersex, asexual, plus (LGBTQ2SPIA+) population faces unique cancer health risks and barriers to competent healthcare. This study aimed to identify current knowledge, attitudes, and practice behaviours amongst radiation therapists regarding the LGBTQ2SPIA+ community to ultimately improve care given to this population. METHODS: A 22-item online survey was sent out to Canadian radiation therapy department managers and forwarded to radiation therapists. The survey collected demographics and addressed knowledge, attitudes, and practice behaviours regarding the LGBTQ2SPIA+ population. Results were analyzed using descriptive statistics, inferential statistics and thematic analysis. RESULTS: 214 radiation therapists completed the survey. Over 70% were unfamiliar with all terms associated with "LGBTQ2SPIA+". 91.6% believed that being conscious of the LGBTQ2SPIA+ community is important to their role as a therapist; however, 34.5% reported "rarely" or "never" adapting practice behaviours when caring for this community. Only 17.3% felt they had received adequate information to comfortably care for the LGBTQ2SPIA+ population, with 86.9% interested in receiving more education on specific patient needs. The open-ended questions revealed four themes: uncertainty regarding knowledge of the LGBTQ2SPIA+ community; willingness and/or desire to improve practice behaviours; therapists are already aware of some unique needs of the LGBTQ2SPIA+ community; and some therapists believe that all patients should be treated equally. National generalizability is limited due to insufficient data collected from all geographical regions. CONCLUSION: Overall, this study was unable to provide national generalizability, however the results suggest that amongst the respondents there are knowledge gaps and inconsistencies in practice when caring for LGBTQ2SPIA+ cancer patients. Given the limited literature available, and the results from this study, more education and research is warranted to bridge knowledge gaps and aid in providing inclusive patient care.

Live Discharge From Hospice: A Systematic Review.

Live discharges from hospice may occur because of patient choice or provider choice. However, when discharges occur before death, patients and families may feel abandoned and left to manage care needs previously provided by hospice. The purpose of this systematic review was to better understand the nature of live discharges, including frequency, patient characteristics, and hospice characteristics. Of 44 studies identified for review, 13 met inclusion criteria and were published between 2008 and 2018. Live discharge rates varied from 5% to 23%. Patients' prehospice characteristics varied widely based on diagnosis, comorbidities, gender, race, and ethnicity. Hospice characteristics indicated that the likelihood of a live discharge was increased for patients enrolled in for-profit hospices and in rural areas. Only 2 studies captured the patient/family perspective of the live discharge experience, finding that the loss of hospice support was fraught with difficulties. A need for further study of the live discharge experience and the practices of hospices with high live discharge rates was identified.

A qualitative study exploring women's beliefs about physical activity after stillbirth.

BACKGROUND: Research provides strong evidence for improvements in depressive symptoms as a result of physical activity participation in many populations including pregnant and post-partum women. Little is known about how women who have experienced stillbirth (defined as fetal death at 20 or more weeks of gestation) feel about physical activity or use physical activity following this experience. The purpose of this study was to qualitatively explore women's beliefs about physical activity following a stillbirth. METHODS: This was an exploratory qualitative research study. Participants were English-speaking women between the ages of 19 and 44 years who experienced a stillbirth in the past year from their recruitment date. Interviews were conducted over the phone or in-person based on participants' preferences and location of residence and approximately 30-45 minutes in length. RESULTS: Twenty-four women participated in the study (M age = 33 ± 3.68 years; M time since stillbirth = 6.33 ± 3.06 months). Women's beliefs about physical activity after stillbirth were coded into the following major themes: barriers to physical activity (emotional symptoms and lack of motivation, tired, lack of time, guilt, letting go of a pregnant body, and seeing other babies), benefits to physical activity (feeling better emotionally/mentally, helping women to cope or be therapeutic), importance of physical activity (working through grief, time for self), motivators for physical activity (body shape/weight, health, more children, be a role model, already an exerciser). Health care providers and their role in physical activity participation was also a major theme. CONCLUSIONS: This is the first study to qualitatively explore beliefs about physical activity in women after a stillbirth. Women who have experienced stillbirth have unique beliefs about physical activity related to their experience with stillbirth. Findings from this study may help to improve the health and quality of life for women who have experienced stillbirth by utilizing physical activity as a strategy for improving depressive symptoms associated with experiencing a stillbirth. Future research in this area is highly warranted.

Contraception and fertility awareness among women with solid organ transplants.

OBJECTIVE: To assess the contraception and fertility counseling provided to women with solid organ transplants. METHODS: A telephone survey of 309 women aged 19-49 years who had received a solid organ transplant at the University of Nebraska Medical Center was performed. Of the 309 eligible women, 183 responded. Patients were asked 19 questions regarding pretransplant and posttransplant fertility awareness and contraception counseling. Data were summarized using descriptive statistics. RESULTS: Patients had undergone a variety of solid organ transplantations: 40% kidney (n=73); 32% liver (n=59); 6% pancreas (n=11); 5% heart (n=9); 3% intestine (n=5); and 14% multiple organs (n=26). Before their transplantations, 79 women (44%) reported they were not aware that a woman could become pregnant after transplantation. Only 66 women aged 13 and older at the time of transplantation reported that a health care provider discussed contraception before transplantation. Approximately half of women surveyed were using a method of contraception. Oral contraceptive pills were the most commonly recommended method. Twenty-two of the 31 pregnancies after organ transplantation were planned, which is higher than that of the general population. CONCLUSION: Few women with transplants are educated regarding the effect of organ transplantation on fertility and are not routinely counseled about contraception or the potential for posttransplant pregnancy. Health care providers should incorporate contraceptive and fertility counseling as part of routine care for women with solid organ transplants. LEVEL OF EVIDENCE: : II.

Placenta accreta: depth of invasion and neonatal outcomes.

OBJECTIVE: The purpose of this study was to compare the risk of adverse neonatal outcomes between women with placenta accreta and placenta increta or percreta. METHODS: This was a single institution retrospective cohort study of women with abnormal placentation (placenta accreta, increta, and percreta) who delivered from 1982-2002. Cases were divided into superficial invasion (placenta accreta) and deep invasion (placenta increta or percreta), and compared. The primary outcomes studied were gestational age at delivery, birth weight, and size for gestational age. RESULTS: 103 viable pregnancies with abnormal placentation were observed (1.6/1000 pregnancies). Cases of deep invasion had higher parity and were more likely to have had a prior cesarean delivery. The mean gestational age at delivery was 33 5/7 weeks with deep placental invasion and 35 2/7 weeks in the superficial invasion group (p = 0.18). Rates of preterm birth were 64.7% and 52.3% (p = 0.43) and low birthweight were 24% and 29% (p = 0.76) in the deep and superficial invasion groups respectively. There were no differences in the remaining outcomes. CONCLUSIONS: Neonatal outcomes of pregnancies complicated by placenta increta and percreta are not different than those with placenta accreta.

Fetal lower urinary tract obstruction.

The authors present an overview of the prenatal diagnosis, evaluation, contemporary intervention, and antenatal management of lower urinary tract obstruction. They review early experimental models that confirmed the relation between urinary tract obstruction and renal fibrocystic dysplasia and that early in utero relief of the obstruction could prevent irreversible renal injury. Subsequent studies of the electrolyte and protein concentrations in fetal urine from human cases established prognostic threshold values and helped to develop an algorithm to select candidates for antenatal therapy. Although shunting has improved survival, long-term morbidities remain a significant challenge.

Obstetrical antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease manifested by a thrombotic or obstetrical event in the presence of antiphospholipid antibodies. Obstetrical APS was initially described in the 1950s. Obstetrical features presently include recurrent pre-embryonic and embryonic miscarriage, fetal demise, preeclampsia, intrauterine growth restriction, and possibly placental abruption. Since the first description of obstetrical APS, researchers have unraveled some of the pathophysiology involved in the disease. At present, there are numerous antiphospholipid antibodies that can be measured in human serum, each of which requires evaluation with regard to whether an association with obstetrical events exists. Clinical trials have provided some insight into optimal treatment protocols, but to date, such trials are limited. On the basis of small, randomized trials, live birth rates of approximately 70 to 80% have been reported with the use of low-dose acetylsalicylic acid and heparin. Despite such encouraging results, ongoing pregnancies are fraught with maternal and fetal morbidity. This review will highlight the obstetrical morbidity associated with APS, discuss the limitations of the present criteria for diagnosis, appraise published treatment trials, and summarize directions for future study of obstetrical APS.

Abnormal placentation: twenty-year analysis.

OBJECTIVE: This study was undertaken to determine whether the rate of abnormal placentation is increasing in conjunction with the cesarean rate and to evaluate incidence, risk factors, and outcomes. STUDY DESIGN: Cases from 1982-2002 were identified by histopathologic or strong clinical criteria. Risk factors were assessed in a matched case-control study, and analyzed using conditional logistic regression models. RESULTS: There were 64,359 deliveries, with cesarean rates increasing from 12.5% (1982) to 23.5% (2002). The overall incidence of placenta accreta was 1 in 533. Significant risk factors for placenta accreta in our final analysis included advancing maternal age (odds ratio [OR] 1.13, 95% CI 1.089-1.194, P < .0001), 2 or more cesarean deliveries (OR 8.6, 95% CI 3.536-21.078, P < .0001), and previa (OR 51.4, 95% CI: 10.646-248.390, P < .0001). CONCLUSION: The rate of placenta accreta increased in conjunction with cesarean deliveries; the most important risk factors were previous cesarean delivery, previa, and advanced maternal age.