Dysregulated clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in amyloid precursor protein transgenic mice.

Patients with Alzheimer's disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock) in Tg-SwDI mice with human amyloid-beta precursor protein mutations. Here, we report that Tg-SwDI mice failed to show day/night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimer's disease symptoms or delay pathological onset.

Misaligned core body temperature rhythms impact cognitive performance of hospital shift work nurses.

Circadian rhythms greatly influence 24-h variation in cognition in nearly all organisms, including humans. Circadian clock impairment and sleep disruption are detrimental to hippocampus-dependent memory and negatively influence the acquisition and recall of learned behaviors. The circadian clock can become out of sync with the environment during circadian misalignment. Shift work represents a real-world model of circadian misalignment that can be studied for its physiological implications. The present study aimed to test the hypothesis that circadian misalignment disrupts vigilance and cognitive performance on occupationally relevant tasks using shift work as a model. As such, we sought to (1) explore the general effects of night- and day-shift worker schedules on sleep-wake parameters and core body temperature (CBT) phase, and (2) determine whether shift-type and CBT phase impact cognitive performance and vigilance at the end of a 12-h shift. We observed a sample of day-shift and night-shift hospital nurses over a 10-day period. At the end of three, consecutive, 12-h shifts (7 pm-7am or 7am-7 pm), participants completed a cognitive battery assessing vigilance, cognitive throughput, and medication calculation fluency (via an investigator developed and tested metric). Night-shift nurses exhibited significantly greater sleep fragmentation as well as a greater disparity between their wake-time and time of CBT minimum compared to day-shift nurses. Night-shift nurses exhibited significantly slower cognitive proficiency at the end of their shifts, even after adjustment for CBT phase. These results suggest that circadian disruption and reduced sleep quality both contribute to cognitive functioning and performance.

Over-the-Counter Progestin-Only Oral Contraceptives.

This JAMA Patient Page describes progestin-only oral contraceptive pills, which recently have been approved to be sold over the counter.

Mifepristone use for early pregnancy loss: A qualitative study of barriers and facilitators among OB/GYNS in Massachusetts, USA.

CONTEXT: Early pregnancy loss (EPL) affects 1 million patients in the United States (US) annually, but integration of mifepristone into EPL care may be complicated by regulatory barriers, practice-related factors, and abortion stigma. METHODS: We conducted qualitative, semi-structured interviews among obstetrician-gynecologists in independent practice in Massachusetts, US on mifepristone use for EPL. We recruited participants via professional networks and purposively sampled for mifepristone use, practice type, time in practice, and geographic location within Massachusetts until we reached thematic saturation. We analyzed interviews using inductive and deductive coding under a thematic analysis framework to identify facilitators of and barriers to mifepristone use. RESULTS: We interviewed 19 obstetrician-gynecologists; 12 had used mifepristone for EPL and 7 had not. Participants were in private practice (n = 12), academic practice (n = 6), or worked at a federally qualified health center (n = 1). Seven had fellowship training, including four in complex family planning. The most common facilitators of mifepristone use for EPL were access to the expertise or protocols of local-regional experts, leadership from a "champion," prior experience with abortion care, and hospital capacity constraints during the COVID-19 pandemic. The most common barriers were related to the Mifepristone Risk Evaluation and Mitigation Strategy (REMS) Program imposed by the US Food and Drug Administration (FDA). Additionally, mifepristone's affiliation with abortion was a barrier to its use in EPL for some obstetrician-gynecologists. CONCLUSION: The FDA Mifepristone REMS Program presents substantial barriers to obstetrician-gynecologists incorporating mifepristone into their EPL care.

Acute complications with same-day versus overnight cervical preparation before dilation and evacuation at 14 to 16 weeks.

OBJECTIVE: Evaluate if same-day cervical preparation is associated with a clinically acceptable complication rate compared with overnight osmotic dilators for dilation and evacuation (D&E). STUDY DESIGN: This retrospective, noninferiority, cohort study compared complication rates for same-day versus overnight cervical preparation with D&E between 14 and 16 weeks gestation. Cervical preparation was achieved with misoprostol, osmotic dilators, or both. Our primary outcome was the acute complication rate, defined as: hemorrhage (≥500 mL); hospitalization or hospital transfer; transfusion; or unplanned procedure occurring within 24 hours of the index procedure. Secondarily we evaluated nonmajor (re-aspiration, suture repair of cervical laceration, uterine tamponade, or emergency department only transfer) and major (transfusion, uterine artery embolization, abdominal surgery, or hospital admission) complications separately. Inverse probability of treatment weighting using the propensity score was used to perform an adjusted analysis, taking into account age, ethnicity, clinic location, insurance, gestational age, gravidity, and prior pregnancy outcomes. RESULTS: We analyzed 1,319 subjects (n = 864 same-day, n = 455 overnight). Same-day cervical preparation patients were more likely to have Medicaid and a prior vaginal delivery. In both unadjusted and adjusted analyses, acute complication rates for same-day were noninferior to overnight preparation (unadjusted 0.93% vs 1.98%, difference of -1.05%, CI: -2.48% to 0.38%; adjusted difference -0.50%, CI: -1.45 to 0.44%). Only one major complication in the same-day group, a cervical laceration resulting in hemorrhage requiring transfusion, occurred in the entire sample. CONCLUSIONS: In this retrospective review, same-day cervical preparation was noninferior to overnight preparation for D&E between 14 and 16 weeks gestation, both with low complication rates. IMPLICATIONS: For early second trimester dilation and evacuation, same-day cervical preparation should be considered a safe alternative to overnight cervical preparation.

"We're called upon to be nonjudgmental": A qualitative exploration of United States medical students' discussions of abortion as a reflection of their professionalism.

OBJECTIVES: Medical educators may assess learners' professionalism through clinical scenarios eliciting value conflicts - situations in which an individual's values differ from others' perceived values. We examined the extent to which United States (US) medical students' discussion of abortion highlights their professionalism according to the 6 American Association of Medical Colleges (AAMC) professionalism competencies. STUDY DESIGN: We conducted anonymous, semistructured qualitative interviews with 74 US medical students applying to OB/GYN residency. Interviews explored attitudes toward abortion and abortion case vignettes. We analyzed interview transcripts using directed content analysis for alignment with the AAMC professionalism competencies: humanism, patient needs superseding self-interest, patient autonomy, physician accountability, sensitivity to diverse populations, and commitment to ethical principles. RESULTS: Students' genders, races, religions, and geographic regions were diverse. Attitudes toward abortion varied, but all students commented on themes related to at least 1 AAMC professionalism competency when discussing abortion care. Statements demonstrating students' humanism, prioritization of patient autonomy, and sense of physician accountability were common. Most comments reflected positive professionalism practices, regardless of personal views on abortion or provision intentions; very few students made statements that were not aligned with the AAMC professionalism competencies. CONCLUSIONS: All students in this study exhibited professionalism when discussing abortion, regardless of personal views on abortion or intention to provide this care. Case-based discussions involving abortion could be used to explore professionalism competencies among medical learners. IMPLICATIONS: Discussing abortion has the potential to elicit values conflict, which enables learners to exhibit professionalism. Case-based abortion education should be included in medical school curricula to measure medical professionalism in future physicians, and to serve as a tool for teaching professionalism in medical school.

Circadian disruption of hippocampus in an early senescence male mouse model.

Age-related cognitive decline and disruptions in circadian rhythms are growing problems as the average human life span increases. Multiple strains of the senescence-accelerated mouse (SAM) show reduced life span, and the SAMP8 strain in particular has been well documented to show cognitive deficits in behavior as well as a bimodal pattern of circadian locomotor activity. However, little is known about circadian regulation within the hippocampus of these strains of mice. Here we test the hypothesis that in this early senescence model, disruption of the molecular circadian clock in SAMP8 animals drives disrupted behavior and physiology. We found normal rhythms in PER2 protein expression in the SCN of SAMP8 animals at 4 months, despite the presence of disrupted wheel-running activity rhythms at this age. Interestingly, a significant rhythm in PER2 expression was not observed in the hippocampus of SAMP8 animals, despite a significant 24-h rhythm in SAMR1 controls. We also examined time-restricted feeding as a potential strategy to rescue disrupted hippocampal plasticity. Time-restricted feeding increased long-term potentiation at Schaffer collateral-CA1 synapses in SAMP8 mice (compared to SAMR1 controls). Overall, we confirm disrupted circadian locomotor rhythms in this early senescence model (as early as 4 months) and discovered that this disruption is not due to arrhythmic PER2 levels in the SCN; however, other extra-SCN circadian oscillators (i.e., hippocampus) are likely impaired with accelerated aging.

Health risks and outcomes that disproportionately affect women during the Covid-19 pandemic: A review.

BACKGROUND: The Covid-19 pandemic is straining healthcare systems in the US and globally, which has wide-reaching implications for health. Women experience unique health risks and outcomes influenced by their gender, and this narrative review aims to outline how these differences are exacerbated in the Covid-19 pandemic. OBSERVATIONS: It has been well described that men suffer from greater morbidity and mortality once infected with SARS-CoV-2. This review analyzed the health, economic, and social systems that result in gender-based differences in the areas healthcare workforce, reproductive health, drug development, gender-based violence, and mental health during the Covid-19 pandemic. The increased risk of certain negative health outcomes and reduced healthcare access experienced by many women are typically exacerbated during pandemics. We assess data from previous disease outbreaks coupled with literature from the Covid-19 pandemic to examine the impact of gender on women's SARS-CoV-2 exposure and disease risks and overall health status during the Covid-19 pandemic. CONCLUSIONS: Gender differences in health risks and implications are likely to be expanded during the Covid-19 pandemic. Efforts to foster equity in health, social, and economic systems during and in the aftermath of Covid-19 may mitigate the inequitable risks posed by pandemics and other times of healthcare stress.