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The aim of this study was to examine individual differences in a large sample of complete melatonin profiles not suppressed by light and search for possible associations between the amount and timing of melatonin secretion and a multitude of lifestyle variables. The melatonin profiles were derived from saliva samples collected every 30 minutes in dim light from 85 healthy women and 85 healthy men aged 18-45 years. There was a large individual variability in the amount of melatonin secreted with peak values ranging from 2 to 84 pg/ml. The onset of melatonin secretion ranged from 18:13 to 00:26 hours. The use of hormonal birth control, reduced levels of employment, a smaller number of days on a fixed sleep schedule, increased day length and lower weight were associated with an increased amplitude of melatonin secretion. The use of hormonal birth control, contact lenses, a younger age, and lower ratings of mania and paranoia were associated with a longer duration of melatonin secretion. An earlier occurrence of the onset of melatonin secretion was associated with an earlier wake time, more morningness and the absence of a bed partner. Lifestyle and behavioral variables were only able to explain about 15% of the individual variability in the amount of melatonin secretion, which is likely because of a substantial genetic influence on the levels of melatonin secretion.

Background Accurate diagnostic biomarker testing is crucial to treatment decisions in breast cancer. Biomarker testing is performed on core needle biopsies (CNB) and is often repeated in the surgical specimen (SS) after resection. As differences between CNB and SS testing may alter treatment decisions, we evaluated concordance between CNB and SS as well as associated changes in treatment and clinical outcomes. Methods We performed a retrospective analysis of breast cancer patients at our institution between January 2010 and May 2020. Concordance between CNB and SS was assessed for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Survival in patients, including recurrence, metastatic recurrence, and death, were assessed using chi‐squared likelihood ratio. Results In total, 961 patients met eligibility criteria. Concordance, minor discordance, total concordance (concordance plus minor discordance), and major discordance between CNB and SS were reported for ER (87.7%, 9.2%, 90.8%, and 2.9%), PR (58.1%, 29.1%, 87.2%, and 12.8%), and HER2 IHC (52.5%, 20.9%, 73.4%, 26.6%), respectively. HER2 FISH concordance and major discordance were 58.5% and 1.2%, respectively. Of major discordance, ER (48.2%, p < 0.001) and HER2 FISH (50.0%) led to more management changes than HER2 IHC (2.4%, p = 0.04) and PR (1.6%, p = 0.10). Patients with ER major discordance had increased risk of death (6.7% concordance vs. 22.2% major discordance, p = 0.004). Conclusion Overall, retesting ER and HER2 was more clinically beneficial than retesting PR. To aid decision‐making and minimize healthcare costs, we propose patient‐centered guidelines on retesting biomarker profiles. Retesting estrogen receptor and HER2 status provides more clinical benefit than retesting progesterone receptor status. We propose guidelines for retesting receptor profiles to aid patient care management decisions, prioritize clinical benefits, and minimize healthcare costs.

There are differences in sleep duration between Blacks/African-Americans and Whites/European-Americans. Recently, we found differences between these ancestry groups in the circadian system, such as circadian period and the magnitude of phase shifts. Here we document the role of ancestry on sleep and cognitive performance before and after a 9-h advance in the sleep/wake schedule similar to flying east or having a large advance in sleep times due to shiftwork, both of which produce extreme circadian misalignment. Non-Hispanic African and European-Americans (N = 20 and 17 respectively, aged 21-43 years) were scheduled to four baseline days each with 8 h time in bed based on their habitual sleep schedule. This sleep/wake schedule was then advanced 9 h earlier for three days. Sleep was monitored using actigraphy. During the last two baseline/aligned days and the first two advanced/misaligned days, beginning 2 h after waking, cognitive performance was measured every 3 h using the Automated Neuropsychological Assessment Metrics (ANAM) test battery. Mixed model ANOVAs assessed the effects of ancestry (African-American or European-American) and condition (baseline/aligned or advanced/misaligned) on sleep and cognitive performance. There was decreased sleep and impaired performance in both ancestry groups during the advanced/misaligned days compared to the baseline/aligned days. In addition, African-Americans obtained less sleep than European-Americans, especially on the first two days of circadian misalignment. Cognitive performance did not differ between African-Americans and European-Americans during baseline days. During the two advanced/misaligned days, however, African-Americans tended to perform slightly worse compared to European-Americans, particularly at times corresponding to the end of the baseline sleep episodes. Advancing the sleep/wake schedule, creating extreme circadian misalignment, had a greater impact on the sleep of African-Americans than European-Americans. Ancestry differences in sleep appear to be exacerbated when the sleep/wake schedule is advanced, which may have implications for individuals undertaking shiftwork and transmeridian travel.

Background Various priming techniques to enhance neuroplasticity have been examined in stroke rehabilitation research. Most priming techniques are costly and approved only for research. Here, we describe a priming technique that is cost-effective and has potential to significantly change clinical practice. Bilateral motor priming uses the Exsurgo priming device (Exsurgo Rehabilitation, Auckland, NZ) so that the less affected limb drives the more affected limb in bilateral symmetrical wrist flexion and extension. The aim of this study is to determine the effects of a 5-week protocol of bilateral motor priming in combination with task-specific training on motor impairment of the affected limb, bimanual motor function, and interhemispheric inhibition in moderate to severely impaired people with stroke. Methods Seventy-six participants will be randomized to receive either 15, 2-h sessions, 3 times per week for 5 weeks (30 h of intervention) of bilateral motor priming and task-specific training (experimental group) or the same dose of control priming plus the task-specific training protocol. The experimental group performs bilateral symmetrical arm movements via the Exsurgo priming device which allows both wrists to move in rhythmic, symmetrical wrist flexion and extension for 15 min. The goal is one cycle (wrist flexion and wrist extension) per second. The control priming group receives transcutaneous electrical stimulation below sensory threshold for 15 min prior to the same 45 min of task-specific training. Outcome measures are collected at pre-intervention, post-intervention, and follow-up (8 weeks post-intervention). The primary outcome measure is the Fugl-Meyer Test of Upper Extremity Function. The secondary outcome is the Chedoke Arm and Hand Activity Index-Nine, an assessment of bimanual functional tasks. Discussion To date, there are only 6 studies documenting the efficacy of priming using bilateral movements, 4 of which are pilot or feasibility studies. This is the first large-scale clinical trial of bilateral priming plus task-specific training. We have previously completed a feasibility intervention study of bilateral motor priming plus task-specific training and have considerable experience using this protocol. Trial registration ClinicalTrials.gov NCT03517657 . Retrospectively registered on May 7, 2018.

The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study, subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays, relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep phase disorder.

Context: Intralipid is used to improve clinical outcomes in patients with recurrent pregnancy loss (RPL) or recurrent implantation failure (RIF) with elevated natural killer (NK) cells. Data supporting this practice is conflicting but suggestive of minimal benefit. Aims: The aims of this study are to determine if intralipid infusion improves live birth rates and if is a cost-effective therapy in the RPL/RIF population. Settings and Design: This was a large REI private practice, retrospective cohort study. Subjects and Methods: Charts of 127 patients who received intralipid from 2012 to 2015 were reviewed and compared to historical control data. T-tests and Chi-square analyses evaluated demographics and cycle statistics. Chi-square analyses assessed impact on clinical pregnancy and live birth rates. Cost analysis was performed from societal perspective with a one-way sensitivity analysis. Results: Patients with live births were noted to have a higher average number of previous live births and were more likely to have had a frozen embryo transfer in the intralipid cycle in comparison to those with unsuccessful pregnancy outcomes. Neither clinical pregnancy nor live birth rates were significantly improved from baseline rates quoted in the literature (P = 0.12 and 0.80, respectively). Intralipid increased costs by $681 per live birth. If live birth rates were >40% using intralipid and <51% without intervention, neither strategy was favored. Conclusions: Intralipid does not improve live birth rates and is not cost-effective for patients with RIF or RPL and elevated NK cells. This study supports the growing literature demonstrating the minimal benefit of screening for and treating elevated peripheral NK cells.

Purpose The purpose of this study was to assess nurses’ knowledge, perceived self‐efficacy, and intended behaviors relative to integrating the social determinants of health (SDoH) into clinical practice. Design and Methods A cross‐sectional study was completed with 768 nurses working in three hospitals within a large regional healthcare system located in the Midwest. Data were collected using an adapted 71‐item SDoH Survey, which measured nurses’ confidence in and frequency of discussing the SDoH with patients, general knowledge of the SDoH, familiarity with patients’ social and economic conditions, and awareness of their institution’s health equity strategic plan to achieve health equity. The institution’s health equity strategic plan reflects the organization’s commitment to improving the health of individuals and neighborhoods by addressing the SDoH known to influence health status and life expectancy. Finally, participants were asked to describe barriers to incorporating the SDoH into practice along with completing five demographic items. Descriptive statistics were used to describe the findings. Findings Of the 768 respondents, 63% had a baccalaureate degree in nursing and 33.1% reported more than 20 years in nursing. Fifty percent of respondents reported feeling more knowledgeable or confident in their ability to discuss access to care issues with patients compared to the other SDoH. Identified barriers to discussing the SDoH included insufficient time to address identified needs and unfamiliarity with internal and external resources. Respondents stressed the need for interdisciplinary education and collaboration along with more information on the role of social workers. Conclusions Nurses are more confident in discussing certain determinants of health and could benefit from more skill development in discussing SDoH issues and stronger collaborative partnerships to address identified needs. Clinical Relevance Findings from the study have implications for supporting the educational and resource needs of front‐line nurses employed in hospitals and health systems seeking to address broader societal issues influencing the health status and outcomes of patients and communities.

There is a need for treatments to reduce coronavirus disease 2019 (COVID-19) mortality. Alpha-2 adrenergic receptor (α 2 AR) agonists can dampen immune cell and inflammatory responses as well as improve oxygenation through physiologic respiratory parameters. Therefore, α 2 AR agonists may be effective in reducing mortality related to hyperinflammation and acute respiratory failure in COVID-19. Dexmedetomidine (DEX) is an α 2 AR agonist used for sedation. We performed a retrospective analysis of adults at Rush University System for Health hospitals between March 1, 2020 and July 30, 2020 with COVID-19 requiring invasive mechanical ventilation and sedation ( n = 214). We evaluated the association of DEX use and 28-day mortality from time of intubation. Overall, 28-day mortality in the cohort receiving DEX was 27.0% as compared to 64.5% in the cohort that did not receive DEX (relative risk reduction 58.2%; 95% CI 42.4–69.6). Use of DEX was associated with reduced 28-day mortality on multivariable Cox regression analysis (aHR 0.19; 95% CI 0.10–0.33; p < 0.001). Adjusting for time-varying exposure to DEX also demonstrated that DEX was associated with reduced 28-day mortality (aHR 0.51; 95% CI 0.28–0.95; p = 0.03). Earlier DEX use, initiated <3.4 days from intubation, was associated with reduced 28-day mortality (aHR 0.25; 95% CI 0.13–0.50; p < 0.001) while later DEX use was not (aHR 0.64; 95% CI 0.27–1.50; p = 0.30). These results suggest an α 2 AR agonist might reduce mortality in patients with COVID-19. Randomized controlled trials are needed to confirm this observation.

Abstract Study Objectives Shift sleep onset earlier and extend school-night sleep duration of adolescents. Methods Forty-six adolescents (14.5–17.9 years; 24 females) with habitual short sleep (≤7 h) and late bedtimes (≥23:00) on school nights slept as usual for 2 weeks (baseline). Then, there were three weekends and two sets of five weekdays in between. Circadian phase (Dim Light Melatonin Onset, DLMO) was measured in the laboratory on the first and third weekend. On weekdays, the “Intervention” group gradually advanced school-night bedtime (1 h earlier than baseline during week 1; 2 h earlier than baseline during week 2). Individualized evening time management plans (“Sleep RouTeen”) were developed to facilitate earlier bedtimes. On the second weekend, Intervention participants received bright light (~6000 lux; 2.5 h) on both mornings. A control group completed the first and third weekend but not the second. They slept as usual and had no evening time management plan. Weekday sleep onset time and duration were derived from actigraphy. Results Dim light melatonin onset (DLMO) advanced more in the Intervention (0.6 ± 0.8 h) compared to the Control (−0.1 ± 0.8 h) group. By week 2, the Intervention group fell asleep 1.5 ± 0.7 h earlier and sleep duration increased by 1.2 ± 0.7 h; sleep did not systematically change in the Control group. Conclusions This multi-pronged circadian-based intervention effectively increased school-night sleep duration for adolescents reporting chronic sleep restriction. Adolescents with early circadian phases may only need a time management plan, whereas those with later phases probably need both time management and morning bright light. Clinical Trials Teen School-Night Sleep Extension: An Intervention Targeting the Circadian System (#NCT04087603): https://clinicaltrials.gov/ct2/show/NCT04087603 Graphical Abstract Graphical Abstract

BackgroundPulmonary endothelial cells’ (ECs) injury and apoptotic death are necessary and sufficient for the pathogenesis of the acute respiratory distress syndrome (ARDS), regardless of epithelial damage. Interaction of dysfunctional ECs with circulatory extracellular vesicles (EVs) holds therapeutic promise in ARDS. However, the presence in the blood of long-term ARDS survivors of EVs with a distinct phenotype compared to the EVs of non-surviving patients is not reported. With a multidisciplinary translational approach, we studied EVs from the blood of 33 patients with moderate-to-severe ARDS.ResultsThe EVs were isolated from the blood of ARDS and control subjects. Immunoblotting and magnetic beads immunoisolation complemented by standardized flow cytometry and nanoparticles tracking analyses identified in the ARDS patients a subset of EVs with mesenchymal stem cell (MSC) origin (CD73+CD105+Cd34−CD45−). These EVs have 4.7-fold greater counts compared to controls and comprise the transforming growth factor-beta receptor I (TβRI)/Alk5 and the Runx1 transcription factor. Time course analyses showed that the expression pattern of two Runx1 isoforms is critical for ARDS outcome: the p52 isoform shows a continuous expression, while the p66 is short-lived. A high ratio Runx1p66/p52 provided a survival advantage, regardless of age, sex, disease severity or length of stay in the intensive care unit. Moreover, the Runx1p66 isoform is transiently expressed by cultured human bone marrow-derived MSCs, it is released in the EVs recoverable from the conditioned media and stimulates the proliferation of lipopolysaccharide (LPS)-treated ECs. The findings are consistent with a causal effect of Runx1p66 expression on EC proliferation. Furthermore, morphological and functional assays showed that the EVs bearing the Runx1p66 enhanced junctional integrity of LPS-injured ECs and decreased lung histological severity in the LPS-treated mice.ConclusionsThe expression pattern of Runx1 isoforms might be a reliable circulatory biomarker of ARDS activity and a novel determinant of the molecular mechanism for lung vascular/tissue repair and recovery after severe injury.