Assessment of extremely premature lambs supported by the Extrauterine Environment for Neonatal Development (EXTEND).

BACKGROUND: Our team has previously reported physiologic support by the EXTra-uterine Environment for Neonatal Development (EXTEND) of 105 to 117 days gestational age (GA) lambs for up to 28 days with normal organ maturation. However, the fetal lamb brain matures more rapidly, requiring the study of 90-105 day GA fetal lambs to assess more neurodevelopmentally equivalent lambs to the 23-25 week GA extreme premature infant. METHODS: Extremely preterm lambs (90-95 days of GA) were delivered by C-section and supported by EXTEND. Estimated circuit flows were maintained at around 325 ml/kg/min. After support on EXTEND, MRI and histopathologic analysis were performed and compared to 105-112 days GA control lambs. RESULTS: The extremely preterm group includes 10 animals with a mean GA of 91.6 days, a mean weight at cannulation of 0.98 kg and a mean length of stay on EXTEND of 13.5 days (10-21 days). Hemodynamics and oxygenation showed stable parameters. Animals showed growth and physiologic cardiac function. MRI volumetric and diffusion analysis was comparable to controls. Histologic brain analysis revealed no difference between study groups. CONCLUSION: EXTEND appears to support brain and cardiac development in an earlier gestation, less mature, lamb model. IMPACT: Prolonged (up to 21 days) physiological support of extremely preterm lambs of closer neurodevelopmental equivalence to the 24-28 gestational week human was achieved using the EXTEND system. EXTEND treatment supported brain growth and development in extremely preterm fetal lambs and was not associated with intraventricular hemorrhage or white matter injury. Daily echocardiography demonstrated physiologic heart function, absence of cardiac afterload, and normal developmental increase in cardiac chamber dimensions. This study demonstrates hemodynamic and metabolic support by the EXTEND system in the extremely preterm ovine model.

tauFisher predicts circadian time from a single sample of bulk and single-cell pseudobulk transcriptomic data.

As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tauFisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample. We demonstrate tauFisher's performance in adding timestamps to both bulk and single-cell transcriptomic samples collected from multiple tissue types and experimental settings. Application of tauFisher at a cell-type level in a single-cell RNAseq dataset collected from mouse dermal skin implies that greater circadian phase heterogeneity may explain the dampened rhythm of collective core clock gene expression in dermal immune cells compared to dermal fibroblasts. Given its robustness and generalizability across assay platforms, experimental setups, and tissue types, as well as its potential application in single-cell RNAseq data analysis, tauFisher is a promising tool that facilitates circadian medicine and research.

Protocol of a 12-week eHealth programme designed to reduce concerns about falling in community-living older people: Own Your Balance randomised controlled trial.

INTRODUCTION: Concerns about falling (CaF) are common in older people and have been associated with avoidance of activities of daily life. Exercise designed to prevent falls can reduce CaF, but the effects are usually short-lived. Cognitive behavioural therapy (CBT) can reduce CaF for longer but is not readily available in the community and unlikely to prevent falls. A multidomain intervention that combines CBT, motivational interviewing and exercise could be the long-term solution to treat CaF and reduce falls in older people with CaF. This paper describes the design of a randomised controlled trial to test the effectiveness of two different 12 week self-managed eHealth programmes to reduce CaF compared with an active control. METHODS: A total of 246 participants (82 per group) aged 65 and over, with substantial concerns about falls or balance will be recruited from the community. They will be randomised into: (1) myCompass-Own Your Balance (OYB) (online CBT programme) intervention or (2) myCompass-OYB plus StandingTall intervention (an eHealth balance exercise programme), both including motivational interviewing and online health education or (3) an active control group (online health education alone). The primary outcome is change in CaF over 12 months from baseline of both intervention groups compared with control. The secondary outcomes at 2, 6 and 12 months include balance confidence, physical activity, habitual daily activity, enjoyment of physical activity, social activity, exercise self-efficacy, rate of falls, falls health literacy, mood, psychological well-being, quality of life, exercise self-efficacy, programme adherence, healthcare use, user experience and attitudes towards the programme. An intention-to-treat analysis will be applied. The healthcare funder's perspective will be adopted for the economic evaluation if appropriate. ETHICS AND DISSEMINATION: Ethical approval was obtained from the South Eastern Sydney Local Health District Human Research Ethics Committee (2019/ETH12840). Results will be disseminated via peer-reviewed journals, local and international conferences, community events and media releases. TRIAL REGISTRATION NUMBER: ACTRN12621000440820.

tauFisher accurately predicts circadian time from a single sample of bulk and single-cell transcriptomic data.

As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tau-Fisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample. We demonstrate tauFisher's out-standing performance in both bulk and single-cell transcriptomic data collected from multiple tissue types and experimental settings. Application of tauFisher at a cell-type level in a single-cell RNA-seq dataset collected from mouse dermal skin implies that greater circadian phase heterogeneity may explain the dampened rhythm of collective core clock gene expression in dermal immune cells compared to dermal fibroblasts. Given its robustness and generalizability across assay platforms, experimental setups, and tissue types, as well as its potential application in single-cell RNA-seq data analysis, tauFisher is a promising tool that facilitates circadian medicine and research.

Exploring the Usability of a Community Resiliency Model Approach in a High Need/Low Resourced Traumatized Community.

This study tested the usability of a non-stigmatizing community-based trauma intervention delivered by trained community members. The Community Resiliency Model (CRM) was taught to a high-crime, low-income community designated as a Mental Health Provider Shortage Area (19 MPSA score). Five groups of Latino, African-American, LGBTQ, Asian Pacific Islander, and Veteran participants (N-57) with a history of complex/cumulative traumas and untreated posttraumatic stress undertook a five-day 40-h CRM training with master trainers. Measures included Treatment Relevance, Use and Satisfaction (TRUSS), Brief CRM Questionnaire (Brief CRM), and Symptom Questionnaire (SQ). Participant preparedness to teach CRM to others was high (98%) and sustained at the 3-6 months follow-up with 93% reporting a daily use. Pre-to post comparison analyses showed a significant decrease in distress indicators and increase in wellbeing indicators. CRM's high usability holds promise for a broader, low cost and sustainable implementation in traumatized and under-resourced communities.

Protocol of a 12-month multifactorial eHealth programme targeting balance, dual-tasking and mood to prevent falls in older people: the StandingTall+ randomised controlled trial.

INTRODUCTION: Falls have a multifactorial aetiology, which may limit the effectiveness of the common approach of exercise as the sole intervention strategy. Multifactorial interventions could be more effective in people at high risk of falling; however, the focus of such interventions has traditionally been quite narrow. This paper describes the design of a randomised controlled trial that will evaluate the effectiveness of an eHealth programme, which addresses cumulative effects of key fall-risk factors across the triad of physical, affective and cognitive functions on falls in older people. METHODS AND ANALYSIS: 518 older people aged 65 years and over with high fall risk, defined as having a history of falls in the past 6 months, self-reported fear of falling or being aged 80 years or over, will be recruited via local advertisements, newsletters and presentations, and randomised to an intervention or health education control group. The intervention comprises balance exercise, cognitive-motor exercise and cognitive-behavioural therapy, with their dosage based on participant's baseline balance, executive function and mood. The primary outcome is the rate of falls in the 12 months after randomisation. Secondary outcomes at 6 and 12 months comprise programme adherence, healthcare use, physical activity, balance and mobility, cognitive function, psychological well-being, quality of life, health literacy and user experience and attitudes towards the programme. Data will be analysed following intention to treat to gauge real-world effectiveness. We will further determine complier averaged causal effects to correct for varying adherence and conduct economic analyses to gain insight into cost-effectiveness and cost-utility. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of New South Wales (UNSW) Human Research Ethics Committee in December 2017. Outcomes will be disseminated via peer-reviewed articles, conference presentations, community events and media releases. TRIAL REGISTRATION NUMBER: ACTRN12619000540112.

Seasons, Searches, and Intentions: What The Internet Can Tell Us About The Bed Bug (Hemiptera: Cimicidae) Epidemic.

The common bed bug (Cimex lectularius L.) is once again prevalent in the United States. We investigated temporal patterns in Google search queries for bed bugs and co-occurring terms, and conducted in-person surveys to explore the intentions behind searches that included those terms. Searches for "bed bugs" rose steadily through 2011 and then plateaued, suggesting that the epidemic has reached an equilibrium in the United States. However, queries including terms that survey respondents associated strongly with having bed bugs (e.g., "exterminator," "remedies") continued to climb, while terms more closely associated with informational searches (e.g., "hotels," "about") fell. Respondents' rankings of terms and nonseasonal trends in Google search volume as assessed by a cosinor model were significantly correlated (Kendall's Tau-b P = 0.015). We find no evidence from Google Trends that the bed bug epidemic in the United States has reached equilibrium.

Body weight as a prognostic factor for day hospital success in adolescents with anorexia nervosa.

For female adolescents with anorexia nervosa, body weight at admission as a predictor of treatment outcome in the day hospital setting was examined. A retrospective review of patient charts was completed to determine success or failure in the day hospital program based on weight above or below 85% of ideal body weight. There was not a greater risk of failure in the day hospital program for patients with ideal body weight below 85% compared to those patients with an ideal body weight of ≥ to 85%. Body weight did not predict day hospital success in adolescents with anorexia nervosa in this study.

Substance-related problems in patients visiting an urban Canadian emergency department.

OBJECTIVE: For many patients with addiction and other substance problems, the emergency department (ED) is the sole provider of medical care. This study sought to determine the prevalence and characteristics of substance-related medical problems in ED patients, as defined by documentation in the medical record. We also sought to compare the ED resource use (length of ED stay and number of revisits) of patients with and without substance problems. METHODS: Trained evaluators using explicit criteria reviewed all ED charts during a 6-week period at a Canadian tertiary care teaching centre. Data was collected on demographics, documentation of problematic substance use and whether the ED visit was due to substance problems. Using a computerized database, we determined how many patients with and without substance problems had 1 or more subsequent ED visits during the 1-year period from Sept. 1, 2002, to Aug. 31, 2003. RESULTS: Of 6064 visits made by 5194 patients, 6026 visits (99.4%) representing 5188 patients (99.9%) were captured for review. Of those visits, 674 (11.2%, 95% confidence interval [CI] 10.4%-12.0%), made by 600 patients, had documentation of problematic substance use and 521 visits (8.6%, 95% CI 7.9%-9.4%) by 469 patients were caused by substance problems. The mean age of patients with a visit due to a substance problem was 39.2 years, compared with 48.5 years for those with other visits (p < 0.001). The admission rate for substance-related visits was 25.3%, compared with 17.6% for other visits (p < 0.001). For discharged patients, the median length of the ED visit owing to substance-related problems lasted 232 minutes (IQR [interquartile range] 267 min), compared with 164 minutes (IQR 167 min) for other visits (p < 0.001). In 1 year of follow-up, 161 of 600 patients (26.8%) with a substance problem made 466 revisits (mean 0.78 revisits/patient), compared with 975 of 4588 patients (21.3%) without a substance problem who made a total of 2150 revisits (mean 0.47 revisits/patient, p < 0.001). CONCLUSION: Substance problems contribute significantly to ED visits, hospital admissions and duration of ED stay at a tertiary centre. It is likely that our methodology underestimates the scope of the problem and that a universal screening program would find a higher prevalence. The magnitude of this problem supports the need for an interdisciplinary identification and intervention program for ED patients with substance-related issues.

Abrogation of ionizing radiation-induced G2 checkpoint and inhibition of nuclear export by Cryptocarya pyrones.

G(2) checkpoint inhibitors can force cells arrested in G(2) phase by DNA damage to enter mitosis. In this manner, several G(2) checkpoint inhibitors can enhance killing of cancer cells by ionizing radiation and DNA-damaging chemotherapeutic agents, particularly in cells lacking p53 function. All G(2) checkpoint inhibitors identified to date target protein phosphorylation by inhibiting checkpoint kinases or phosphatases. Using a phenotypic cell-based assay for G(2) checkpoint inhibitors, we have screened a large collection of plant extracts and identified Z-Cryptofolione and Cryptomoscatone D2 as highly efficacious inhibitors of the G(2) checkpoint. These compounds and related pyrones also inhibit nuclear export. Leptomycin B, a potent inhibitor of Crm1-mediated nuclear export, is also a very potent G(2) checkpoint inhibitor. These compounds possess a reactive Michael acceptor site and do not appear promising as a radiosensitizing agents because they are toxic to unirradiated cells at checkpoint inhibitory concentrations. Nevertheless, the results show that inhibition of nuclear export is an alternative to checkpoint kinase inhibition for abrogating the G(2) checkpoint and they should stimulate the search for less toxic nuclear export inhibitors.

Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus.

Here, using a genetic approach, we dissect the roles of EphB receptor tyrosine kinases in dendritic spine development. Analysis of EphB1, EphB2, and EphB3 double and triple mutant mice lacking these receptors in different combinations indicates that all three, although to varying degrees, are involved in dendritic spine morphogenesis and synapse formation in the hippocampus. Hippocampal neurons lacking EphB expression fail to form dendritic spines in vitro and they develop abnormal spines in vivo. Defective spine formation in the mutants is associated with a drastic reduction in excitatory glutamatergic synapses and the clustering of NMDA and AMPA receptors. We show further that a kinase-defective, truncating mutation in EphB2 also results in abnormal spine development and that ephrin-B2-mediated activation of the EphB receptors accelerates dendritic spine development. These results indicate EphB receptor cell autonomous forward signaling is responsible for dendritic spine formation and synaptic maturation in hippocampal neurons.