Behavior, synaptic mitochondria, and microglia are differentially impacted by chronic adolescent stress and repeated endotoxin exposure in male and female rats.

Early life adversity and chronic inflammation have both been associated with cognitive impairment and neural compromise. In this study, we investigated the interactions between a history of chronic adolescent stress (CAS) and repeated endotoxin exposure on behavior, synaptic mitochondria, and microglia in adult male and female Wistar rats. Adult rats from chronic stress and control conditions were exposed to either repeated endotoxin (lipopolysaccharide; LPS) or saline injections every 3 days for 9 weeks. In both sexes, repeated LPS, regardless of stress history, impaired working memory in the Y maze. Regarding spatial memory, LPS impaired function for females; whereas, CAS altered function in males. Although males had an increase in anxiety-like behavior shortly after CAS, there were no long-term effects on anxiety-like behavior or social interaction observed in males or females. Stress did not alter synaptic mitochondrial function in either sex. Repeated LPS altered synaptic mitochondrial function such that ATP production was increased in females only. There were no observed increases in IBA-1 positive cells within the hippocampus for either sex. However, LPS and CAS altered microglia morphology in females. Impact of repeated LPS was evident at the terminal endpoint with increased spleen weight in both sexes and decreased adrenal weight in males only. Circulating cytokines were not impacted by repeated LPS at the terminal endpoint, but evidence of CAS effects on cytokines in females were evident. These data suggest a long-term impact of chronic stress and an impact of repeated endotoxin challenge in adulthood; however, not all physiological and behavioral metrics examined were impacted by the paradigm employed in this study and the two environmental challenges rarely interacted.

Immobilised teicoplanin does not demonstrate antimicrobial activity against Staphylococcus aureus.

Antibacterial bone biomaterial coatings appeal to orthopaedics, dentistry and veterinary medicine. Achieving the successful, stable conjugation of suitable compounds to biomaterial surfaces is a major challenge. A pragmatic starting point is to make use of existing, approved antibiotics which are known to remain functional in a stationary, immobilised state. This includes the macrocyclic glycopeptide, teicoplanin, following the discovery, in the 1990's, that it could be used as a chiral selector in chromatographic enantiomeric separations. Importantly teicoplanin works at the level of the bacterial cell wall making it a potential candidate for biomaterial functionalisations. We initially sought to functionalise titanium (Ti) with polydopamine and use this platform to capture teicoplanin, however we were unable to avoid the natural affinity of the antibiotic to the oxide surface of the metal. Whilst the interaction between teicoplanin and Ti was robust, we found that phosphate resulted in antibiotic loss. Before contemplating the covalent attachment of teicoplanin to Ti we examined whether a commercial teicoplanin stationary phase could kill staphylococci. Whilst this commercially available material could bind N-Acetyl-L-Lys-D-Ala-D-Ala it was unable to kill bacteria. We therefore strongly discourage attempts at covalently immobilising teicoplanin and/or other glycopeptide antibiotics in the pursuit of novel antibacterial bone biomaterials.

Comparative Effectiveness Analyses of Salvage Prostatectomy and Salvage Radiotherapy Outcomes Following Focal or Whole-Gland Ablative Therapy (High-Intensity Focused Ultrasound, Cryotherapy or Electroporation) for Localised Prostate Cancer.

AIMS: Ablative therapy, such as focal therapy, cryotherapy or electroporation, aims to treat clinically significant prostate cancer with reduced treatment-related toxicity. Up to a third of patients may require further local salvage treatment after ablative therapy failure. Limited descriptive, but no comparative, evidence exists between different salvage treatment outcomes. The aim of this study was to compare oncological and functional outcomes after salvage robot-assisted radical prostatectomy (SRARP) and salvage radiotherapy (SRT). MATERIALS AND METHODS: Data were collected prospectively and retrospectively on 100 consecutive SRARP cases and 100 consecutive SRT cases after ablative therapy failure in a high-volume tertiary centre. RESULTS: High-risk patients were over-represented in the SRARP group (66.0%) compared with the SRT group (48.0%) (P = 0.013). The median (interquartile range) follow-up after SRARP was 16.5 (10.0-30.0) months and 37.0 (18.5-64.0) months after SRT. SRT appeared to confer greater biochemical recurrence-free survival at 1, 2 and 3 years compared with SRARP in high-risk patients (year 3: 86.3% versus 66.0%), but biochemical recurrence-free survival was similar for intermediate-risk patients (year 3: 90.0% versus 75.6%). There was no statistical difference in pad-free continence at 12 and 24 months between SRARP (77.2 and 84.7%) and SRT (75.0 and 74.0%) (P = 0.724, 0.114). Erectile function was more likely to be preserved in men who underwent SRT. After SRT, cumulative bowel and urinary Radiation Therapy Oncology Group toxicity grade I were 25.0 and 45.0%, grade II were 11.0 and 11.0% and grade III or IV complications were 4.0 and 5.0%, respectively. CONCLUSION: We report the first comparative analyses of salvage prostatectomy and radiotherapy following ablative therapy. Men with high-risk disease appear to have superior oncological outcomes after SRT; however, treatment allocation does not appear to influence oncological outcomes for men with intermediate-risk disease. Treatment allocation was associated with a different spectrum of toxicity profile. Our data may inform shared decision-making when considering salvage treatment following focal or whole-gland ablative therapy.

Chronic adolescent stress causes sustained impairment of cognitive flexibility and hippocampal synaptic strength in female rats.

Females that experience chronic stress during development, particularly adolescence, are the most vulnerable group to stress-induced disease. While considerable attention has been devoted to stress-induced manifestation of anxiety, depression, and PTSD, evidence indicates that a history of chronic stress is also a risk factor for cognitive decline and dementia - with females again in a higher risk group. This interplay between sex and stress history indicates specific mechanisms drive neural dysfunction across the lifespan. The presence of sex and stress steroid receptors in the hippocampus provides a point of influence for these variables to drive changes in cognitive function. Here, we used a rodent model of chronic adolescent stress (CAS) to determine the extent to which CAS modifies glutamatergic signaling resulting in cognitive dysfunction. Male and female Wistar rats born in-house remained non-stressed (NS), unmanipulated aside from standard cage cleaning, or were exposed to either physical restraint (60 min) or social defeat (CAS) each day (6 trials each), along with social isolation, throughout the adolescent period (PND 35-47). Cognition was assessed in adult (PND 80-130) male and female rats (n = 10-12) using the Barnes Maze task and the Attention Set-Shift task. Whole hippocampi were extracted from a second cohort of male and female rats (NS and CAS; n = 9-10) and processed for RNA sequencing. Brain tissue from the first cohort (n = 6) was processed for density of glutamatergic synaptic markers (GluA1, NMDA1a, and synaptophysin) or whole-cell patch clamping (n = 4) to determine glutamatergic activity in the hippocampus. Females with a history of chronic stress had shorter latencies to locate the goal box than NS controls during acquisition learning but showed an increased latency to locate the new goal box during reversal learning. This reversal deficit persisted across domains as females with a history of stress required more trials to reach criterion during the reversal phases of the Attention Set-Shift task compared to controls. Ovariectomy resulted in greater performance variability overall during reversal learning with CAS females showing worse performance. Males showed no effects of CAS history on learning or memory performance. Bioinformatic prediction using gene ontology categorization indicated that in females, postsynaptic membrane gene clusters, specifically genes related to glutamatergic synapse remodeling, were enriched with a history of stress. Structural analysis indicated that CAS did not alter glutamate receptor density in females. However, functionally, CAS females had a decreased AMPA/NMDA-dependent current ratio compared to controls indicating a weakening in synaptic strength in the hippocampus. Males showed only a slight change in density of NMDA1a labeling in the CA3 region with a history of stress. The data observed here suggest that females are at risk for impaired cognitive flexibility following a history of adolescent stress, possibly driven by changes in glutamatergic signaling.

Associations between interpregnancy interval and preterm birth by previous preterm birth status in four high-income countries: a cohort study.

OBJECTIVE: To investigate the effect of interpregnancy interval (IPI) on preterm birth (PTB) according to whether the previous birth was preterm or term. DESIGN: Cohort study. SETTING: USA (California), Australia, Finland, Norway (1980-2017). POPULATION: Women who gave birth to first and second (n = 3 213 855) singleton livebirths. METHODS: Odds ratios (ORs) for PTB according to IPIs were modelled using logistic regression with prognostic score stratification for potential confounders. Within-site ORs were pooled by random effects meta-analysis. OUTCOME MEASURE: PTB (gestational age <37 weeks). RESULTS: Absolute risk of PTB for each IPI was 3-6% after a previous term birth and 17-22% after previous PTB. ORs for PTB differed between previous term and preterm births in all countries (P-for-interaction ≤ 0.001). For women with a previous term birth, pooled ORs were increased for IPI <6 months (OR 1.50, 95% CI 1.43-1.58); 6-11 months (OR 1.10, 95% CI 1.04-1.16); 24-59 months (OR 1.16, 95% CI 1.13-1.18); and ≥ 60 months (OR 1.72, 95%CI 1.60-1.86), compared with 18-23 months. For previous PTB, ORs were increased for <6 months (OR 1.30, 95% CI 1.18-1.42) and ≥60 months (OR 1.29, 95% CI 1.17-1.42), but were less than ORs among women with a previous term birth (P < 0.05). CONCLUSIONS: Associations between IPI and PTB are modified by whether or not the previous pregnancy was preterm. ORs for short and long IPIs were higher among women with a previous term birth than a previous PTB, which for short IPI is consistent with the maternal depletion hypothesis. Given the high risk of recurrence and assuming a causal association between IPI and PTB, IPI remains a potentially modifiable risk factor for women with previous PTB. TWEETABLE ABSTRACT: Short versus long interpregnancy intervals associated with higher ORs for preterm birth (PTB) after a previous PTB.

A role for Msx genes in mammalian embryonic diapause.

Mammalian embryonic diapause is a reproductive phenomenon defined by the reversible arrest in blastocyst development and metabolic activity within the uterus which synchronously becomes quiescent to implantation. This natural strategy, evident in over 130 species across eight orders, can temporally uncouple conception from delivery until conditions are favorable for the survival of the mother and newborn. While the maternal endocrine milieu has been shown to be important for this process, the local molecular mechanisms by which the uterus and embryo achieve quiescence, maintain blastocyst survival and then resumes blastocyst activation with subsequent implantation in response to endocrine cues remains unclear. Here we review the first evidence that the proximal molecular control of embryonic diapause is conserved in three unrelated mammalian species which employ different endocrine programs to initiate diapause. In particular, uterine expression of muscle segment homeobox (Msx) genes Msx1 or Msx2 persists during diapause, followed by downregulation with blastocyst reactivation and implantation. Mice (Mus musculus) with conditional inactivation of Msx1 and Msx2 in the uterus fail to achieve diapause and reactivation. Remarkably, the mink (Neovison vison) and tammar wallaby (Macropus eugenii) share this pattern of MSX1 or MSX2 expression as in mice during delay - it persists during diapause and is rapidly downregulated upon implantation. Therefore, these findings were the first to provide evidence that there are common conserved molecular regulators in the uterus of unrelated mammals during embryonic diapause.

You Have Control: aviation communication application for safety-critical times in surgery.

High-risk organisations (HRO), including aviation, undergo formal communication training, with emphasis on safety-critical moments. Such training is not widespread or mandatory in healthcare, and while there are many differences both share the 'human element' with circumstances leading to an increased risk of harm. A typical operating theatre consists of an operating surgeon, and an assisting surgeon, roles that may change throughout the course of a procedure. Similarly, a training aircraft or multi-crew cockpit (flight deck) has a pilot in control, or 'pilot flying', and a 'pilot not flying'. Both interact with wider teams, for example the scrub team and air traffic controllers, respectively. Surgical error is the second most prevalent cause of preventable harm to patients after drug errors. Every year in the UK National Health Service (NHS), there are typically 500 never events, 21,000 serious incidents, and many more episodes of physical or psychological harm. Ineffective communication (46%) is the most common behavioural factor leading to a never event. In this review, we examine the concept of 'sterile cockpit', use of unambiguous terminology, callsigns, important information readback, sharing of mental models, and the mini-brief, and how these may be used to reduce patient harm during safety-critical moments.

Profiling cytotoxic microRNAs in pediatric and adult glioblastoma cells by high-content screening, identification, and validation of miR-1300.

MicroRNAs play an important role in the regulation of mRNA translation and have therapeutic potential in cancer and other diseases. To profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen in adult and pediatric GBM cells using a synthetic oligonucleotide library representing all known human microRNAs. Bioinformatics analysis was used to refine this list and the top seven microRNAs were validated in a larger panel of GBM cells using state-of-the-art in vitro assays. The cytotoxic effect of our most relevant candidate was assessed in a preclinical model. Our screen identified ~100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR-1300 transfected cells due to cytokinesis failure followed by apoptosis. This was also observed in two stem-like patient-derived cultures. We identified the physiological role of miR-1300 as a regulator of endomitosis in megakaryocyte differentiation where blockade of cytokinesis is an essential step. In GBM cells, where miR-1300 is normally not expressed, the oncogene Epithelial Cell Transforming 2 (ECT2) was validated as a direct key target. ECT2 siRNA phenocopied the effects of miR-1300, and ECT2 overexpression led to rescue of miR-1300 induced binucleation. We showed that ectopic expression of miR-1300 led to decreased tumor growth in an orthotopic GBM model. Our screen provides a resource for the neuro-oncology community and identified miR-1300 as a novel regulator of endomitosis with translatable potential for therapeutic application.

Kinetics of uranium(VI) lability and solubility in aerobic soils.

Uranium may pose a hazard to ecosystems and human health due to its chemotoxic and radiotoxic properties. The long half-life of many U isotopes and their ability to migrate raise concerns over disposal of radioactive wastes. This work examines the long-term U bioavailability in aerobic soils following direct deposition or transport to the surface and addresses two questions: (i) to what extent do soil properties control the kinetics of U speciation changes in soils and (ii) over what experimental timescales must U reaction kinetics be measured to reliably predict long-term of impact in the terrestrial environment? Soil microcosms spiked with soluble uranyl were incubated for 1.7 years. Changes in UVI fractionation were periodically monitored by soil extractions and isotopic dilution techniques, shedding light on the binding strength of uranyl onto the solid phase. Uranyl sorption was rapid and strongly buffered by soil Fe oxides, but UVI remained reversibly held and geochemically reactive. The pool of uranyl species able to replenish the soil solution through several equilibrium reactions is substantially larger than might be anticipated from typical chemical extractions and remarkably similar across different soils despite contrasting soil properties. Modelled kinetic parameters indicate that labile UVI declines very slowly, suggesting that the processes and transformations transferring uranyl to an intractable sink progress at a slow rate regardless of soil characteristics. This is of relevance in the context of radioecological assessments, given that soil solution is the key reservoir for plant uptake.

Human factors recognition at virtual meetings and video conferencing: how to get the best performance from yourself and others.

During the current coronavirus pandemic, social distancing and restrictions on travel have resulted in a dramatic rise in the use of technology (including video conferencing) for remote meetings. From local multidisciplinary team (MDT) meetings to national and international committees, this form of communication has been vital to ensure patient-related and other business can continue, albeit in a sometimes unfamiliar environment. In this article we consider some of the human factors elements of remote meetings and provide suggestions to enhance the experience of team and committee members during this unsettling time. It is possible that this form of communication will continue to flourish after the pandemic is over.

Cheek support affects lung mechanics measurements of tidal-based spontaneous breathing.

BACKGROUND AND OBJECTIVE: Patients are required to support their cheeks during breath-occluding lung function tests. This prevents cheek expansion which would alter pressure measured at the mouth, and, consequently, lung mechanics measurements. To date, the effect of cheek support on airway resistance measurements has been assessed. However other lung mechanics have not been studied as thoroughly, and no algorithm to account for the effect of missing cheek support on lung mechanics measurements has been developed. METHODS: Lung mechanics were assessed with a breath occlusion test during light panting in healthy subjects with and without cheek support in a body plethysmograph. Average model-based airway resistance, lung elastance, and a parameter representing the viscoelastic were measured. Results were compared to quantify the effect of cheek support on these three parameters. RESULTS: In the nine healthy subjects (5 Female, 4 Male) recruited for this study, all mechanics tended to be underestimated when cheeks were unsupported. Changes in elastance, resistance, and viscoelastic parameter ranged between 1.6-66.8 %, -4.5-21.8 %, and -4.7-68.2 %, respectively, when cheek support was added. The underestimation was due to reduced mouth pressure during cheek expansion when the breath was occluded. The variance of lung mechanics parameters did not change with cheek support in all subjects. CONCLUSIONS: The error in lung mechanics measurement caused by unsupported cheeks was subject dependent. Hence, no rule-of-thumb could be identified to reconstruct missing cheek support. For correct lung mechanics measurements during breath-occluding lung tests, patients must have adequate cheek support. ABBREVIATIONS: ROCC: Occlusion resistance; COPD: Chronic Obstructive Pulmonary Disorder; SB: spontaneous breathing.

Foot and ankle service adaptation in response to COVID-19 and beyond.

The disruption to healthcare provision as a result of the COVID-19 pandemic has compelled us to streamline healthcare delivery. This has given us an opportunity to implement healthcare technology, reform inter-disciplinary collaboration and ultimately enhance patient care. We discuss some of the advances made by the foot and ankle department at our hospital. These innovations have broad applicability and will hopefully ignite discussion amoung a number of healthcare teams about improving the future care of their patients.

Are COPD self-management mobile applications effective? A systematic review and meta-analysis.

The burden of chronic obstructive pulmonary disease (COPD) to patients and health services is steadily increasing. Self-management supported by mobile device applications could improve outcomes for people with COPD. Our aim was to synthesize evidence on the effectiveness of mobile health applications compared with usual care. A systematic review was conducted to identify randomized controlled trials. Outcomes of interest included exacerbations, physical function, and Quality of Life (QoL). Where possible, outcome data were pooled for meta-analyses. Of 1709 citations returned, 13 were eligible trials. Number of exacerbations, quality of life, physical function, dyspnea, physical activity, and self-efficacy were reported. Evidence for effectiveness was inconsistent between studies, and the pooled effect size for physical function and QoL was not significant. There was notable variation in outcome measures used across trials. Developing a standardized outcome-reporting framework for digital health interventions in COPD self-management may help standardize future research.

Moving Towards Common Data Elements and Core Outcome Measures in Frailty Research.

With aging populations around the world, frailty is becoming more prevalent increasing the need for health systems and social systems to deliver optimal evidence based care. However, in spite of the growing number of frailty publications, high-quality evidence for decision making is often lacking. Inadequate descriptions of the populations enrolled including frailty severity and frailty conceptualization, lack of use of validated frailty assessment tools, utilization of different frailty instruments between studies, and variation in reported outcomes impairs the ability to interpret, generalize and implement the research findings. The utilization of common data elements (CDEs) and core outcome measures (COMs) in clinical trials is increasingly being adopted to address such concerns. To catalyze the development and use of CDEs and COMs for future frailty studies, the Canadian Frailty Network (www.cfn-nce.ca; CFN), a not-for-profit pan-Canadian nationally-funded research network, convened an international group of experts to examine the issue and plan the path forward. The meeting was structured to allow for an examination of current frailty evidence, ability to learn from other COMs and CDEs initiatives, discussions about specific considerations for frailty COMs and CDEs and finally the identification of the necessary steps for a COMs and CDEs consensus initiative going forward. It was agreed at the onset of the meeting that a statement based on the meeting would be published and herein we report the statement.

Leading article: What can we do to improve individual and team situational awareness to benefit patient safety?

It is increasingly being recognised that human factors can contribute to error in complex safety systems. Healthcare, however, has a long way to go before the promotion of training in, and awareness of, human factors will catch up with other high-risk organisations. A critical component that is deemed essential both for improving clinical performance and reducing medical error is situational awareness (SA). This is dynamic and can reduce quickly or be lost entirely, particularly when the workload is heavy. Tunnel vision, in which healthcare professionals concentrate on a single aspect of a patient's care, is just one example of reduced awareness that can be detrimental to safety. As in aviation and other high-risk organisations, a reduction in SA, if not recognised by individuals or the wider team, can lead to serious or potentially fatal outcomes. We therefore give an overview of SA and show how it can easily be reduced. We also suggest some simple but effective ways to improve it and in turn improve patient safety. We emphasise the importance of clinical teams looking out for each other, particularly in the operating theatre.

Preterm birth phenotypes in women with autoimmune rheumatic diseases: a population-based cohort study.

OBJECTIVE: To investigate preterm birth (PTB) phenotypes in women with different autoimmune rheumatic diseases in a large population-based cohort. DESIGN: Retrospective cohort study. SETTING: California, USA. POPULATION: All live singleton births in California between 2007 and 2011 were analysed. Patients with autoimmune disease at delivery were identified by International Classification of Diseases, Ninth Revision , Clinical Modification (ICD-9-CM), codes for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and juvenile idiopathic arthritis (JIA). METHODS: Maternally linked hospital and birth certificate records of 2 481 516 deliveries were assessed (SLE n = 2272, RA n = 1501, SSc n = 88, JIA n = 187, DM/PM n = 38). Multivariable Poisson regression models estimated the risk ratios (RRs) for different PTB phenotypes (relative to term deliveries) for each autoimmune disease compared with the general obstetric population, adjusting for maternal age, race/ethnicity, body mass index, smoking, education, payer, parity, and prenatal care. MAIN OUTCOME MEASURES: Preterm birth (PTB) was assessed overall (20-36 weeks of gestation) and by subphenotype: preterm prelabour rupture of membranes (PPROM), spontaneous birth, or medically indicated PTB. The risk of PTB overall and for each phenotype was partitioned by gestational age: early (20-31 weeks of gestation) and late (32-36 weeks of gestation). RESULTS: Risks for PTB were elevated for each autoimmune disease evaluated: SLE (RR 3.27, 95% CI 3.01-3.56), RA (RR 2.04, 95% CI 1.79-2.33), SSc (RR 3.74, 95% CI 2.51-5.58), JIA (RR 2.23, 95% CI 1.54-3.23), and DM/PM (RR 5.26, 95% CI 3.12-8.89). These elevated risks were observed for the majority of PTB phenotypes as well. CONCLUSIONS: Women with systemic autoimmune diseases appear to have an elevated risk of various PTB phenotypes. Therefore, preconception counselling and close monitoring during pregnancy is crucial. TWEETABLE ABSTRACT: This study found that women with systemic autoimmune diseases have an elevated risk of preterm birth phenotypes.

Disease burden in offspring is associated with changing paternal demographics in the United States.

BACKGROUND: Average paternal age in the United States has increased substantially in the last few decades. Children of advanced age fathers have a higher incidence of early onset cancer and neuropsychiatric disease. OBJECTIVES: To quantify the number of population adjusted cases of early-onset cancer and neuropsychiatric disease in children attributable to increasing paternal age in the United States. METHODS: Paternal age in the United States from 1972 to 2015 was collected using the National Vital Statistics System (NVSS). Population attributable fraction and paternal age-specific cumulative incidence rates of several cancers and neuropsychiatric disorders were obtained from peer-reviewed publications. Paternal age-specific birth rates were correlated with paternal age-specific cumulative incidence rates to determine the number of attributable cases of disease caused by advancing age of fathers in the United States. RESULTS: The 2015 birth cohort in the United States is estimated to expect 9.2% more cases of acute lymphoblastic leukemia (ALL) diagnosed before 16 years of age (157 additional cases), 13.2% more cases of embryonal tumors in children <5 years of age (209 additional cases), and 13.0% more cases of breast cancer in females younger than 40 years old (424 additional cases) compared to the 1972 birth cohort. We can estimate to expect 10.5% more cases of schizophrenia diagnosed before 21 years of age (2864 additional cases), 6.3% more cases of autism spectrum disorder (ASD) in adolescents <17 years of age (2934 additional cases), 4.5% more cases of anorexia nervosa (AN) in females 8-30 years old (620 additional cases), and 9.2% more cases of bipolar disorder in young patients 16-25 years old (252 additional cases) in the 2015 birth cohort compared to the 1972 birth cohort. CONCLUSION: Increasing paternal age in the United States is associated with a substantial increase in the number of cases of early-onset cancer and neuropsychiatric disease in offspring.