Search

Background: We examined the feasibility and outcomes of Artificial Intelligence (AI) as a virtual coach in guided self-help (GSH-AI) compared to pure self-help (PSH). Method: Participants (N = 85 undergraduate university students; M age = 20.65 years [SD = 2.38]; 84 % female) were randomised to PSH (N = 42) or GSH-AI (N = 43). The intervention was a brief 11-module online cognitive behaviour therapy for perfectionism intervention completed over 4-weeks. GSH-AI participants were given suggested questions to ask AI for guidance in completing the intervention. Data were collected at baseline, 4- and 8-weeks post-randomisation. Results: Engagement was good, only one person in each group did not use any modules; module completion was equivalent across conditions (6.67, SD = 3.22 and 6.18, SD = 3.42 respectively). Between baseline and post-intervention people in the GSH-AI condition showed an almost 3.5 times increase in preferring support to be received from AI versus other modes of support. Only 52 % and 22 % of participants completed 4- and 8-week post-randomisation surveys, with no differences in psychological outcomes between the PSH and GSH-AI groups. Main effects of time indicated moderate to large within-group effect size improvements for disordered eating, stress, anxiety, and perfectionism. Conclusions: Qualitative feedback indicated that AI was initially acceptable as a guide and became even more acceptable after it had been experienced. Fully powered trials are required to determine the impact of AI guidance on outcomes, and whether type of AI platform (customised versus generic) and type of mental health disorder interact with its effects.

The Coastal and Marine Ecological Classification Standard (CMECS) was applied to four portions of Acadia National Park, USA, focusing on intertidal rocky and tidal flat habitats. Side-scan sonar coupled with multi-phase echo sounder bathymetry are the primary data sources used to map the seafloor, coupled with underwater video imagery and surface grab samples for grain size and macrofaunal analysis. The CMECS Substrate, Geoform, and Biotic components were effective in describing the study areas. However, integrating the CMECS components to define Biotopes was more challenging due to the limited number of grab samples available and because the dominant species within a given map unit is largely inconsistent. While Biotopes ultimately could not be defined in this study, working within the CMECS framework to create statistically significant biotopes revealed the complexity of these study areas that may otherwise have been overlooked. This study demonstrates the effectiveness of the CMECS classification, including the framework’s ability to be flexible in communicating information.

Perfectionism is a transdiagnostic process associated with a range of psychological disorders. Cognitive Behaviour Therapy for Perfectionism (CBT-P) has been demonstrated as efficacious across guided and unguided internet delivered interventions in reducing perfectionism and psychopathology. The aim of this pilot study was to understand perceptions and acceptability of an artificial intelligence supplemented CBT-P intervention (AI-CBT-P) in young people with lived experience of anxiety and depression (n = 8; age range 19–29 years, M = 24 years, SD = 3.77; 50 % female, 38 % male, 12 % non-binary). Young people reported that they were frequent users of artificial intelligence for study, work and general information, were positive about the intervention and using artificial intelligence for guidance in a self-help intervention, but also noted several concerns. Young people perceived numerous benefits to AI-CBT-P, including ease of access, low cost, lack of stigma and benefits for individuals with social anxiety. Overall, young people appear to be interested in, and have a positive view of, AI-CBT-P. Further research is now required to examine the feasibility and acceptability of the intervention.

Abstract Background Oesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations. Methods PALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy. Discussion This unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response. Trial registration Australian and New Zealand Clinical Trials Registry: ACTRN12619001371189 , registered 8 October 2019.

Plain English summary Many people with eating disorders (EDs) either do not access treatment, access it well after symptoms first start, or drop out of treatment. This study evaluated ways to improve early access to the best treatments for those with EDs in regional Australia. Links were formed between general medical practitioners and treatment providers (such as psychologists and dietitians) who received ongoing training, feedback and support. This approach achieved completion rates and outcomes equivalent to those found in specialised clinical trials of ED treatments. A key finding was the benefit of a care coordinator to connect users to services and help navigate barriers to ongoing treatment.

Abstract The Martian bow shock stands as the first defense against the solar wind and shapes the Martian magnetosphere. Previous studies showed the correlation between the Martian bow shock location and solar wind parameters. Here we present direct evidence of solar wind effects on the Martian bow shock by analyzing Tianwen‐1 and MAVEN data. We examined three cases where Tianwen‐1 data show rapid oscillations of the bow shock, while MAVEN data record changes in solar wind plasma and magnetic field. The results indicate that the bow shock is rapidly compressed and then expanded during the dynamic pressure pulse in the solar wind, and is also oscillated during the IMF rotation. The superposition of variations in multiple solar wind parameters leads to more intensive bow shock oscillation. This study emphasizes the importance of joint observations by Tianwen‐1 and MAVEN for studying the real‐time response of the Martian magnetosphere to the solar wind.

Abstract Background teen Mental Health First Aid (tMHFA) is a universal mental health literacy, stigma reduction, help-seeking, and suicide prevention program designed for adolescents in Years 10–12 of secondary school (16–18 years). tMHFA is delivered by trained instructors, in a regular classroom setting, to increase the knowledge, attitudes and behaviours that adolescents’ require to better support peers with mental health problems or mental health crises. Methods To explore the efficacy of tMHFA, a cluster crossover randomised controlled trial was conducted with Year 10 students in four schools in Victoria, Australia, using physical first aid training as the control intervention. Of the 1942 eligible students, 1,624 completed baseline and 894 completed follow-up surveys. Online surveys, administered one week before training and again 12-months later, included vignettes depicting peers John (depression and suicide risk) and Jeanie (social anxiety/phobia), measures of mental health first aid (quality of first aid intentions, confidence, first aid behaviours provided, and first aid behaviours received), mental health literacy (beliefs about adult help, help-seeking intentions), and stigma (social distance, weak-not-sick, dangerous/unpredictable, and would not tell anyone). Results The primary outcome—quality of first aid intentions towards the John vignette—showed statistically significant group x time interactions, with tMHFA students reporting more helpful and less unhelpful first aid intentions, than PFA students did over time. Confidence in providing first aid also showed significant interactions. First aid behaviours—both those provided to a peer with a mental health problem and those received from a peer—showed null results. Ratings of both beliefs about adult help and help-seeking intentions were found to be significantly improved among tMHFA students at follow-up. A group x time interaction was found on one stigma scale (would not tell anyone). Conclusions This trial showed that, one year after training, tMHFA improves first aid intentions towards peers with depression and suicide risk, confidence in helping peers with mental health problems, willingness to tell someone and seek help from an adult or health professional if experiencing a mental health problem. Trial registration This research was registered with Australia New Zealand Clinical Trials Registry: ACTRN12614000061639 .

It has been estimated that in the next decade, IHD prevalence, DALYs and deaths will increase more significantly in EMR than in any other region of the world. This study aims to provide a comprehensive description of the trends in the burden of ischemic heart disease (IHD) across the countries of the Eastern Mediterranean Region (EMR) from 1990 to 2019. Data on IHD prevalence, disability-adjusted life years (DALYs), mortality, DALYs attributable to risk factors, healthcare access and quality index (HAQ), and universal health coverage (UHC) were extracted from the Global Burden of Disease (GBD) database for EMR countries. The data were stratified based on the social demographic index (SDI). Information on cardiac rehabilitation was obtained from publications by the International Council of Cardiovascular Prevention and Rehabilitation (ICCPR), and additional country-specific data were obtained through advanced search methods. Age standardization was performed using the direct method, applying the estimated age structure of the global population from 2019. Uncertainty intervals were calculated through 1000 iterations, and the 2.5th and 97.5th percentiles were derived from these calculations. The age-standardized prevalence of IHD in the EMR increased from 5.0% to 5.5% between 1990 and 2019, while it decreased at the global level. In the EMR, the age-standardized rates of IHD mortality and DALYs decreased by 11.4% and 15.4%, respectively, during the study period, although both rates remained higher than the global rates. The burden of IHD was found to be higher in males compared to females. Bahrain exhibited the highest decrease in age-standardized prevalence (-3.7%), mortality (-65.0%), and DALYs (-69.1%) rates among the EMR countries. Conversely, Oman experienced the highest increase in prevalence (14.5%), while Pakistan had the greatest increase in mortality (30.0%) and DALYs (32.0%) rates. The top three risk factors contributing to IHD DALYs in the EMR in 2019 were high systolic blood pressure, high low-density lipoprotein cholesterol, and particulate matter pollution. The trend analysis over the 29-year period (1990-2019) revealed that high fasting plasma glucose (64.0%) and high body mass index (23.4%) exhibited increasing trends as attributed risk factors for IHD DALYs in the EMR. Our findings indicate an increasing trend in the prevalence of IHD and a decrease in mortality and DALYs in the EMR. These results emphasize the need for well-planned prevention and treatment strategies to address the risk factors associated with IHD. It is crucial for the countries in this region to prioritize the development and implementation of programs focused on health promotion, education, prevention, and medical care.

Abstract White‐nose syndrome (WNS) is a disease caused by the fungus Pseudogymnoascus destructans which has resulted in the deaths of millions of bats across eastern North America. To date, hibernacula counts have been the predominant means of tracking the spread and impact of this disease on bat populations. However, an understanding of the impacts of WNS on demographic parameters outside the winter season is critical to conservation and recovery of bat populations impacted by this disease. We used long‐term monitoring data to examine WNS‐related impacts to summer populations in West Virginia, where WNS has been documented since 2009. Using capture data from 290 mist‐net sites surveyed from 2003 to 2019 on the Monongahela National Forest, we estimated temporal patterns in presence and relative abundance for each bat species. For species that exhibited a population‐level response to WNS, we investigated post‐WNS changes in adult female reproductive state and body mass. Myotis lucifugus (little brown bat), M. septentrionalis (northern long‐eared bat), and Perimyotis subflavus (tri‐colored bat) all showed significant decreases in presence and relative abundance during and following the introduction of WNS, while Eptesicus fuscus (big brown bat) and Lasiurus borealis (eastern red bat) responded positively during the WNS invasion. Probability of being reproductively active was not significantly different for any species, though a shift to earlier reproduction was estimated for E. fuscus and M. septentrionalis. For some species, body mass appeared to be influenced by the WNS invasion, but the response differed by species and reproductive state. Results suggest that continued long‐term monitoring studies, additional research into impacts of this disease on the fitness of WNS survivors, and a focus on providing optimal nonwintering habitat may be valuable strategies for assessing and promoting recovery of WNS‐affected bat populations.

Neurocognitive consequences of blast-induced traumatic brain injury (bTBI) pose significant concerns for military service members and veterans with the majority of “invisible injury.” However, the underlying mechanism of such mild bTBI by low-intensity blast (LIB) exposure for long-term cognitive and mental deficits remains elusive. Our previous studies have shown that mice exposed to LIB result in nanoscale ultrastructural abnormalities in the absence of gross or apparent cellular damage in the brain. Here we tested the hypothesis that glutamatergic hyperexcitability may contribute to long-term learning deficits. Using brain slice electrophysiological recordings, we found an increase in averaged frequencies with a burst pattern of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal CA3 neurons in LIB-exposed mice at 1- and 7-days post injury, which was blocked by a specific NMDA receptor antagonist AP5. In addition, cognitive function assessed at 3-months post LIB exposure by automated home-cage monitoring showed deficits in dynamic patterns of discrimination learning and cognitive flexibility in LIB-exposed mice. Collected hippocampal tissue was further processed for quantitative global-proteomic analysis. Advanced data-independent acquisition for quantitative tandem mass spectrometry analysis identified altered expression of proteins involved in synaptic plasticity and serine protease inhibitors in LIB-exposed mice. Some were correlated with the ability of discrimination learning and cognitive flexibility. These findings show that acute glutamatergic hyperexcitability in the hippocampus induced by LIB may contribute to long-term cognitive dysfunction and protein alterations. Studies using this military-relevant mouse model of mild bTBI provide valuable insights into developing a potential therapeutic strategy to ameliorate hyperexcitability-modulated LIB injuries.

Abstract Pulmonary arterial hypertension (PAH) is characterized by increased resistance in the pulmonary arterioles as a result of remodeled blood vessels. We sought all available epidemiologic data on population‐based prevalence, incidence, and 1‐year survival of PAH as part of the Global Burden of Disease Study. We performed a systematic review searching Global Index Medicus (GIM) for keywords related to PAH between 1980 and 2021 and identified population‐representative sources of prevalence, incidence, and mortality for clinically diagnosed PAH. Of 6772 articles identified we found 65 with population‐level data: 17 for prevalence, 17 for incidence, and 58 reporting case fatality. Reported prevalence ranged from 0.37 cases/100,000 persons in a referral center of French children to 15 cases/100,000 persons in an Australian study. Reported incidence ranged from 0.008 cases/100,000 person‐years in Finland, to 1.4 cases/100,000 person‐years in a retrospective chart review at a clinic in Utah, United States. Reported 1‐year survival ranged from 67% to 99%. All studies with sex‐specific estimates of prevalence or incidence reported higher levels in females than males. Studies varied in their size, study design, diagnostic criteria, and sampling procedures. Reported PAH prevalence, incidence, and mortality varied by location and study. Prevalence ranged from 0.4 to 1.4 per 100,000 persons. Harmonization of methods for PAH registries would improve efforts at disease surveillance. Results of this search contribute to ongoing efforts to quantify the global burden of PAH.

Detecting the presence of prostate cancer (PCa) and distinguishing low- or intermediate-risk disease from high-risk disease early, and without the need for potentially unnecessary invasive biopsies remains a significant clinical challenge. The aim of this study is to determine whether the T and B cell phenotypic features which we have previously identified as being able to distinguish between benign prostate disease and PCa in asymptomatic men having Prostate-Specific Antigen (PSA) levels < 20 ng/ml can also be used to detect the presence and clinical risk of PCa in a larger cohort of patients whose PSA levels ranged between 3 and 2617 ng/ml. The peripheral blood of 130 asymptomatic men having elevated Prostate-Specific Antigen (PSA) levels was immune profiled using multiparametric whole blood flow cytometry. Of these men, 42 were subsequently diagnosed as having benign prostate disease and 88 as having PCa on biopsy-based evidence. We built a bidirectional Long Short-Term Memory Deep Neural Network (biLSTM) model for detecting the presence of PCa in men which combined the previously-identified phenotypic features (CD8+CD45RA-CD27-CD28- (CD8+ Effector Memory cells), CD4+CD45RA-CD27-CD28- (CD4+ Effector Memory cells), CD4+CD45RA+CD27-CD28- (CD4+ Terminally Differentiated Effector Memory Cells re-expressing CD45RA), CD3-CD19+ (B cells), CD3+CD56+CD8+CD4+ (NKT cells) with Age. The performance of the PCa presence ‘detection’ model was: Acc: 86.79 ( ± 0.10), Sensitivity: 82.78% (± 0.15); Specificity: 95.83% (± 0.11) on the test set (test set that was not used during training and validation); AUC: 89.31% (± 0.07), ORP-FPR: 7.50% (± 0.20), ORP-TPR: 84.44% (± 0.14). A second biLSTM ‘risk’ model combined the immunophenotypic features with PSA to predict whether a patient with PCa has high-risk disease (defined by the D’Amico Risk Classification) achieved the following: Acc: 94.90% (± 6.29), Sensitivity: 92% (± 21.39); Specificity: 96.11 (± 0.00); AUC: 94.06% (± 10.69), ORP-FPR: 3.89% (± 0.00), ORP-TPR: 92% (± 21.39). The ORP-FPR for predicting the presence of PCa when combining FC+PSA was lower than that of PSA alone. This study demonstrates that AI approaches based on peripheral blood phenotyping profiles can distinguish between benign prostate disease and PCa and predict clinical risk in asymptomatic men having elevated PSA levels.

We demonstrate that prostate cancer can be identified by flow cytometric profiling of blood immune cell subsets. Herein, we profiled natural killer (NK) cell subsets in the blood of 72 asymptomatic men with Prostate-Specific Antigen (PSA) levels < 20 ng ml-1, of whom 31 had benign disease (no cancer) and 41 had prostate cancer. Statistical and computational methods identified a panel of eight phenotypic features ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]) that, when incorporated into an Ensemble machine learning prediction model, distinguished between the presence of benign prostate disease and prostate cancer. The machine learning model was then adapted to predict the D’Amico Risk Classification using data from 54 patients with prostate cancer and was shown to accurately differentiate between the presence of low-/intermediate-risk disease and high-risk disease without the need for additional clinical data. This simple blood test has the potential to transform prostate cancer diagnostics.

The phenomenon of combustible dust explosions is present within many industries. Tests for explosibility of dust clouds per ASTM E1226 use a 20 L explosive chamber that places the combustible dust directly below the dispersion nozzle which generates a thorough mixture for testing purposes. However, in the underground coal mining industry, there are a number of geologic, mining, and regulatory factors that change the deposition scheme of combustible coal dust. This causes the atmosphere of a coal mine to have a variable rock dust-coal dust mixture at the time of ignition. To investigate the impact of this variable atmosphere, a series of lean explosibility tests were conducted on a sample of Pittsburgh Pulverized coal dust. These explosibility tests were conducted in a 38 L chamber with a 5 kJ Sobbe igniter. The 38 L chamber generates a variable air-dust mixture prior to ignition. The test results indicate that the 38 L chamber experiences reduced explosive pressures, and lower explosibility index values when compared to the 20 L chamber. Keywords: Dust explosion, Coal mining, Coal dust, Explosibility testing

An individual’s social network—their friends, family, and acquaintances—is important for their health, but existing tools for assessing social networks have limitations. Here, the authors introduce a quantitative social network assessment tool on a secure open-source web platform and show its utility in a nation-wide study.

Loss of the genome maintenance factor Elg1 causes serious genome instability that leads to cancer, but the underlying mechanism is unknown. Elg1 forms the major subunit of a replication factor C-like complex, Elg1-RLC, which unloads the ring-shaped polymerase clamp PCNA from DNA during replication. Here, we show that prolonged retention of PCNA on DNA into G2/M phase is the major cause of genome instability in elg1Δ yeast. Overexpression-induced accumulation of PCNA on DNA causes genome instability. Conversely, disassembly-prone PCNA mutants that relieve PCNA accumulation rescue the genome instability of elg1Δ cells. Covalent modifications to the retained PCNA make only a minor contribution to elg1Δ genome instability. By engineering cell-cycle-regulated ELG1 alleles, we show that abnormal accumulation of PCNA on DNA during S phase causes moderate genome instability and its retention through G2/M phase exacerbates genome instability. Our results reveal that PCNA unloading by Elg1-RLC is critical for genome maintenance.

Summary: Background: The burden of cardiovascular diseases is increasing in India, but a systematic understanding of its distribution and time trends across all the states is not readily available. In this report, we present a detailed analysis of how the patterns of cardiovascular diseases and major risk factors have changed across the states of India between 1990 and 2016. Methods: We analysed the prevalence and disability-adjusted life-years (DALYs) due to cardiovascular diseases and the major component causes in the states of India from 1990 to 2016, using all accessible data sources as part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. We placed states into four groups based on epidemiological transition level (ETL), defined using the ratio of DALYs from communicable diseases to those from non-communicable diseases and injuries combined, with a low ratio denoting high ETL and vice versa. We assessed heterogeneity in the burden of major cardiovascular diseases across the states of India, and the contribution of risk factors to cardiovascular diseases. We calculated 95% uncertainty intervals (UIs) for the point estimates. Findings: Overall, cardiovascular diseases contributed 28·1% (95% UI 26·5–29·1) of the total deaths and 14·1% (12·9–15·3) of the total DALYs in India in 2016, compared with 15·2% (13·7–16·2) and 6·9% (6·3–7·4), respectively, in 1990. In 2016, there was a nine times difference between states in the DALY rate for ischaemic heart disease, a six times difference for stroke, and a four times difference for rheumatic heart disease. 23·8 million (95% UI 22·6–25·0) prevalent cases of ischaemic heart disease were estimated in India in 2016, and 6·5 million (6·3–6·8) prevalent cases of stroke, a 2·3 times increase in both disorders from 1990. The age-standardised prevalence of both ischaemic heart disease and stroke increased in all ETL state groups between 1990 and 2016, whereas that of rheumatic heart disease decreased; the increase for ischaemic heart disease was highest in the low ETL state group. 53·4% (95% UI 52·6–54·6) of crude deaths due to cardiovascular diseases in India in 2016 were among people younger than 70 years, with a higher proportion in the low ETL state group. The leading overlapping risk factors for cardiovascular diseases in 2016 included dietary risks (56·4% [95% CI 48·5–63·9] of cardiovascular disease DALYs), high systolic blood pressure (54·6% [49·0–59·8]), air pollution (31·1% [29·0–33·4]), high total cholesterol (29·4% [24·3–34·8]), tobacco use (18·9% [16·6–21·3]), high fasting plasma glucose (16·7% [11·4–23·5]), and high body-mass index (14·7% [8·3–22·0]). The prevalence of high systolic blood pressure, high total cholesterol, and high fasting plasma glucose increased generally across all ETL state groups from 1990 to 2016, but this increase was variable across the states; the prevalence of smoking decreased during this period in all ETL state groups. Interpretation: The burden from the leading cardiovascular diseases in India—ischaemic heart disease and stroke—varies widely between the states. Their increasing prevalence and that of several major risk factors in every part of India, especially the highest increase in the prevalence of ischaemic heart disease in the less developed low ETL states, indicates the need for urgent policy and health system response appropriate for the situation in each state. Funding: Bill & Melinda Gates Foundation; and Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India.

Background: Interactions between the immune system and tumors are highly reciprocal in nature, leading to speculation that tumor recurrence or therapeutic resistance could be influenced or predicted by immune events that manifest locally, but can be detected systemically.Methods: Multi-parameter flow cytometry was used to examine the percentage and phenotype of natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), monocyte subsets and regulatory T (Treg) cells in the peripheral blood of of 85 patients with breast cancer (50 of whom were assessed before and after one cycle of anthracycline-based chemotherapy), and 23 controls. Transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) in 23 patients were generated using a NanoString gene profiling platform.Results: An increased percentage of immunosuppressive cells such as granulocytic MDSCs, intermediate CD14++CD16+ monocytes and CD127negCD25highFoxP3+ Treg cells was observed in patients with breast cancer, especially patients with stage 3 and 4 disease, regardless of ER status. Following neoadjuvant chemotherapy, B cell numbers decreased significantly, whereas monocyte numbers increased. Although chemotherapy had no effect on the percentage of Treg, MDSC and NK cells, the expression of inhibitory receptors CD85j, LIAR and NKG2A and activating receptors NKp30 and NKp44 on NK cells increased, concomitant with a decreased expression of NKp46 and DNAM-1 activating receptors. Transcriptomic profiling revealed a distinct group of 3 patients in the triple negative breast cancer (TNBC) cohort who expressed high levels of mRNA encoding genes predominantly involved in inflammation. The analysis of a large transcriptomic dataset derived from the tumors of patients with TNBC revealed that the expression of CD163, CXCR4, THBS1 predicted relapse-free survival.Conclusions: The peripheral blood immunome of patients with breast cancer is influenced by the presence and stage of cancer, but not by molecular subtypes. Furthermore, immune profiling coupled with transcriptomic analyses of peripheral blood cells may identify patients with TNBC that are at risk of relapse after chemotherapy.

Objective: There is global imperative to reduce the burden of noncommunicable diseases (NCD′s). NCD′s are the leading cause of death and disability globally. In Australia, 2010, the World Health Organization estimated cancer deaths attributable to NCD′s accounted for approximately 29% of all deaths and most are preventable by modifying lifestyle associated risk factors. The International Council of Nurses (2010) identified nurses are ideally placed to contribute to prevention and control of NCD′s through evidence based strategies (EBS). The aim of this study was to explore the Australian cancer nurses role, knowledge, and skills to prevent and control NCD′s. Methods: We used nonprobability snowball sampling to collect data from an online survey distributed to 899 members of the Cancer Nurses Society of Australia. Results: Two hundred and fifty-seven nurses responded; >90% found it is within the scope of their role to contribute to prevention and control of NCDs, >70% assess for modifiable risk factors, >85% refer to support services, and 70% were interested in spending more time addressing prevention. Over 60% indicated they had adequate resources, appropriate personal skills, and adequate knowledge; however 73% felt they had inadequate time to incorporate strategies within their existing workload, 56% believed their physical environment was inadequate, and 48% felt a lack of culturally appropriate resources were identified as barrier to contributing to the prevention and control of NCDs. Conclusions: Australian cancer nurses want to contribute to the prevention and control of NCD′s although workload, physical environment, and culturally inadequate resources hinder the implementation of EBS to combat NCD′s.

The mechanistic Target of Rapamycin complex 1 (mTORC1) senses intracellular amino acid levels through an intricate machinery, which includes the Rag GTPases, Ragulator and vacuolar ATPase (V-ATPase). The membrane-associated E3 ubiquitin ligase ZNRF2 is released into the cytosol upon its phosphorylation by Akt. In this study, we show that ZNRF2 interacts with mTOR on membranes, promoting the amino acid-stimulated translocation of mTORC1 to lysosomes and its activation in human cells. ZNRF2 also interacts with the V-ATPase and preserves lysosomal acidity. Moreover, knockdown of ZNRF2 decreases cell size and cell proliferation. Upon growth factor and amino acid stimulation, mTORC1 phosphorylates ZNRF2 on Ser145, and this phosphosite is dephosphorylated by protein phosphatase 6. Ser145 phosphorylation stimulates vesicle-to-cytosol translocation of ZNRF2 and forms a novel negative feedback on mTORC1. Our findings uncover ZNRF2 as a component of the amino acid sensing machinery that acts upstream of Rag-GTPases and the V-ATPase to activate mTORC1.

Phytoplankton community structure and phytoplankton size class (PSC) are linked to ecological and biogeochemical changes in the oceanic environment. Many models developed to obtain the fraction of PSCs from satellite remote sensing have only been evaluated in open oceans, and very limited effort has been carried out to report on the performance of these PSC models in productive continental shelf waters. In this study, we evaluated the performance of nine PSC models in the coastal Northwest Atlantic (NWA) by comparison of in situ phytoplankton pigment measurements with coincidental satellite data from the Sea-Viewing Wide Field-of-View Sensor (SeaWiFS), Moderate-resolution Imaging Spectroradiometer (MODIS), and the Visible Infrared Imaging Radiometer Suite (VIIRS). Our results show that no PSC model retrieved all three phytoplankton size classes (pico-, nano-, and micro-phytoplankton) with reliable accuracy in the region of interest. In particular, these PSC models showed poor performance for retrieval of the picophytoplankton fraction of total phytoplankton in our study region, which could be related to the under-representation of pico-dominated samples in the productive waters of the NWA. For the accuracy of retrieved microphytoplankton and combined nano–pico phytoplankton fraction, the regional model developed by Devred et al. (2011) yielded the best result, followed by the model of Brewin et al. (2011). The model of Devred et al. (2011) was applied to satellite-derived chlorophyll-a concentration from the Ocean Color Climate Change Initiative (OC-CCI) archive in the NWA from 1998 to 2016. We report solely on the microphytoplankton biomass and fraction given the inverse relationship that exists with the nano–pico class. The multi-decadal trend along with the deseasonalized trend of microphytoplankton fraction was computed and analyzed for six biogeochemical provinces located in the NWA. Over the 19-year time series, there were significant, positive trends for four of the six provinces, with a slope of 0.36%·yr−1 in the Northwest Continental Shelf (NWCS), 0.25%·yr−1 in the Arctic Waters (ARCT), 0.12%·yr−1 in the Slope Waters (SW) and 0.06%·yr−1 in the Gulf Stream (GFST). Strong positive anomalies of microphytoplankton fraction were found in winter months in NWCS between 2009 and 2014, which could be associated with changes in environmental factors.

The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey has become a key metric used by organizations and patients to evaluate patient experience. Readmissions also continue to be a metric used to evaluate performance because of the added cost to both healthcare systems and patients. Both measures are also seen in programs such as Value Based Purchasing that have an effect on hospital reimbursements. Previous studies have demonstrated a relationship between patient perceptions and quality of care, and have found patients to be reliable evaluators of their care. While good communication and positive provider relationships have been related to higher satisfaction and higher rates of treatment compliance, past research has been limited to evaluating the relationship between readmissions and satisfaction at an organizational level. This retrospective, cross-sectional study will examine the relationship between communication and discharge HCAHPS questions and readmissions at 30 days, specifically at the patient level. Of the eight HCAHPS questions analyzed, higher scores on questions regarding “nurses listening” and “doctors explaining information” were linked to a decreased risk of readmission, while higher scores regarding “help after discharge” were linked to an increased risk for readmission. These results show the importance that a patient’s severity of illness and hospital procedures have on explaining HCAHPS results. This study’s seemingly paradoxical findings suggest the need to recognize potential trade-offs when reviewing HCAHPS results and using them to drive patient experience initiatives.

14-3-3 proteins regulate cellular responses to stimuli by docking onto pairs of phosphorylated residues on target proteins. The present study shows that the human 14-3-3-binding phosphoproteome is highly enriched in 2R-ohnologues, which are proteins in families of two to four members that were generated by two rounds of whole genome duplication at the origin of the vertebrates. We identify 2R-ohnologue families whose members share a ‘lynchpin’, defined as a 14-3-3-binding phosphosite that is conserved across members of a given family, and aligns with a Ser/Thr residue in pro-orthologues from the invertebrate chordates. For example, the human receptor expression enhancing protein (REEP) 1–4 family has the commonest type of lynchpin motif in current datasets, with a phosphorylatable serine in the –2 position relative to the 14-3-3-binding phosphosite. In contrast, the second 14-3-3-binding sites of REEPs 1–4 differ and are phosphorylated by different kinases, and hence the REEPs display different affinities for 14-3-3 dimers. We suggest a conceptual model for intracellular regulation involving protein families whose evolution into signal multiplexing systems was facilitated by 14-3-3 dimer binding to lynchpins, which gave freedom for other regulatory sites to evolve. While increased signalling complexity was needed for vertebrate life, these systems also generate vulnerability to genetic disorders.

Declaring "replication" from results of genome wide association (GWA) studies is straightforward when major gene effects provide genome-wide significance for association of the same allele of the same SNP in each of multiple independent samples. However, such unambiguous replication is unlikely when phenotypes display polygenic genetic architecture, allelic heterogeneity, locus heterogeneity and when different samples display linkage disequilibria with different fine structures. We seek chromosomal regions that are tagged by clustered SNPs that display nominally-significant association in each of several independent samples. This approach provides one "nontemplate" approach to identifying overall replication of groups of GWA results in the face of difficult genetic architectures. We apply this strategy to 1 M SNP GWA results for dependence on: a) alcohol (including many individuals with dependence on other addictive substances) and b) at least one illegal substance (including many individuals dependent on alcohol). This approach provides high confidence in rejecting the null hypothesis that chance alone accounts for the extent to which clustered, nominally-significant SNPs from samples of the same racial/ethnic background identify the same sets of chromosomal regions. It identifies several genes that are also reported in other independent alcohol-dependence GWA datasets. There is more modest confidence in: a) identification of individual chromosomal regions and genes that are not also identified by data from other independent samples, b) the more modest overlap between results from samples of different racial/ethnic backgrounds and c) the extent to which any gene not identified herein is excluded, since the power of each of these individual samples is modest. Nevertheless, the strong overlap identified among the samples with similar racial/ethnic backgrounds supports contributions to individual differences in vulnerability to addictions that come from newer allelic variants that are common in subsets of current humans.

BackgroundVulnerabilities to dependence on addictive substances are substantially heritable complex disorders whose underlying genetic architecture is likely to be polygenic, with modest contributions from variants in many individual genes. "Nontemplate" genome wide association (GWA) approaches can identity groups of chromosomal regions and genes that, taken together, are much more likely to contain allelic variants that alter vulnerability to substance dependence than expected by chance.Methodology/principal findingsWe report pooled "nontemplate" genome-wide association studies of two independent samples of substance dependent vs control research volunteers (n = 1620), one European-American and the other African-American using 1 million SNP (single nucleotide polymorphism) Affymetrix genotyping arrays. We assess convergence between results from these two samples using two related methods that seek clustering of nominally-positive results and assess significance levels with Monte Carlo and permutation approaches. Both "converge then cluster" and "cluster then converge" analyses document convergence between the results obtained from these two independent datasets in ways that are virtually never found by chance. The genes identified in this fashion are also identified by individually-genotyped dbGAP data that compare allele frequencies in cocaine dependent vs control individuals.Conclusions/significanceThese overlapping results identify small chromosomal regions that are also identified by genome wide data from studies of other relevant samples to extents much greater than chance. These chromosomal regions contain more genes related to "cell adhesion" processes than expected by chance. They also contain a number of genes that encode potential targets for anti-addiction pharmacotherapeutics. "Nontemplate" GWA approaches that seek chromosomal regions in which nominally-positive associations are found in multiple independent samples are likely to complement classical, "template" GWA approaches in which "genome wide" levels of significance are sought for SNP data from single case vs control comparisons.