Search

Surgical repair in anomalous aortic origin of a coronary artery aims at mitigating the risk of sudden cardiac death in a subset of patients. The pattern and behavior of electrocardiogram changes in a large cohort of these patients are lacking. We aim to describe postoperative electrocardiogram changes in this population and its clinical implications on follow-up.All patients aged less than 21 years who underwent surgical repair for anomalous aortic origin of a coronary artery between December 2012 and June 2020 at our institution were considered for inclusion. Electrocardiograms were reviewed at 5 defined time intervals, from preoperative to 90-day follow-up, with attention to significant findings of ST-segment changes, abnormal T waves, and pathologic Q waves. The electrocardiogram changes were analyzed for correlation with surgical reintervention and medium-term outcomes.Sixty-two patients met inclusion criteria (median age 13.7 years, 61% male). ST-segment changes in the initial postoperative period were seen in 52 patients (84%), all resolving over time. Abnormal T waves were seen in 19 patients (31%), occurred commonly at the predischarge period, and mostly resolved over time. Pathologic Q waves were observed in only 1 patient and associated with reintervention due to coronary artery stenosis. There was no association between postoperative electrocardiogram changes and inducible myocardial ischemia, ventricular dysfunction, or restriction from exercise at follow-up.ST-segment changes and T-wave abnormalities are commonly seen in the postoperative period after anomalous aortic origin of a coronary artery repair, tend to resolve over time, and are not associated with adverse medium-term outcomes. Pathologic Q waves were associated with the need for early coronary reintervention.

In proliferating cells and tissues a number of checkpoints (G1/S and G2/M) preceding cell division (M-phase) require the signal provided by growth factors present in serum. IGFs (I and II) have been demonstrated to constitute key intrinsic components of the peptidic active fraction of mammalian serum. In vivo genetic ablation studies have shown that the cellular signal triggered by the IGFs through their cellular receptors represents a non-replaceable requirement for cell growth and cell cycle progression. Retroactive and current evaluation of published literature sheds light on the intracellular circuitry activated by these factors providing us with a better picture of the pleiotropic mechanistic actions by which IGFs regulate both cell size and mitogenesis under developmental growth as well as in malignant proliferation. The present work aims to summarize the cumulative knowledge learned from the IGF ligands/receptors and their intracellular signaling transducers towards control of cell size and cell-cycle with particular focus to their actionable circuits in human cancer. Furthermore, we bring novel perspectives on key functional discriminants of the IGF growth-mitogenic pathway allowing re-evaluation on some of its signal components based upon established evidences.

Monopile mounted offshore wind turbines (OWTs) are expected to experience a very large number of cyclic loads throughout their operational lifetime, and the existing p–y method of foundation modelling does not fully account for the effects of dynamic cyclic loading, such as pile–soil gapping. In this paper a dynamic model based on the beam on non-linear Winkler foundation scheme with a novel algorithm capable of capturing the effects of pile–soil gapping is presented. It can account for gap cave-in, and the resulting gap size can react dynamically to changing loading amplitudes, using only two calibration parameters. Static and dynamic cyclic loaded model validations are presented, and give very good agreement with experimental results, performing better than existing p–y curves for dynamic loading. The model is also applied to an OWT case study and predictions of natural frequency reduction due to soil erosion agree well with measured results. It is shown that the inclusion of gapping may result in a significant decrease to the natural frequency prediction of OWTs relative to the value predicted without gapping. As such, not to consider gapping could lead to unconservative predictions, and any additional soil degradation throughout the serviceable lifetime could therefore result in unwanted resonance. The method provided in this paper provides a simple and accurate model to predict this behaviour which is crucial to ascertain during the design phase.

EphB4 angiogenic kinase over-expression in Mesothelioma cells relies upon a degradation rescue signal provided by autocrine IGF-II activation of Insulin Receptor A. However, the identity of the molecular machinery involved in EphB4 rapid degradation upon IGF-II signal deprivation are unknown. Using targeted proteomics, protein–protein interaction methods, PCR cloning, and 3D modeling approaches, we identified a novel ubiquitin E3 ligase complex recruited by the EphB4 C tail upon autocrine IGF-II signal deprivation. We show this complex to contain a previously unknown N-Terminal isoform of Deltex3 E3-Ub ligase (referred as “DTX3c”), along with UBA1(E1) and UBE2N(E2) ubiquitin ligases and the ATPase/unfoldase Cdc48/p97. Upon autocrine IGF-II neutralization in cultured MSTO211H (a Malignant Mesothelioma cell line that is highly responsive to the EphB4 degradation rescue IGF-II signal), the inter-molecular interactions between these factors were enhanced and their association with the EphB4 C-tail increased consistently with the previously described EphB4 degradation pattern. The ATPase/unfoldase activity of Cdc48/p97 was required for EphB4 recruitment. As compared to the previously known isoforms DTX3a and DTX3b, a 3D modeling analysis of the DTX3c Nt domain showed a unique 3D folding supporting isoform-specific biological function(s). We shed light on the molecular machinery associated with autocrine IGF-II regulation of oncogenic EphB4 kinase expression in a previously characterized IGF-II+/EphB4+ Mesothelioma cell line. The study provides early evidence for DTX3 Ub-E3 ligase involvement beyond the Notch signaling pathway.

Mitochondrial DNA (mtDNA) content has been shown to be associated with cancer susceptibility. We identified 926 bladder cancer patients and compared these with 926 healthy controls frequency matched on age, gender, and ethnicity. Patients diagnosed with bladder cancer had significantly decreased mtDNA content when compared with control subjects (median, 0.98 vs. 1.04, P < 0.001). Low mtDNA content (i.e., less than the median in control subjects) was associated with a statistically significant increased risk of bladder cancer, when compared with high mtDNA content [Odds ratio (OR), 1.37; 95% confidence interval (CI), 1.13–1.66; P < 0.001). In a trend analysis, a statistically significant dose–response relationship was detected between lower mtDNA content and increasing risk of bladder cancer (Ptrend 65 years), male sex and positive smoking history were significantly associated with low mtDNA content and increased risk of bladder cancer. We identified two unique mtDNA polymorphisms significantly associated with risk of bladder cancer: mitot10464c (OR, 1.39; 95% CI, 1.00–1.93; P = 0.048) and mitoa4918g (OR, 1.40; 95% CI, 1.00–1.95; P = 0.049). Analysis of the joint effect of low mtDNA content and unfavorable mtDNA polymorphisms revealed a 2.5-fold increased risk of bladder cancer (OR, 2.50; 95% CI, 1.60–3.94; P < 0.001). Significant interaction was observed between mitoa4918g and mtDNA content (Pinteraction = 0.028). Low mtDNA content was associated with increased risk of bladder cancer and we identified new susceptibility mtDNA alleles associated with increased risk that require further investigation into the biologic underpinnings of bladder carcinogenesis. Cancer Prev Res; 8(7); 607–13. ©2015 AACR.

Supplemental Table 1. Association of bladder cancer with mtDNA copy number stratified by gender

There is an unmet need for development of non-invasive tests for the diagnostic assessment and monitoring of nonalcoholic fatty liver disease (NAFLD).Using modified-aptamer proteomics, we assayed 5220 proteins in each of 2852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models for clinically relevant severity of steatosis (grade 0 vs 1-3), hepatocellular ballooning (0 vs 1 or 2), lobular inflammation (0-1 versus 2-3) and fibrosis (stages 0-1 vs 2-4).Results for the 4 protein models, based on 37 analytes (18 not previously linked to NAFLD), in training/paired validation were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at risk NASH, defined as steatohepatitis with NAS ≥ 4 with one or more points in each of the components and fibrosis stage 2 or higher, was created by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid (OCA). Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and OCA were identified.Serum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD.Individuals with NASH may have liver inflammation and scarring, along with fat in their liver, all of which are assessed by liver biopsy. In this study, we use an innovative protein scanning technology to develop and validate blood-based signatures of liver damage that have the potential to replace liver biopsy for NASH diagnosis and monitoring response to treatment. These signatures can also provide NASH drug developers with insights into treatment-mediated responses and mechanisms of action.An aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of nonalcoholic steatohepatitis for which there are no approved non-invasive diagnostic tools currently available. Specific protein signatures related to presence and severity of NASH and its histological components that were also sensitive to change over time were identified. These are fundamental initial steps in establishing a serum-proteome based diagnostic signature of NASH and provide a rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NASH.Not applicable.

A new study combines large-scale proteomics and machine learning to identify proteins that can be used to identify individuals with isolated impaired glucose tolerance, who would otherwise only be detectable with oral glucose tolerance tests.The implementation of recommendations for type 2 diabetes (T2D) screening and diagnosis focuses on the measurement of glycated hemoglobin (HbA1c) and fasting glucose. This approach leaves a large number of individuals with isolated impaired glucose tolerance (iIGT), who are only detectable through oral glucose tolerance tests (OGTTs), at risk of diabetes and its severe complications. We applied machine learning to the proteomic profiles of a single fasted sample from 11,546 participants of the Fenland study to test discrimination of iIGT defined using the gold-standard OGTTs. We observed significantly improved discriminative performance by adding only three proteins (RTN4R, CBPM and GHR) to the best clinical model (AUROC = 0.80 (95% confidence interval: 0.79-0.86), P = 0.004), which we validated in an external cohort. Increased plasma levels of these candidate proteins were associated with an increased risk for future T2D in an independent cohort and were also increased in individuals genetically susceptible to impaired glucose homeostasis and T2D. Assessment of a limited number of proteins can identify individuals likely to be missed by current diagnostic strategies and at high risk of T2D and its complications.

Objective Transarterial radioembolization (TARE) offers a minimally invasive and safe treatment option for primary and metastatic hepatic malignancies. The benefits of TARE are manifold including prolonged overall survival, low associated morbidities, and improved time to progression allowing prolonged treatment-free intervals. The rapid development of new systemic therapies including immunotherapy has radically changed the treatment landscape for primary and metastatic liver cancer. Given the current climate, it is critical for interventional oncologists to understand the benefits of TARE relative to these other therapies. Therefore, this report aims to review quality-of-life outcomes and the cost comparisons of TARE as compared with systemic therapies.

Objectives As we pass the anniversary of the declaration of a global pandemic by the World Health Organisation, it invites us to reflect upon the inescapable changes that coronavirus has wrought upon ENT and, in particular, rhinological practice. As it remains unclear when we will globally emerge from the shadow of COVID-19, a critical analysis of the evidence base on both the assessment and mitigation of risk is vital for ENT departments worldwide. This article presents a systematic review of the literature examining articles which consider either the quantification of risk or strategies to mitigate risk specifically in the setting of rhinological surgery. Design Systematic literature review. Results The literature search yielded a total of 3406 returns with 24 articles meeting eligibility criteria. A narrative synthesis stratified results into two broad themes: (1) those which made an assessment as to the aerosolisation of droplets during sinus surgery, further subdivided into work which considered macroscopically visible droplets and that which considered smaller particles; (2) and those studies which examined the mitigation of this risk. Conclusion Studies considering the aerosolisation of both droplets and smaller particles suggest endonasal surgery carries significant risk. Whilst results both highlight a range of innovative adjunctive strategies and support suction as an important variable to reduce aerosolisation, appropriate use of personal protective equipment (PPE) should be considered mandatory for all healthcare professionals involved in rhinological surgery given studies have demonstrated that close adherence to PPE use is effective at preventing COVID-19 infection.

Measurements in the field on dry days indicate that when the traps of Dionaea muscipula (Venus’ flytraps) close, they capture prey about 40% of the time at one site and 44% at another. The 60% and 56% of traps that close but do not catch prey reach their maximum closure on average in about 10 minutes, begin reopening in about 7 hours and completely reopen in 22 hours. Traps that have captured prey tighten along their rims, sealing the lobes and forcing the margins outward into a “narrowed” condition that takes 4 to 6 hours to achieve. Reopening of narrowed traps begins, on average, after 9.2 days and they are fully open in 12.8 days. A few traps that capture large prey never reopen. In dry weather closure frequency of traps capable of closure was low, averaging 3.5%/day at one site and 3.1%/day at another. At both sites the capture frequency of traps capable of closing was only 1.4%/day. The low frequency of capture, and high percentage of closures that result in capture, indicate that the low capture frequency is due to a low number potential prey entering and triggering the trap rather than a low efficiency of capturing the prey that enters. Traps that close, but fail to capture prey, have been observed to be triggered by insects, spiders, snails, and even toads that were far too large to be captured. A few captured beetles have been observed to force their way out of trap lobes. Dionaea traps capture prey at all hours of the day. The capture frequencies are variable and are not significantly higher in any specific time period. Both nocturnal and diurnal animals were captured.

Objectives Anecdotal evidence suggests that oropharyngeal squamous cell carcinoma (OPSCC) should be suspected in patients presenting with symptoms of peritonsillar abscess (PTA) or cellulitis (PTC). The aim of this study was to estimate the prevalence of OPSCC in patients presenting with symptoms of PTA/PTC. Method, Setting and Participants We retrospectively identified all adults with a coded diagnosis of PTA or PTC who presented between 2012-2016 inclusive, across six ENT units in ——–. Records were compared to that of the centralised regional head and neck cancer database. The clinical records of a subset of patients were reviewed for the purposes of data validation. Results A total of 1975 patients with PTA/PTC were identified. Three patients were subsequently diagnosed with OPSCC. None of the three actually had an objective underlying diagnosis of PTA/PTC on the same side. The prevalence of OPSCC in patients admitted with symptoms of PTA/PTC was 0.15%, or approximately 1:650 admissions. The records of 510 patients who presented over a one-year period (2016) were reviewed in even greater detail. There were 298 patients with PTA (59.4%), 151 with PTC (29.1%) and 61 had an alternative diagnosis (11.9%). High risk features (age ≥40, tonsillar asymmetry or tonsillar lesion) were present in 106 patients (24%). Urgent follow up was expedited for 77 patients (73%). Conclusion This study estimates the risk of OPSCC in patients with peritonsillar symptoms. The prevalence is low, even in a region with a relatively heavy disease burden. Clinicians should, however, retain a high level of suspicion in patients with persistent symptoms.

Advances in functional magnetic resonance spectroscopy (fMRS) have enabled the quantification of activity-dependent changes in neurotransmitter concentrations in vivo. However, the physiological basis of the large changes in GABA and glutamate observed by fMRS (>10%) over short time scales of less than a minute remain unclear as such changes cannot be accounted for by known synthesis or degradation metabolic pathways. Instead, it has been hypothesized that fMRS detects shifts in neurotransmitter concentrations as they cycle from presynaptic vesicles, where they are largely invisible, to extracellular and cytosolic pools, where they are detectable. The present paper uses a computational modelling approach to demonstrate the viability of this hypothesis. A new mean-field model of the neural mechanisms generating the fMRS signal in a cortical voxel is derived. The proposed macroscopic mean-field model is based on a microscopic description of the neurotransmitter dynamics at the level of the synapse. Specifically, GABA and glutamate are assumed to cycle between three metabolic pools: packaged in the vesicles; active in the synaptic cleft; and undergoing recycling and repackaging in the astrocytic or neuronal cytosol. Computational simulations from the model are used to generate predicted changes in GABA and glutamate concentrations in response to different types of stimuli including pain, vision, and electric current stimulation. The predicted changes in the extracellular and cytosolic pools corresponded to those reported in empirical fMRS data. Furthermore, the model predicts a selective control mechanism of the GABA/glutamate relationship, whereby inhibitory stimulation reduces both neurotransmitters, whereas excitatory stimulation increases glutamate and decreases GABA. The proposed model bridges between neural dynamics and fMRS and provides a mechanistic account for the activity-dependent changes in the glutamate and GABA fMRS signals. Lastly, these results indicate that echo-time may be an important timing parameter that can be leveraged to maximise fMRS experimental outcomes.

Primary care healthcare organizations are complex and multidimensional, and there has been much discussion about the potential dangers of focusing on outcomes as quality indicators in isolation without understanding the processes and system characteristics that drive them. Organizational health, as a concept, shifts the focus of measurement upstream and considers the elements needed for sustainable long-term success. This study has both designed and tested the first survey seeking to measure organizational health specifically within the context of primary care. A stepwise approach was taken to ensure that the validity and reliability of the survey was examined at multiple stages.Supplemental data for this article is available online at https://doi.org/10.1080/00185868.2021.1947164.

Dionaea muscipula traps, in a natural setting, are sometimes triggered to close without capturing prey. In the Florida panhandle, in dry weather, time-lapse photographs show the frequency of closure without capture to be 2.1 closures/% of active-traps/day. A sudden burst of intense rain can increase this by two to three orders of magnitude for a brief time. Frequencies of 15.5 closures/% of active-traps/hour and 148 closures/% of active-traps/hour have been measured. The large increase in closures occurs when rain first starts, because the most exposed and most sensitive traps are triggered early, leaving traps in a more sheltered position and those with a less sensitive response open. Only 6 to 12% of the traps in the field of view were closed by intense rain. Even rain so heavy that the traps were submerged in water left most of the traps open. Gentle rain can close traps, but this is not a common event. The necessity of two or more stimuli to close a trap accounts for traps general lack of responsiveness to raindrops in light rainfall. Traps observed to be closed by raindrops began reopening in an average of 4.5 hours and full reopening averaged 15.8 hours. Since partially open traps are capable of capturing prey, the average trap closed by rain is effective at trapping in about 12 hours. Rainfall is only a minor factor interfering with traps’ ability to catch prey.

Trail cameras can be used for the study of the interaction between plants and insects if they have a close-up lens and the capability of doing time-lapse photographs or videos. Typical trail cameras are mounted vertically, often on unstable camera stands. We have used the Bushnell NatureView HD Cam Model# 119740 and RC Williams Co. TopView Quick-Mount camera-stand to study the behavior of insects interacting with Venus flytraps (Dionaea muscipula). The combination allows photographs and videos to be made of insects and plants from above, with the camera held in a position that allows the plants to be observed from the exact same position for months at a time. Every five minutes a photograph and a one-minute video are recorded. We have developed methods of searching through this data for important events that involve producing “slide shows” of the photographs overlain by a grid, that can be quickly scanned for events of interest. Video of these events near the time of the sequentially numbered photograph can then be viewed. The slides and videos can also be sampled at intervals for more gradual changes.

Dionaea flowers are pollinated by insects, primarily bees, in both their native habitat in the Carolinas and in the population growing from seed scattered many years ago in the Florida panhandle, the location of this study. The green sweat bee (Augochlorella sp. is a major pollinator in both habitats, while various flower visiting beetles play a prominent role in the Carolinas and bumblebees (Bombus sp.) play a major role in the Florida population. Flowers open in late morning and pollen is on anthers arrayed directly above the center of the flower by 11:30 EST. Twenty-four hours later the stamens have bent so that the anthers are at the periphery of the flower and the stigma has expanded, presenting a papillate surface receptive to pollen. Insects visit the flower between 11:30 EST and 18:00 EST. Rewards for pollinators are pollen and nectar from glands at the base of the petals. Possible attractants include the bright white radially symmetrical corolla with radiating grey veins, and on the second day, the radially displayed stamens that may act as a 'nectar guide'. No markings on the petals are visible in the ultraviolet light but the pollen-laden anthers are UV-fluorescent and would stand out as a ring of dots to any UV-perceptive insect.

We used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex (DLPFC). We identified extensive layer-enriched expression signatures, and refined associations to previous laminar markers. We overlaid our laminar expression signatures onto large-scale single nuclei RNA sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially-defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions where morphological architecture is not as well-defined as cortical laminae. We lastly created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research (http://research.libd.org/spatialLIBD).

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, β = 3.73, 95% CI = 1.26–6.20, P = 0.004; Glx, β = 3.38, 95% CI = 0.84–5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (β = 3.12, 95% CI = 0.01–6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique used to modulate cortical excitability in the human brain. However, one major challenge with rTMS is that the responses to stimulation are highly variable across individuals. The underlying reasons why responses to rTMS are highly variable between individuals still remain unclear. Here, we investigated whether the response to continuous theta-burst stimulation (cTBS) - an effective rTMS protocol for decreasing cortical excitability - is related to individual differences in glutamate and GABA neurotransmission. We acquired resting-state magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) during semantic processing. Then, we applied cTBS over the anterior temporal lobe (ATL), a hub for semantic representation, to explore the relationship between the baseline neurochemical profiles in this region and the response to cTBS. We found that the baseline excitation-inhibition balance (glutamate + glutamine/GABA ratio) in the ATL was associated with individual cTBS responsiveness during semantic processing. Specifically, individuals with lower excitation-inhibition balance showed stronger inhibitory effect - poorer semantic performance. Our results revealed that non-responders (subjects who did not show an inhibitory effect of cTBS on subsequent semantic performance) had higher excitatory-inhibitory balance in the ATL, which led to up-regulated task-induced regional activity as well as increased ATL-connectivity with other semantic regions compared to responders. These results disclose that the baseline neurochemical state of a cortical region can be a significant factor in predicting responses to cTBS.

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Rationale Chronic fatigue syndrome (CFS) is a common and burdensome illness with a poorly understood pathophysiology, though many of the characteristic symptoms are likely to be of brain origin. The use of high-field proton magnetic resonance spectroscopy (MRS) enables the detection of a range of brain neurochemicals relevant to aetiological processes that have been linked to CFS, for example, oxidative stress and mitochondrial dysfunction. Methods We studied 22 CFS patients and 13 healthy controls who underwent MRS scanning at 7 T with a voxel placed in the anterior cingulate cortex. Neurometabolite concentrations were calculated using the unsuppressed water signal as a reference. Results Compared to controls, CFS patients had lowered levels of glutathione, total creatine and myo-inositol in anterior cingulate cortex. However, when using N-acetylaspartate as a reference metabolite, only myo-inositol levels continued to be significantly lower in CFS participants. Conclusions The changes in glutathione and creatine are consistent with the presence of oxidative and energetic stress in CFS patients and are potentially remediable by nutritional intervention. A reduction in myo-inositol would be consistent with glial dysfunction. However, the relationship of the neurochemical abnormalities to the causation of CFS remains to be established, and the current findings require prospective replication in a larger sample.

BACKGROUND: Disparity in mental health care among cancer patients remains understudied. METHODS: We conducted a large, retrospective, single tertiary-care institution cohort study based on de-identified electronic health record data of 54,852 adult cancer patients without prior mental health diagnosis (MHD) diagnosed at the University of California, San Francisco between 1/2012 and 9/2019. The exposure of interest was early onset MHD with or without psychotropic medication (PM) within 12 months of cancer diagnosis and primary outcome was all-cause mortality. RESULTS: 8.2% of patients received a new MHD at a median of 197 days (interquartile-range [IQR] 61-553) after incident cancer diagnosis, 31.0% received a PM prescription, and 3.7% a MHRV. 62.6% of patients were non-Hispanic white (NHW), 10.8% Asian, 9.8% Hispanic, and 3.8% Black. Compared to NHWs, minority cancer patients had reduced adjusted odds of MHDs, PM prescriptions, and MHRVs, particularly for generalized anxiety (Asian: odds ratio [OR] 0.66, 95% confidence interval 0.55-0.78; Black: OR 0.60, 0.45-0.79; Hispanic: OR 0.72, 0.61-0.85) and selective-serotonin-reuptake-inhibitors (SSRI; Asian: OR 0.43, 0.37-0.50; Black: OR 0.51, 0.40-0.61; Hispanic: OR 0.79, 0.70-0.89). New early MHD with PM was associated with elevated all-cause mortality (12-24 months: hazard ratio [HR] 1.43, 1.25-1.64) that waned by 24-36 months (HR 1.18, 0.95-1.45). CONCLUSIONS AND RELEVANCE: New mental health diagnosis with psychotropic medication was a marker of early mortality among cancer patients. Minority cancer patients were less likely to receive documentation of mental health diagnoses or treatment, which may represent missed opportunities to identify and treat cancer related mental health conditions.

With an increasing proportion of UK healthcare delivered by independent sector providers (ISPs) it is important that performance data is reviewed with a similar rigour as within the public sector. However, there is a relative paucity of work considering quotients of performance in the independent healthcare sector. This study sets out to measure organizational health within ISPs in the UK and juxtapose this with contemporaneous data taken from public sector NHS organizations. Survey data was tested for construct validity with fit of the existing factor structure of the Healthcare-OH survey examined using confirmatory factor analysis (CFA). Multiple-group CFA was used to establish measurement invariance to permit comparison of latent sum scores between ISP and NHS organizations. Measurement invariance analysis evaluated the fit of sequential invariance models, proceeding iteratively to establish partial metric and scalar invariance. Latent sum scores comparisons demonstrated ISPs outperformed NHS trusts across all elements of organizational health. This is the first time organizational health has been measured in ISPs explicitly for comparison with results in the public sector. Comparative measurement and analysis in this way is novel and has the potential of fostering a two-way learning process for the ultimate benefit of both NHS and ISP organizations.

Context Immune therapy has emerged as a powerful treatment of metastatic urothelial carcinoma. Over 20 ongoing studies are exploring this strategy in the neoadjuvant setting in patients with localized muscle-invasive bladder cancer. Objective To summarize the rationale and the clinical outcomes regarding the use of immune checkpoint blockade in the neoadjuvant setting before radical cystectomy. Evidence acquisition A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, mice, human, immunotherapy, neoadjuvant therapy, atezolizumab, pembrolizumab, durvalumab, nivolumab, avelumab, ipilimumab, and tremelimumab. The search was limited to publications between January 2008 and February 2020. Publicly available relevant abstracts from recent meetings were also included. Evidence synthesis Phase II trials investigating neoadjuvant immune checkpoint blockade as a single agent before radical cystectomy reported a rate of pathological complete response (CR), ranging from 31% with an anti–PD-L1 monoclonal antibody (mAb) atezolizumab (n = 27/88) to 37% with anti–PD-1 mAb pembrolizumab (n = 42/114). Overall, 92% (n = 87/95) and 98% (n = 112/114) of the patients underwent radical cystectomy. Neoadjuvant immune checkpoint blockade did not delay planned surgery. Checkpoint inhibitor monotherapy was well tolerated, with no unexpected toxicity in the presurgical setting. Early phase I/II trials investigating neoadjuvant combination chemotherapy strategies with immune checkpoint blockers reported enhanced antitumor efficacy, with a pathological CR ranging from 33% to 50%. Conclusions Although limited clinical data are available on long-term survival, neoadjuvant immune checkpoint blockade demonstrated effective antitumor efficacy for localized muscle-invasive bladder cancer. Phase III trials are currently investigating this strategy in the presurgical setting. Patient summary Immunotherapy prior to surgery has been evaluated for patients with muscle-invasive bladder cancer. Although long-term survival benefit is unknown, such treatment strategy revealed a promising antitumor response rate for patients who underwent radical cystectomy. Ongoing prospective clinical trials will define the potential advantage of this approach over current cisplatin-based chemotherapeutic regimens alone or in combination.

No-tillage is often suggested as a strategy to reduce greenhouse gas emissions. Modeling tillage effects on nitrous oxide (N2O) emissions is challenging and subject to great uncertainties as the processes producing the emissions are complex and strongly nonlinear. Previous findings have shown deviations between the LPJmL5.0-tillage model (LPJmL: Lund–Potsdam–Jena managed Land) and results from meta-analysis on global estimates of tillage effects on N2O emissions. Here we tested LPJmL5.0-tillage at four different experimental sites across Europe and the USA to verify whether deviations in N2O emissions under different tillage regimes result from a lack of detailed information on agricultural management, the representation of soil water dynamics or both. Model results were compared to observational data and outputs from field-scale DayCent model simulations. DayCent has been successfully applied for the simulation of N2O emissions and provides a richer database for comparison than noncontinuous measurements at experimental sites. We found that adding information on agricultural management improved the simulation of tillage effects on N2O emissions in LPJmL. We also found that LPJmL overestimated N2O emissions and the effects of no-tillage on N2O emissions, whereas DayCent tended to underestimate the emissions of no-tillage treatments. LPJmL showed a general bias to overestimate soil moisture content. Modifications of hydraulic properties in LPJmL in order to match properties assumed in DayCent, as well as of the parameters related to residue cover, improved the overall simulation of soil water and N2O emissions simulated under tillage and no-tillage separately. However, the effects of no-tillage (shifting from tillage to no-tillage) did not improve. Advancing the current state of information on agricultural management and improvements in soil moisture highlights the potential to improve LPJmL5.0-tillage and global estimates of tillage effects on N2O emissions.