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Stereo-electroencephalography (SEEG) has gained global popularity in recent years. In Japan, a country in which invasive studies using subdural electrodes (SDEs) have been the mainstream, SEEG has been approved for insurance coverage in 2020 and is expected to gain in popularity. Some concepts supporting SEEG methodology are fundamentally different from that of SDE studies. Clinicians interested in utilizing SEEG in their practice should be aware of those aspects in which they differ. Success in utilizing the SEEG methodology relies heavily on the construction of an a priori hypothesis regarding the putative seizure onset zone (SOZ) and propagation. This article covers the technical and theoretical aspects of SEEG, including the surgical techniques and precautions, hypothesis construction, and the interpretation of the recording, all with the aim of providing an introductory guide to SEEG.

We previously reported that feeding Se-biofortified alfalfa hay to weaned beef calves in a preconditioning program decreases morbidity and mortality during the feedlot period. To understand the mode of action by which supranutritional Se supplementation supports calf health, we examined the effect of agronomic Se-biofortification on nasal microbiome and fecal parasites. Recently weaned Angus-cross beef calves (n = 30) were randomly assigned to two groups and fed an alfalfa hay-based diet for 9 weeks in a preconditioning program. Alfalfa hay was harvested from fields fertilized with sodium selenate at a rate of 0 or 90 g Se/ha. Calculated Se intake from dietary sources was 1.09 and 27.45 mg Se/calf per day for calves consuming alfalfa hay with Se concentrations of 0.06 and 3.47 mg Se/kg dry matter, respectively. Feeding Se-biofortified alfalfa hay for 9 weeks was effective at increasing whole-blood Se concentrations (556 ± 11 vs 140 ± 11 ng/mL; P < 0.001) and increasing body weight (PTreatment, = 0.03) in weaned beef calves. Slaughter yield grades were higher for calves that had been fed Se-enriched alfalfa hay during the preconditioning period (PTreatment = 0.008). No significant differences were observed in fecal parasite load, which remained low. The nasal microbiome and microbiota diversity within calves and across calves expanded from weaning (week 0) to the feedlot period (week 12), which was promoted by feeding Se-biofortified alfalfa hay. Especially concerning was the expansion of nasal Mycoplasmataceae in the feedlot, which reached over 50% of the total microbiota in some calves. In conclusion, we identified dietary Se-biofortified alfalfa hay as a potential promoter of nasal microbiome genome and microbiota diversity, which may explain in part high-Se benefits for prevention of bovine respiratory disease complex in beef calves., Competing Interests: The authors have declared that no competing interests exist.

The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here, we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico-cortical wiring established by postmortem anatomical studies and capitalises on cutting-edge in vivo neuroimaging and machine learning. The new model expands the currently prevailing diffusion magnetic resonance imaging (MRI) tractography approach by incorporation of additional features of cortical microstructure and cortico-cortical proximity. Studying several datasets and different parcellation schemes, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior-posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics based on resting-state functional magnetic resonance imaging (rs-fMRI) and human intracranial electroencephalography (EEG) coherence. Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals., Competing Interests: The authors have declared that no competing interests exist.

Purpose of Review: Epilepsy associated with periventricular nodular heterotopia (PNH), a developmental malformation, is frequently drug-resistant and requires focal therapeutic intervention. Invasive EEG study is usually necessary to delineate the epileptogenic zone, but constructing an accurate hypothesis to define an appropriate electrode implantation scheme and the treatment is challenging. This article reviews recent studies that help understanding the epileptogenicity and potential therapeutic options in PNH., Recent Findings: New noninvasive diagnostic and intracerebral EEG analytic tools demonstrated that cortical hyperexcitability and aberrant connectivity (between nodules and cortices and among nodules) are likely mechanisms causing epilepsy in most patients. The deeply seated PNH, if epileptogenic, are ideal target for stereotactic ablative techniques, which offer concomitant ablation of multiple regions with relatively satisfactory seizure outcome. Advance in diagnostic and analytic tools have enhanced our understanding of the complex epileptogenicity in PNH. Development in stereotactic ablative techniques now offers promising therapeutic options for these patients.

The thiazolidinediones (TZDs) are ligands of PPARγ that improve insulin sensitivity, but their use is limited by significant side effects. Recently, we demonstrated a mechanism wherein TZDs improve insulin sensitivity distinct from receptor agonism and adipogenesis: reversal of obesity-linked phosphorylation of PPARγ at serine 273. However, the role of this modification hasn't been tested genetically. Here we demonstrate that mice encoding an allele of PPARγ that cannot be phosphorylated at S273 are protected from insulin resistance, without exhibiting differences in body weight or TZD-associated side effects. Indeed, hyperinsulinemic-euglycemic clamp experiments confirm insulin sensitivity. RNA-seq in these mice reveals reduced expression of Gdf3, a BMP family member. Ectopic expression of Gdf3 is sufficient to induce insulin resistance in lean, healthy mice. We find Gdf3 inhibits BMP signaling and insulin signaling in vitro. Together, these results highlight the diabetogenic role of PPARγ S273 phosphorylation and focus attention on a putative target, Gdf3., Competing Interests: Declaration of Interests E.D.R. is a paid consultant of Novartis. B.B.K. consults for Alterna and serves on the Scientific Advisory Board of Janssen Pharmaceuticals. A.S.B. and B.M.S. hold a patent related to this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Patients with cirrhosis and splenomegaly commonly develop cytopenias and require the transfusion of blood products. In this study, we evaluated spleen size as a clinical indicator for red blood cell transfusion effectiveness and hypothesized that transfusion would be less effective in patients with splenomegaly. Our retrospective cohort study compared 215 cirrhotic patients with splenomegaly and 114 cirrhotic patients without splenomegaly and measured their respective change in hemoglobin concentration after a unit of transfused red blood cells. The primary endpoint was the percent difference between the measured rise in hemoglobin after transfusion in these cohorts. Patient sex ( P  < 0.0035), body mass index ( P  < 0.0001), and the change in hemoglobin concentration after a leukocyte-reduced red blood transfusion ( P  < 0.0001) were found to be significantly related to spleen size. When compared to the nonsplenomegaly cohort, it was found that the splenomegaly cohort experienced 79.70% (95% CI 71.26%-89.14%) of the change in hemoglobin concentration after red blood cell transfusion when adjusted for patient sex and body mass index. In conclusion, in patients with cirrhosis, increased spleen size was correlated with a decreased responsiveness to red blood cell transfusion when adjusted for patient sex and body mass index., (Copyright © 2020 Baylor University Medical Center.)

Background: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) activators have anti-cancer effects. Our objective was to determine the effect of PPAR-γ ligands 15-deoxy-D 12,14 -Prostaglandin J 2 (15-PGJ 2 ) and ciglitazone on proliferation, apoptosis, and NF-κB in human oral squamous cell carcinoma cell lines., Methods: NA and CA9-22 cells were treated in vitro with 15-PGJ 2 and ciglitazone. Proliferation was measured by MTT colorimetric assay and cell cycle analysis performed via flow cytometry, apoptosis by caspase-3 colorimetric assay and poly-(ADP-ribose) polymerase cleavage on Western blot, and NF-κB activation by luciferase assays., Results: MTT assays demonstrated dose-dependent decreases after 15-PGJ 2 treatment in both cell lines, and S-phase cell cycle arrest was also demonstrated. NF-κB luciferase reporter gene activity decreased seven- and eightfold in NA and CA9-22 cells, respectively. Caspase-3 activity increased two- and eightfold in NA and CA9-22 cells, respectively., Conclusions: Our results suggest these agents, in addition to activating PPAR-γ, can downregulate NF-κB and potentiate apoptosis in oral cancer cells., (© 2020 Wiley Periodicals, Inc.)

The objective of this study was to determine if serum amyloid A (SAA), a major acute-phase protein, could help support the diagnosis of equine proliferative enteropathy (EPE) caused by Lawsonia intracellularis infection in foals. Archived serum samples from 101 foals with enteric signs and hypoproteinemia were available for SAA testing. Based on immunodiagnostics for L. intracellularis, the foals were divided into EPE-suspect (67) and non-EPE-suspect cases (34). Serum amyloid A values ranged from 0 to 2,761 μg/mL (median 466 μg/mL) and from 0 to 2,555 μg/mL (median 192 μg/mL) for the EPE-suspect and the non-EPE-suspect cases, respectively. Although SAA can be measured patient-side and help determine the severity of the underlying inflammatory condition, SAA was unable to consistently support the diagnosis of EPE in hypoproteinemic foals with enteric signs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Previous reports show conflicting results regarding hepatitis B virus (HBV) vaccine efficacy in Hepatitis C virus (HCV)-infected individuals., Aims: To evaluate HBV-vaccine response and identify possible factors that may contribute to lower vaccine efficacy in patients infected with HCV., Methods: We retrospectively evaluated all patients with chronic HCV infection at Hennepin County Medical Center, in Minneapolis, Minnesota, between 2002 and 2018. We addressed laboratory, liver-related, virus-related as well as vaccine-related variables, and their association to HBV vaccine response. Differences were tested using either a Chi-squared test or a T test to compare means between the two populations. Multivariate regression was modeled as a logistic regression., Results: 1506 patients were evaluated, of which 525 received appropriate HBV vaccination and were assessed for response. Among those, 79% were vaccine responders and 21% were non-responders. On multivariate analysis, cirrhosis was associated with lower response to the vaccine (OR 0.6, CI 0.44-0.94). We found no significant differences for vaccine response in relation to smoking (87% vs 86%), IV drug abuse (74% vs 72%), Diabetes Mellitus (26% vs 22%) being on hemodialysis (2% vs.5%), or virus related variables., Conclusion: HCV infection seems to impair HBV vaccine response, with cirrhosis being the only identifiable risk factor for hypo-responsiveness among studied clinical and virus-related variables., Competing Interests: The authors have declared that no competing interests exist.

The objective was to determine the effects of feeding different fiber sources to cats with chronic kidney disease (CKD) compared with healthy cats (both n = 10) on fecal metabolites. A cross-over within split-plot study design was performed using healthy and CKD cats (IRIS stage 1, 2, and 3). After cats were fed a complete and balanced dry food designed to aid in the management of renal disease for 14 days during a pre-trial period, they were randomly assigned to two fiber treatments for 4 weeks each. The treatment foods were formulated similar to pre-trial food and contained 0.500% betaine, 0.586% oat beta glucan, and either 0.407% short chain fructooligosaccharides (scFOS) fiber or 3.44% apple pomace. Both treatment foods had similar crude fiber (2.0 and 2.1% for scFOS and apple pomace, respectively) whereas soluble fiber was 0.8 and 1.6%, respectively. At baseline, CKD had very little impact on the fecal metabolome. After feeding both fiber sources, some fecal metabolite concentrations were significantly different compared with baseline. Many fecal uremic toxins decreased, although in healthy cats some increased; and some more so when feeding apple pomace compared with scFOS, e.g., hippurate, 4-hydroxyhippurate, and 4-methylcatechol sulfate; the latter was also increased in CKD cats. Changes in secondary bile acid concentrations were more numerous in healthy compared with CKD cats, and cats in both groups had greater increases in some secondary bile acids after consuming apple pomace compared with scFOS, e.g., tauroursodeoxycholate and hyocholate. Although changes associated with feeding fiber were more significant than changes associated with disease status, differential modulation of the gut-kidney axis using dietary fiber may benefit cats.

Methods: A cross-over study within a split-plot design was performed using healthy (n = 10) and CKD cats [IRIS Stage 1 and 2; n = 10]. Cats were fed dry Prescription Diet® k/d® Feline with chicken, during a pre-trial period and then randomly assigned to two fiber treatments for 4 weeks each. Treatment foods were formulated similar to pre-trial food, with the exception that they contained 0.500% betaine, 0.586% oat beta glucan, and either 0.407% short chain fructooligosaccharides (scFOS) fiber or 3.44% apple pomace. Both foods had similar crude fiber percent (2.0 and 2.1% for scFOS and apple pomace, respectively) whereas soluble fiber was 0.8 and 1.6%, respectively., Results: Plasma metabolites separated cats based on health status. At baseline, cats with CKD had significantly higher circulating concentrations of creatinine, urea, and some microbial and host tryptophan metabolites including several indole sulfates and kynurenate. Healthy cats had higher concentrations of the antioxidant α-tocopherol after consuming apple pomace; alternatively, they had higher concentrations of inflammatory sphingolipid metabolites after consuming scFOS, but not after consuming apple pomace. The CKD cats had higher concentrations of the more oxidized glutathione metabolites after consuming apple pomace compared with scFOS, as well as higher concentrations of inflammatory sphingolipid metabolites after consuming apple pomace, but not scFOS. After consuming scFOS, CKD cats had lower concentrations of the phenolic uremic toxins guaiacol sulfate and 4-vinylphenol sulfate compared with after consuming apple pomace. At baseline, there were five significant microbiota OTU differences in CKD cats compared with healthy cats. Overall, the OTUs in CKD cats were more resistant to change after feeding either fiber source. Counts of an unclassified genus in the family S24-7 in the order Bacteroidales (OTU 100296), were lower in CKD cats compared with healthy cats at baseline (P = 0.001), but increased after consumption of food containing scFOS (P = 0.006). Linear regression analysis showed that this genus had significant negative correlations with several microbial uremic toxins. None of the baseline differences in OTUs between healthy and CKD cats changed after CKD cats consumed food containing apple pomace., Conclusions: Health status impacts the influence of dietary fermentable fibers on the feline plasma metabolome and fecal microbiome. A more readily fermented fiber such as scFOS is preferable to apple pomace as a fiber source for cats with CKD., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: three of the authors (MIJ, EE) have an affiliation or formerly had an affiliation (DEJ) to the commercial funders of this research, as employees of Hill’s Pet Nutrition, Inc. (http://www.hillspet.com/our-company.html). This does not alter our adherence to policies on sharing data and materials. Data is freely available upon request. The funder provided support in the form of salaries for authors (MIJ, DEJ, EE), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

Objective: To determine associations between patient affect and physician liking of the patient, and their associations with physician behavior and patient-reported outcomes., Methods: Structural equation modeling based on coding of 497 videotaped hospital encounters, with questionnaires assessing pre-visit patient affect, post-visit patient affect and encounter evaluations, and physician liking of the patient, involving 71 physicians., Results: In first visits, patient reported outcomes were strongly correlated with physician behavior and less so with physician liking, while in later visits, patient reported outcomes were directly related to physician liking and not mediated by physician behavior. Physician liking predicted physician behavior, more for female physicians in first visits. Patient negative affect before the visit was negatively associated with male physicians' liking. When acquainted, both patient positive and negative affect were associated with physician liking., Conclusion: Physician liking of the patient plays a dynamic role in a consultation, is influenced by patient pre-encounter affect, and influences physician behavior. The dynamics are different in first and later visits, and influenced by physician gender., Practice Implications: Physicians should be aware how patient affect influences their behavior, and administrators should take any prior relationship between patient and physician into account when evaluating patient reported outcomes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Neuronavigation systems making use of augmented reality (AR) have been the focus of much research in the last couple of decades. In recent years, there has been considerable interest in using mobile devices for AR in the operating room (OR). We propose a complete system that performs real-time AR video augmentation on a mobile device in the context of image-guided neurosurgery., Methods: MARIN (mobile augmented reality interactive neuronavigation system) improves upon the state of the art in terms of performance, allowing real-time augmentation, and interactivity by allowing users to interact with the displayed data. The system was tested in a user study with 17 subjects for qualitative and quantitative evaluation in the context of target localization and brought into the OR for preliminary feasibility tests, where qualitative feedback from surgeons was obtained., Results: The results of the user study showed that MARIN performs significantly better in terms of both time ([Formula: see text]) and accuracy ([Formula: see text]) for the task of target localization in comparison with a traditional image-guided neurosurgery (IGNS) navigation system. Further, MARIN AR visualization was found to be more intuitive and allowed users to estimate target depth more easily., Conclusion: MARIN improves upon previously proposed mobile AR neuronavigation systems with its real-time performance, higher accuracy, full integration in the normal workflow and greater interactivity and customizability of the displayed information. The improvement in efficiency and usability over previous systems will facilitate bringing AR into the OR.

Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studies of human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte-lineage cells with stage-specific functional properties. Cells were isolated from surgical tissue samples of second-trimester fetal, 2-year-old pediatric, 13-year-old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet-based RNA sequencing (10X Chromium). Louvain clustering analysis identified three distinct cellular subpopulations based on 5,613 genes, comprised of an early OPC (e-OPC) group, a late OPC group (l-OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e-OPCs included cell cycle and development, for l-OPCs included extracellular matrix and cell adhesion, and for MOLs included myelination and cytoskeleton. The e-OPCs were mostly confined to the premyelinating fetal group, and the l-OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l-OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL-lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination., (© 2020 Wiley Periodicals, Inc.)

Zuckerman et al. (2013) conducted a meta-analysis of 63 studies that showed a negative intelligence-religiosity relation (IRR). As more studies have become available and because some of Zuckerman et al.'s (2013) conclusions have been challenged, we conducted a new meta-analysis with an updated data set of 83 studies. Confirming previous conclusions, the new analysis showed that the correlation between intelligence and religious beliefs in college and noncollege samples ranged from -.20 to -.23. There was no support for mediation of the IRR by education but there was support for partial mediation by analytic cognitive style. Thus, one possible interpretation for the IRR is that intelligent people are more likely to use analytic style (i.e., approach problems more rationally). An alternative (and less interesting) reason for the mediation is that tests of both intelligence and analytic style assess cognitive ability. Additional empirical and theoretical work is needed to resolve this issue.

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls., Competing Interests: Competing interestsA.E. is on the Roche advisory board and has reported honoraria from Amgen, Novartis and Roche. A.J.L. is a consultant for BMS, Merck, AZ/Medimmune, and Genentech. R.S. reports research funding from Roche, Puma, Merck; advisory board and consultancy for BMS; travel funding from Roche, Merck, and Astra Zeneca. S.G. reports Lab research funding from Lilly, Clinical research funding from Eli Lilly and Novartis and is a Paid advisor to Eli Lilly, Novartis, and G1 Therapeutics. J.v.d.L. is member of the scientific advisory boards of Philips, the Netherlands and ContextVision, Sweden and receives research funding from Philips, the Netherlands and Sectra, Sweden. S.A. reports Research funding to institution from Merck, Genentech, BMS, Novartis, Celgene and Amgen and is an uncompensated consultant /steering committee member for Merck, Genentech and BMS. T.O.N. has consulted for Nanostring and received compensation and has intellectual property rights/ownership interests from Bioclassifier LLC [not related to the subject material under consideration]. S.L. receives research funding to institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer and Eli Lilly, has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech and acted as consultant (paid to her institution) to Aduro Biotech. S.R.L. has received travel and educational funding from Roche/Ventana. A.M. is an equity holder in Elucid Bioimaging and in Inspirata Inc., a scientific advisory consultant for Inspirata Inc, has served as a scientific advisory board member for Inspirata Inc, Astrazeneca, Bristol Meyers-Squibb and Merck, has sponsored research agreements with Philips and Inspirata Inc, is involved in a NIH U24 grant with PathCore Inc, and 3 different R01 grants with Inspirata Inc. and his technology has been licensed to Elucid Bioimaging and Inspirata Inc. G.C. is on the advisory boards of Roche, BMS, Pfizer, Seattle Genetics and Ellipsis, and reports personal fees from Roche, BMS, Pfizer, Seattle Genetics, and Ellipsis, outside of the submitted work. J.H. is the director and owner of Vivactiv Ltd. J.H. is the director and owner of Slide Score B.V. F.P.L. reports funding from Astrazeneca, BMS, Roche, MSD, Pfizer, Novartis, Sanofi, Eli Lilly. J.B. reports consultancies from Insight Genetics, BioNTech AG, Biotheranostics, Pfizer, RNA Diagnostics and OncoXchange, research funding from Thermo Fisher Scientific, Genoptix, Agendia, NanoString Technologies, Stratifyer GmbH and Biotheranostics, applied for patents, including Jan 2017: Methods and Devices for Predicting Anthracycline Treatment Efficacy, US utility—15/325,472; EPO—15822898.1; Canada—not yet assigned; Jan 2017: Systems, Devices and Methods for Constructing and Using a Biomarker, US utility—15/328,108; EPO—15824751.0; Canada—not yet assigned; Oct 2016: Histone gene module predicts anthracycline benefit, PCT/CA2016/000247; Dec 2016: 95‐Gene Signature of Residual Risk Following Endocrine Treatment, PCT/CA2016/000304; Dec 2016: Immune Gene Signature Predicts Anthracycline Benefit, PCT/CA2016/000305. M.A.S. reports consulting work for Achilles Therapeutics. C.S. reports receipt of grants/research support from Pfizer, AstraZeneca, BMS and Ventana; receipt of honoraria, consultancy, or SAB Member fees from Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Sarah Canon Research Institute, Genentech, Roche-Ventana, GRAIL, Medicxi; Advisor for Dynamo Therapeutics; Stock shareholder in Apogen Biotechnologies, Epic Bioscience, GRAIL; Co-Founder & stock options in Achilles Therapeutics. A.H.B. is the co-founder and CEO of PathAI. J.K. is an employee of PathAI. D.D. is on the advisory board for Oncology Analytics, Inc, and a consultant for Novartis. D.L.R. is on the advisory board of Amgen, Astra Zeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo, GSK, Konica/Minolta, Merck, NanoString, Perkin Elmer, Ventana, Ultivue; receives research support from Astra Zeneca, Cepheid, Navigate BioPharma, NextCure, Lilly, Ultivue; instrument support from Ventana, Akoya/Perkin Elmer, NanoString; paid consultant for Biocept; received travel honoraria from BMS, founder and equity holder for PixelGear and received royalty from Rarecyte. A.T. reports benefits from ICR’s Inventors Scheme associated with patents for one of PARP inhibitors in BRCA1/2 associated cancers, as well as honoraria from Pfizer, Vertex, Prime Oncology, Artios, honoraria and stock in InBioMotion, honoraria and financial support for research from AstraZeneca, Medivation, Myriad Genetics and Merck Serono. This work includes contributions from, and was reviewed by, individuals at the FDA. This work has been approved for publication by the agency, but it does not necessarily reflect official agency policy. Certain commercial materials and equipment are identified in order to adequately specify experimental procedures. In no case does such identification imply recommendation or endorsement by the FDA, nor does it imply that the items identified are necessarily the best available for the purpose. This work includes contributions from, and was reviewed by, individuals who received funding from the National Institutes of Health, the U.S. Department of Veterans Affairs and the Department of Defense. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, the Department of Defense, or the United States Government., (© The Author(s) 2020.)

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting., Competing Interests: Competing interestsJ.H. is the owner of Slide Score. B.V. L.V., M.v.S., I.N., M.d.M., J.v.d.B., K.K.v.d.V., K.S., S.A., S.D., G.V., S.S.B., S.M., W.F.S., C.S., S.M.H., C.D., S.L., G.P., M.C.U.C., Z.K., and H.M.H. have nothing to disclose. T.O.N. has consulted for Nanostring and received compensation and has intellectual property rights/ownership interests from Bioclassifier LLC, not related to the subject material under consideration and received funding support from the Canadian Cancer Society. D.L.R. reports research funding from AstraZeneca, Cepheid, Navigate BioPharma, NextCure, Lilly, and Ultivue; instrument support from Ventana, Akoya/PerkinElmer, and NanoString; advisory board of Amgen, AstraZeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo, GSK, Konica/Minolta, Merck, NanoString, PerkinElmer, Ventana, and Ultivue; consultancy for Biocept; honorarium and travel support from BMS; royalties from Rarecyte and is a founder and equity holder of PixelGear. Sh.L. receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer, and Eli Lilly, acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche-Genentech and acted as consultant (paid to her institution) to Aduro Biotech. J.M.S.B. reports research funding from ThermoFisher, Genoptix, Agendia, NanoString Technologies, Stratifyer GmbH, and Biotheranostics and advisory roles for Insight Genetics, BioNTech AG, Biotheranostics, Pfizer, RNA Diagnostics, and OncoXchange. J.M.S.B. reports the following patents: Methods and Devices for Predicting Anthracycline Treatment Efficacy, US utility (January 2017; 15/325,472; EPO – 15822898.1; Canada – not yet assigned), Systems, Devices and Methods for Constructing and Using a Biomarker, US utility (January 2017; 15/328,108; EPO – 15824751.0; Canada – not yet assigned), Histone gene module predicts anthracycline benefit (October 2016; PCT/CA2016/000247), 95‐Gene Signature of Residual Risk Following Endocrine Treatment (December 2016; PCT/CA2016/000304), Immune Gene Signature Predicts Anthracycline Benefit (December 2016; PCT/CA2016/000305). D.A.D. is on the advisory board and consults for Oncology Analytics Inc., and has consulted for and received travel funds from Novartis for work unrelated to the current manuscript. A.T. reports benefits from ICR’s Inventors Scheme associated with patents for one of PARP inhibitors in BRCA1/2-associated cancers. A.T. also reports Honoraria from Pfizer, Vertex, Prime Oncology, and Artios, honoraria and stock in InBioMotion, honoraria and financial support for research from AstraZeneca, Medivation, Myriad Genetics, and Merck Serono. J.A.H. is the director and owner of Vivactiv Ltd. R.S. reports research funding from Roche, Puma, and Merck; advisory board and consultancy for BMS; travel funding from Roche, Merck, and AstraZeneca, outside the scope of this work. M.K. reports funding to the institute from BMS, Roche and an advisory role for BMS, outside the submitted work., (© The Author(s) 2020.)

Existing literature provides a complicated picture of the relationship between digital media use and psychological outcomes. Both correlational and some experimental studies suggest that social media use specifically can be associated with diminished psychological functioning in adolescents and young adults. However, these effect sizes are not large, and must be considered in light of studies that suggest some positive outcomes associated with some uses of digital media, and a range of moderators of the identified associations. Although a growing body of evidence suggests that digital stress may be an important intervening factor between digital media use and psychosocial outcomes, this literature is complicated by multiple nomenclatures for similar or identical constructs. Our review of the literature suggests four potentially related components of digital stress, including availability stress, approval anxiety, fear of missing out, and communication overload. This conceptualization is consistent with recent published frameworks for understanding digital media's influence on peer relationships. Clinicians working with adolescents and young adults are encouraged to assess digital media use in the context of clients' overall psychological and social functioning, and in consideration of clients' specific uses of media. Future research is needed to examine the associations among components of digital stress and clinical outcomes, and to provide valid measures to assess digital stress in research and clinical settings.

The objective of this study was to detect Streptococcus equi subspecies equi (S. equi) (Lactobacillales: Streptococcaceae) using quantitative polymerase chain reaction (qPCR) in flies collected from a farm with a documented outbreak of strangles. A total of 1856 face flies [Musca autumnalis (Diptera: Muscidae)] were collected using conventional fly traps. The flies were processed for nucleic acid purification and tested for the presence of S. equi by qPCR. A total of 10/1856 flies (0.54%) tested qPCR-positive for S. equi. The results may implicate the presence of face flies as a risk factor for the transmission of S. equi and highlight the need to institute proper husbandry measures, biosecurity protocols and fly control in order to reduce the potential for infection in at-risk horses., (© 2019 The Royal Entomological Society.)

The ability to recognise others' emotions from nonverbal cues (emotion recognition ability, ERA) is measured with performance-based tests and has many positive correlates. Although researchers have long proposed that ERA is related to general mental ability or intelligence, a comprehensive analysis of this relationship is lacking. For instance, it remains unknown whether the magnitude of the association varies by intelligence type, ERA test features, as well as demographic variables. The present meta-analysis examined the relationship between ERA and intelligence based on 471 effect sizes from 133 samples and found a significant mean effect size (controlled for nesting within samples) of r  = .19. Different intelligence types (crystallized, fluid, spatial, memory, information processing speed and efficiency) yielded similar effect sizes, whereas academic achievement measures (e.g. SAT scores) were unrelated to ERA. Effect sizes were higher for ERA tests that simultaneously present facial, vocal, and bodily cues (as compared to tests using static pictures) and for tests with higher reliability and more emotions. Results were unaffected by most study and sample characteristics, but effect size increased with higher mean age of the sample. These findings establish ERA as sensory-cognitive ability that is distinct from, yet related to, intelligence.

Within the Central Texas Veterans Health Care System, the alcohol-related disorder readmission rate has been recognized as an area that needs improvement. The aim of this quality improvement initiative was to develop an alcohol detoxification protocol. This protocol assesses the need for inpatient vs outpatient management of alcohol withdrawal and provides guidance pertaining to medication options, with emphasis on prescribing gabapentin for treatment of alcohol withdrawal. The protocol also contains the alcohol detox e-consult, which prompts a physician to call the patient daily to assess alcohol withdrawal, ability to abstain from alcohol, medication compliance, interest in substance abuse treatment programs, and appropriate follow-up. After implementing the protocol and e-consult, we saw a reduction in the admission rate of alcohol-related disorders and patients found the consult helpful., (Copyright © 2020 Baylor University Medical Center.)

The Tec kinase IL-2-inducible T cell kinase (ITK) regulates the expression of TCR-induced genes. Itk -/- T cell responses are impaired but not absent. ITK inhibition prevented colitis disease progression and impaired T cell migration to the colon in mice. To examine the function of ITK in T cell migration to the intestine, we examined the number of gut T cells in Itk -/- mice and then evaluated their expression of gut-homing receptors. Combined with in vitro murine T cell stimulation and in vivo migration assay using congenic B6 mice, we demonstrated an essential role for ITK in T cell migration to the intestine in mice. Reconstitution of Itk -/- mouse CD8 + T cells with IFN regulatory factor 4 restored gut-homing properties, providing mechanistic insight into the function of ITK-mediated signaling in CD8 + T cell migration to the intestinal mucosa in mice., (Copyright © 2020 The Authors.)

Background: Compassionate behavior in clinicians is described as seeking to understand patients' psychosocial, physical and medical needs, timely attending to these needs, and involving patients as they desire. The goal of our study was to evaluate compassionate behavior in patient interactions, pain management, and the informed consent process of anesthesia residents in a simulated preoperative evaluation of a patient in pain scheduled for urgent surgery., Methods: Forty-nine Clinical Anesthesia residents in year 1 and 16 Clinical Anesthesia residents in year 3 from three residency programs individually obtained informed consent for anesthesia for an urgent laparotomy from a standardized patient complaining of pain. Encounters were assessed for ordering pain medication, for patient-resident interactions by using the Empathic Communication Coding System to code responses to pain and nausea cues, and for the content of the informed consent discussion., Results: Of the 65 residents, 56 (86%) ordered pain medication, at an average of 4.2 min (95% CI, 3.2 to 5.1) into the encounter; 9 (14%) did not order pain medication. Resident responses to the cues averaged between perfunctory recognition and implicit recognition (mean, 1.7 [95% CI, 1.6 to 1.9]) in the 0 (less empathic) to 6 (more empathic) system. Responses were lower for residents who did not order pain medication (mean, 1.2 [95% CI, 0.8 to 1.6]) and similar for those who ordered medication before informed consent signing (mean, 1.9 [95% CI, 1.6 to 2.1]) and after signing (mean, 1.9 [95% CI, 1.6 to 2.0]; F (2, 62) = 4.21; P = 0.019; partial η = 0.120). There were significant differences between residents who ordered pain medication before informed consent and those who did not order pain medication and between residents who ordered pain medication after informed consent signing and those who did not., Conclusions: In a simulated preoperative evaluation, anesthesia residents have variable and, at times, flawed recognition of patient cues, responsiveness to patient cues, pain management, and patient interactions.

The goal of this study was to determine if modification of currently available maintenance foods with alternative ingredients, botanicals (fruit and vegetables), and increased amounts of functional lipids (fish oil) would delay the age-associated decline in glomerular filtration rate (GFR) and lean body mass (LBM) in senior-adult cats. Forty-four healthy cats (mean age, 12.2 years; range 10.7 to 14.0 years) were fed one of three foods ( n = 14 or 15 per group) for six months: control food with 32.6% protein (as fed), or control food supplemented with increasing amounts of functional food bioactives: fish oil, fruit and vegetables, different protein sources, and <32.0% protein [functional foods one (FF1) and two (FF2)]. Senior-adult cats were compared before and after the feeding trial with 20 young-adult cats (mean age, 3.5 years; range 2.1 to 4.9 years). Compared with younger cats, older cats had decreased lean-body percent and serum albumin concentrations. Feeding FF1 and FF2 for six months increased lean-body percent, maintained serum albumin concentrations, increased GFR, decreased serum symmetric dimethylarginine (SDMA) concentrations, and decreased concentrations of the uremic toxin 3-indoxyl sulfate. These dietary changes may assist in offsetting sarcopenia and the chronic inflammation associated with aging in senior-adult cats.

Objectives: Retrospective, cross-sectional estimates of pregnancy intention, as used in the Demographic Health Survey (DHS), are the global norm. The London Measure of Unplanned Pregnancy (LMUP) is a newer, psychometrically validated measure which may be more reliable. This paper assesses the reliability of the LMUP and the DHS question over the first postnatal year and explores the effects of maternal characteristics or pregnancy outcome on reported pregnancy intention., Methods: We compared the test-retest reliability of the LMUP (using the AC coefficient) and DHS question (using the weighted Kappa) over the first postnatal year using data from Malawian women. We investigated the effect of maternal characteristics and pregnancy outcome using t-tests, Chi squared or Fisher's exact tests, and calculated odds ratios to estimate effect size., Results: The DHS question was associated with a statistically significant decrease in the prevalence of unplanned pregnancies from 1-to-12 months postnatally; the LMUP was not. The LMUP had moderate to substantial reliability (0.51-0.66); the DHS had moderate reliability (0.56-0.58). The LMUP's stability was not related to any of the factors examined; the stability of the DHS varied by marital status (p = 0.033), number of children (p = 0.048) and postnatal depression (p < 0.001). Both underestimated unintended pregnancy postnatally vis-à-vis the LMUP in pregnancy., Conclusions for Practice: The LMUP is a more reliable measure of pregnancy intention than the DHS in the first postnatal year and does not vary by maternal characteristics or pregnancy outcome. The LMUP should become the gold-standard for measuring pregnancy intention and should be collected in pregnancy or at the first postnatal opportunity.

Introduction: Globally, over half of pregnancies in developed countries are unplanned. Identifying and understanding the prevalence and complexity surrounding pregnancy preparation among Australian women is vital to enable sensitive, responsive approaches to addressing preconception and long-term health improvements for these women with varying motivation levels., Aim: This study evaluated the reliability and validity of a comprehensive pregnancy planning/intention measure (London Measure of Unplanned Pregnancy) in a population of pregnant women (over 18 years of age) in Australia., Methods: A psychometric evaluation, within a cross-sectional study comprising cognitive interviews (to assess comprehension and acceptability) and a field test. Pregnant women aged over 18 years were recruited in early pregnancy (approximately 12 weeks' gestation). Reliability (internal consistency) was assessed using Cronbach's alpha, corrected item-total correlations and inter-item correlations, and stability via a test-retest. Construct validity was assessed using principal components analysis and hypothesis testing., Results: Six women participated in cognitive interviews and 317 in the field test. The London Measure of Unplanned Pregnancy was acceptable and well comprehended. Reliability testing demonstrated good internal consistency (alpha = 0.81, all corrected item-total correlations >0.20, all inter-item correlations positive) and excellent stability (weighted kappa = 0.92). Validity testing confirmed the unidimensional structure of the measure and all hypotheses were confirmed., Conclusions: The London Measure of Unplanned Pregnancy is a valid and reliable measure of pregnancy planning/intention for the Australian population. Implementation of this measure into all maternity healthcare, research and policy settings will provide accurate population-level pregnancy planning estimates to inform, monitor and evaluate interventions to improve preconception health in Australia., Competing Interests: We acknowledge Medibank Private Limited for supporting this research. Medibank Private Limited provided funding and in-kind support to enable study recruitment, which would not have otherwise been possible. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Low back pain (LBP) and sciatica place significant burden on individuals and healthcare systems, with societal costs alone likely to be in excess of £15 billion. Two recent systematic reviews for LBP and sciatica identified a shortage of modelling studies in both conditions., Objectives: The aim of this systematic review was to document existing model-based economic evaluations for the treatment and management of both conditions; critically appraise current modelling techniques, analytical methods, data inputs, and structure, using narrative synthesis; and identify unresolved methodological problems and gaps in the literature., Methods: A systematic literature review was conducted whereby 6512 records were extracted from 11 databases, with no date limits imposed. Studies were abstracted according to a predesigned protocol, whereby they must be economic evaluations that employed an economic decision model and considered any management approach for LBP and sciatica. Study abstraction was initially performed by one reviewer who removed duplicates and screened titles to remove irrelevant studies. Overall, 133 potential studies for inclusion were then screened independently by other reviewers. Consensus was reached between reviewers regarding final inclusion., Results: Twenty-one publications of 20 unique models were included in the review, five of which were modelling studies in LBP and 16 in sciatica. Results revealed a poor standard of modelling in both conditions, particularly regarding modelling techniques, analytical methods, and data quality. Specific issues relate to inappropriate representation of both conditions in terms of health states, insufficient time horizons, and use of inappropriate utility values., Conclusion: High-quality modelling studies, which reflect modelling best practice, as well as contemporary clinical understandings of both conditions, are required to enhance the economic evidence for treatments for both conditions.

Interhospital transfers are independently associated with inpatient mortality, and transferred patients have worse outcomes. The aim of this study was to retrospectively assess the 48-hour mortality rate in interhospital transfer cohorts of all transfers to a Central Texas teaching hospital and to identify a primary admitting diagnosis for potential intervention. A total of 15,435 patients with 19,161 transfers over the course of the study were retrospectively reviewed and placed in 18 different categories based upon the primary admitting diagnosis. There were about 5000 transfer patients yearly with ∼1.4% deaths within 48 hours of arrival. The three leading categories for transferred patients were cardiovascular, neurologic, and psychiatric. In this group, 268 of 19,161 transfers died within 48 hours of arrival. Despite being the 10th leading category for transfer, sepsis was the leading primary admitting diagnosis of patients who died within 48 hours of arrival, accounting for nearly 22% of those patients. Given the significant association found between sepsis and 48-hour mortality after transfer, we devised a novel interhospital transfer checklist based upon the Surviving Sepsis guidelines in an attempt to decrease mortality associated with these transfers., (© 2019 Baylor University Medical Center.)

Innate lymphoid cells (ILCs) promote tissue homeostasis and immune defense but also contribute to inflammatory diseases. ILCs exhibit phenotypic and functional plasticity in response to environmental stimuli, yet the transcriptional regulatory networks (TRNs) that control ILC function are largely unknown. Here, we integrate gene expression and chromatin accessibility data to infer regulatory interactions between transcription factors (TFs) and genes within intestinal type 1, 2, and 3 ILC subsets. We predicted the "core" TFs driving ILC identities, organized TFs into cooperative modules controlling distinct gene programs, and validated roles for c-MAF and BCL6 as regulators affecting type 1 and type 3 ILC lineages. The ILC network revealed alternative-lineage-gene repression, a mechanism that may contribute to reported plasticity between ILC subsets. By connecting TFs to genes, the TRNs suggest means to selectively regulate ILC effector functions, while our network approach is broadly applicable to identifying regulators in other in vivo cell populations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We present five studies investigating the predictive validity of thin slices of nonverbal behavior (NVB). Predictive validity of thin slices refers to how well behavior slices excerpted from longer video predict other measured variables. Using six NVBs, we compared predictive validity of slices of different lengths with that obtained when coding is based on full-length (5-min) video, investigating the relative predictive validity of 1-min slices as well as of cumulative slices. Results indicate some loss in predictive validity with 1-min slices, but relatively little loss when Slices 1 and 2 were combined for five of the six NVBs. This research establishes an empirical basis on which researchers can decide how much of their recorded corpus needs to be coded for NVB. The results also provide some guidance on effect sizes in power analyses for researchers coding specific behaviors in a thin-slice design.

Aims: There are limited data on aspirin (ASA) desensitization for patients with coronary disease. We present our experience with a rapid nurse-led oral desensitization regimen in patients with aspirin sensitivity undergoing coronary angiography., Methods: This single-center retrospective observational study includes patients with a history of ASA sensitivity undergoing coronary angiography with intent to perform percutaneous coronary intervention (PCI)., Results: Between January 2012 and January 2017, 24 patients undergoing coronary angiography for stable coronary disease (7 cases) or acute coronary syndromes (non-ST-segment myocardial infarction [NSTEMI; 8 cases], STEMI [9 cases]) underwent aspirin desensitization having reported previous reactions to aspirin. At initial presentation, previous sensitivity reactions were reported as: mucocutaneous reactions in 17 patients (urticaria in 3 [13%], nonurticarial rash in 6 [25%], angio-oedema in 8 [33%]), respiratory sensitivity in 4 (17%), and systemic anaphylactoid reactions in 3 (13%). Seventeen (71%) patients underwent PCI. Desensitization was acutely successful in 22 (92%) patients and unsuccessful in 2 (8%) patients who both had a single short-lived episode of acute bronchospasm treated successfully with nebulized salbutamol. Fifteen successfully desensitized patients completed 12 months of aspirin; no patient had recurrent hypersensitivity reaction. Aspirin was stopped prior to 12 months in 7 patients (replaced by warfarin [1 case], no antiplatelet or single antiplatelet clinically indicated and clopidogrel chosen [4 cases], patient choice without evidence of recurrent hypersensitivity [1 case], and death due to cardiogenic shock following STEMI [1 case])., Conclusion: A rapid aspirin desensitization protocol is safe and effective across a broad spectrum of hypersensitivity reactions and clinical presentations.

Liquid biopsy testing is a new laboratory-based method that detects tumour mutations in circulating free DNA (cfDNA) derived from minimally invasive blood sampling techniques. Recognising the significance for clinical testing, in 2017, IQN Path provided external quality assessment for liquid biopsy testing. Representatives of those participating laboratories were invited to attend a workshop to discuss the findings and how to achieve quality implementation of cfDNA testing in the clinical setting, the discussion and outcomes of this consensus meeting are described below. Predictive molecular profiling using tumour tissue in order to select cancer patients eligible for targeted therapy is now routine in diagnostic pathology. If insufficient tumour tissue material is available, in some circumstances, recent European Medicines Agency (EMA) guidance recommends mutation testing with plasma cfDNA. Clinical applications of cfDNA include treatment selection based on clinically relevant mutations derived from pre-treatment samples and the detection of resistant mutations upon progression of the disease. In order to identify tumour-related mutations in amongst other nucleic acid material found in plasma samples, highly sensitive laboratory methods are needed. In the workshop, we discussed the variable approaches taken with regard to cfDNA extraction methods, the tests, and considered the impact of false-negative test results. We explored the lack of standardisation of complex testing procedures ranging from plasma collection, transport, processing and storage, cfDNA extraction, and mutation analysis, to interpretation and reporting of results. We will also address the current status of clinical validation and clinical utility, and its use in current diagnosis. This workshop revealed a need for guidelines on with standardised procedures for clinical cfDNA testing and reporting, and a requirement for cfDNA-based external quality assessment programs.

Objective: A vast network involving the nodules and overlying cortices is believed to be responsible for the epileptogenicity in gray matter heterotopia with multiple nodules, which often associated with difficult-to-treat epilepsy. We sought to determine if functional magnetic resonance imaging (fMRI) could detect internodular functional connectivity (FC), and if this connectivity reflects an actual synchronized neuronal activity and partakes in epileptogenicity., Methods: We studied 16 epilepsy patients with multiple heterotopic nodules; eight underwent subsequent intracerebral EEG. We examined the internodular FC using fMRI and its correspondence with internodular synchrony of intracerebral interictal activity. We then compared the spreading speed of ictal activity between connected and unconnected nodules; and the FC among possible combinations of nodule pairs in terms of their involvement at seizure onset., Results: Seventy nodules were studied: 83% have significant connection to at least one other nodule. Among the 49 pairs studied with intracerebral EEG, (1) synchronized interictal activity is more prevalent in fMRI-connected pairs ( P  < 0.05), (2) ictal activity spreads faster between connected pairs ( P  < 0.0001), and (3) stronger FC was observed between pairs in which both nodules were involved at seizure onset ( P  < 0.01)., Interpretation: fMRI could reliably and noninvasively detect the FC between heterotopic nodules. These functional connections correspond to the synchrony of interictal epileptic activity between the nodules and to the ability of nodules to generate synchronous seizure onsets or rapid seizure spread. These findings may help in understanding the complexity of the epileptogenic network in multiple heterotopic nodules and better targeting the likely epileptogenic nodules., Competing Interests: The authors report no disclosures relevant to the manuscript.

The aim of this study was to promote nursing and practitioner satisfaction by improving communication and reducing rapid response team (RRT) activations and code blues hospitalwide by implementing the nursing cheat sheet, a list of key steps to be done before calling the primary provider. This prospective observational study took place over a year at a 636-bed teaching hospital in Central Texas. Education regarding the nursing cheat sheet was provided to nurses at monthly meetings, unit huddles, and interdisciplinary rounds. Units received monthly follow-up education and reminders, and the nursing cheat sheet was posted at nursing work areas. RRT activations and code blues were counted daily. After implementing the nursing cheat sheet, RRT activations were lower than the pre-intervention average and were outside the control band for July, August, and November. The number of code blues did not deviate from the control bands. The authors did not see a reduction in code blues after implementation of the nursing cheat sheet, but the average number of RRT activations decreased, indicating a significant difference in the number of RRT activations. It is not clear that this decrease was due to the intervention.

Transcriptional regulatory networks (TRNs) provide insight into cellular behavior by describing interactions between transcription factors (TFs) and their gene targets. The assay for transposase-accessible chromatin (ATAC)-seq, coupled with TF motif analysis, provides indirect evidence of chromatin binding for hundreds of TFs genome-wide. Here, we propose methods for TRN inference in a mammalian setting, using ATAC-seq data to improve gene expression modeling. We test our methods in the context of T Helper Cell Type 17 (Th17) differentiation, generating new ATAC-seq data to complement existing Th17 genomic resources. In this resource-rich mammalian setting, our extensive benchmarking provides quantitative, genome-scale evaluation of TRN inference, combining ATAC-seq and RNA-seq data. We refine and extend our previous Th17 TRN, using our new TRN inference methods to integrate all Th17 data (gene expression, ATAC-seq, TF knockouts, and ChIP-seq). We highlight newly discovered roles for individual TFs and groups of TFs ("TF-TF modules") in Th17 gene regulation. Given the popularity of ATAC-seq, which provides high-resolution with low sample input requirements, we anticipate that our methods will improve TRN inference in new mammalian systems, especially in vivo, for cells directly from humans and animal models., (© 2019 Miraldi et al.; Published by Cold Spring Harbor Laboratory Press.)

Most cancer-related deaths are a result of metastasis, and thus the importance of this process as a target of therapy cannot be understated. By asking 'how can we effectively treat cancer?', we do not capture the complexity of a disease encompassing >200 different cancer types - many consisting of multiple subtypes - with considerable intratumoural heterogeneity, which can result in variable responses to a specific therapy. Moreover, we have much less information on the pathophysiological characteristics of metastases than is available for the primary tumour. Most disseminated tumour cells that arrive in distant tissues, surrounded by unfamiliar cells and a foreign microenvironment, are likely to die; however, those that survive can generate metastatic tumours with a markedly different biology from that of the primary tumour. To treat metastasis effectively, we must inhibit fundamental metastatic processes and develop specific preclinical and clinical strategies that do not rely on primary tumour responses. To address this crucial issue, Cancer Research UK and Cancer Therapeutics CRC Australia formed a Metastasis Working Group with representatives from not-for-profit, academic, government, industry and regulatory bodies in order to develop recommendations on how to tackle the challenges associated with treating (micro)metastatic disease. Herein, we describe the challenges identified as well as the proposed approaches for discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer.

Innate lymphoid cells (ILC) are lymphocytes that lack an antigen-specific receptor and are preferentially localized in non-lymphoid tissues, such as mucosal barriers. In these locations ILC respond to tissue perturbations by producing factors that promote tissue repair and improve barrier integrity. We show that mice lacking the Tec kinase ITK have impaired intestinal tissue integrity, and a reduced ability to restore homeostasis after tissue damage. This defect is associated with a substantial loss of Type 2 ILC (ILC2) in the intestinal lamina propria. Adoptive transfer of bone marrow ILC2 precursors confirms a cell-intrinsic role for ITK. Intestinal ILC2 numbers in Itk -/- mice are restored by the administration of IL-2 complexes, also leading to improved intestinal tissue damage repair. Reduced Bcl-2 expression in intestinal Itk -/- ILC2 is also restored to WT levels after IL-2 complex treatment, indicating a tissue-specific role for ITK in ILC2 survival in the intestine.

A prospective, randomised, 6-month feeding trial was performed in 28 adult cats with International Renal Interest Society (IRIS) stage 1 and 2 chronic kidney disease (CKD). All cats were assigned to either a control food: Royal Canin Renal Support A Feline, dry or a test food: Hill's Prescription Diet k/d Feline with chicken, dry. Food intake was recorded daily; body weight weekly; and serum, urine, dual-energy x-ray absorptiometry (DEXA) and body condition assessments were performed at 0, 1, 3 and 6 months. Twenty cats (9 control, 11 test group) completed the study according to protocol. Cats consuming control food had significant loss of body weight (n=14; mean, -13.0 per cent, P<0.0001) and lean body mass (LBM; mean, -11.1 per cent, P<0.0001) over the 6-month feeding period, whereas cats consuming test food had a significant increase in body weight (n=14; mean, 5.8 per cent, P=0.003) and no change in LBM (P=0.42). Cats consumed 23 per cent more calories (P=0.05) when fed test food (mean, 207.1 kcal/day) compared with cats fed control food (mean, 168.0 kcal/day). Serum creatinine increased at a faster rate (P=0.0004) in cats consuming control food compared with cats consuming test food. Cats consuming test food had increased caloric and essential amino acid intake, increased body weight, stable biomarkers of kidney function and maintained LBM compared with cats consuming control food., Competing Interests: Competing interests: None declared., (© British Veterinary Association 2018. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Objective: Surgical specimens from patients with mesial temporal lobe epilepsy (MTLE) show abnormalities in tissue concentrations of metabotropic glutamate receptor type 5 (mGluR5). To clarify whether these abnormalities are specific to the epileptogenic zone (EZ), we characterized in vivo whole-brain mGluR5 availability in MTLE patients using positron emission tomography (PET) and [ 11 C]ABP688, a radioligand that binds specifically to the mGluR5 allosteric site., Methods: Thirty-one unilateral MTLE patients and 30 healthy controls underwent [ 11 C]ABP688 PET. We compared partial volume corrected [ 11 C]ABP688 nondisplaceable binding potentials (BP ND ) between groups using region-of-interest and whole-brain voxelwise analyses. [ 18 F]Fluorodeoxyglucose (FDG) PET was acquired in 15 patients, for whom we calculated asymmetry indices of [ 11 C]ABP688 BP ND and [ 18 F]FDG uptake to compare lateralization and localization differences., Results: [ 11 C]ABP688 BP ND was focally reduced in the epileptogenic hippocampal head and amygdala (p < 0.001). Patients with hippocampal atrophy showed more extensive abnormalities, including the ipsilateral temporal neocortex (p = 0.006). [ 11 C]ABP688 BP ND showed interhemispheric differences of higher magnitude and discriminated the epileptogenic structures more accurately when compared to [ 18 F]FDG uptake, which showed more widespread hypometabolism. Among 23 of 25 operated patients with >1 year of follow-up, 13 were seizure-free (Engel Ia) and showed significantly lower [ 11 C]ABP688 BP ND in the ipsilateral entorhinal cortex., Interpretation: [ 11 C]ABP688 PET provides a focal biomarker for the EZ in MTLE with higher spatial accuracy compared to [ 18 F]FDG PET. Focally reduced mGluR5 availability in the EZ might reflect receptor internalization or conformational changes in response to excessive extracellular glutamate, supporting a potential role for mGluR5 as therapeutic target in human MTLE. Ann Neurol 2019; 1-11 ANN NEUROL 2019;85:218-228., (© 2018 American Neurological Association.)

Sea-level rise (SLR) is not just a future trend; it is occurring now in most coastal regions across the globe. It thus impacts not only long-range planning in coastal environments, but also emergency preparedness. Its inevitability and irreversibility on long time scales, in addition to its spatial non-uniformity, uncertain magnitude and timing, and capacity to drive non-stationarity in coastal flooding on planning and engineering timescales, create unique challenges for coastal risk-management decision processes. This review assesses past United States federal efforts to synthesize evolving SLR science in support of coastal risk management. In particular, it outlines the: (1) evolution in global SLR scenarios to those using a risk-based perspective that also considers low-probability but high-consequence outcomes, (2) regionalization of the global scenarios, and (3) use of probabilistic approaches. It also describes efforts to further contextualize regional scenarios by combining local mean sea-level changes with extreme water level projections. Finally, it offers perspectives on key issues relevant to the future uptake, interpretation, and application of sea-level change scenarios in decision-making. These perspectives have utility for efforts to craft standards and guidance for preparedness and resilience measures to reduce the risk of coastal flooding and other impacts related to SLR., Competing Interests: Disclosure statement No potential conflict of interest was reported by the authors.

The field of nonverbal communication (NVC) has a long history involving many cue modalities, including face, voice, body, touch, and interpersonal space; different levels of analysis, including normative, group, and individual differences; and many substantive themes that cross from psychology into other disciplines. In this review, we focus on NVC as it pertains to individuals and social interaction. We concentrate specifically on ( a) the meanings and correlates of cues that are enacted (sent) by encoders and ( b) the perception of nonverbal cues and the accuracy of such perception. Frameworks are presented for conceptualizing and understanding the process of sending and receiving nonverbal cues. Measurement issues are discussed, and theoretical issues and new developments are covered briefly. Although our review is primarily oriented within social and personality psychology, the interdisciplinary nature of NVC is evident in the growing body of research on NVC across many areas of scientific inquiry.

The empathy concept has central significance for social and personality psychology and in many other domains, including neuroscience, clinical/abnormal psychology, and the health professions. However, the current diversity in conceptual and operational definitions, and the promiscuous use of the term "empathy," threaten the ability of researchers to advance the field. The present article provides a quantitative review and conceptual analysis of empathy definitions and usages by examining 393 studies published between 2001 and 2013, and 96 studies published in 2017. We document the prevalence and diversity of definitions, as well as inconsistencies between conceptual definitions and measurements employed. We discuss ways to refine the conceptualization and operationalization of the empathy construct, including for many purposes, bypassing the term empathy in favor of lower-level construct labels that more precisely describe what is actually being measured. In many cases we see no added theoretical or empirical value in applying the term empathy.

[This corrects the article DOI: 10.1038/s42003-018-0119-2.].

Objective: Understanding nonverbal behavior is key to the research, teaching, and practice of clinical communication. However, the measurement of nonverbal behavior can be complex and time-intensive. There are many decisions to make and factors to consider when coding nonverbal behaviors., Methods: Based on our experience conducting nonverbal behavior research in clinical interactions, we developed practical advice and strategies for coding nonverbal behavior in clinical communication, including a checklist of questions to consider for any nonverbal coding project., Results: We provide suggestions for beginning the nonverbal coding process, operationalizing the coding approach, and conducting the coding., Conclusion: A key to decision-making around nonverbal behavior coding is establishing clear research questions and using these to guide the process., Practice Implications: The field needs more coding of nonverbal behavior to better describe what happens in clinical interactions, to understand why nonverbal behaviors occur, and to determine the predictors and consequences of nonverbal behaviors in clinical interactions. A larger evidence base can inform better teaching practices and communication interventions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Intestinal absorption of immunoglobulins is critical for health and survival of newborn calves because there is no transfer of immunoglobulins in utero. The objective of this study was to determine if feeding beef cows Se-enriched alfalfa hay during the last trimester of gestation improves passive transfer of ovalbumin (OVA), a surrogate protein marker for IgG absorption. Control cows (n = 15) were fed non-Se-fortified alfalfa hay (5.3 mg Se/head daily) plus a mineral supplement containing inorganic Se (3 mg Se/head daily). Med-Se (n = 15) and High-Se cows (n = 15) were fed Se-biofortified alfalfa hay (27.6 and 57.5 mg Se/head daily, respectively); both groups received mineral supplement without added Se. Calves were randomly assigned to receive orally administered OVA at 12, 24, or 36 h of age. Calves that received their oral dose of OVA at 12 h of age had higher serum OVA concentrations across the first 48 h of life if born to High-Se cows compared to calves born to Control cows (P = 0.05), with intermediate values for calves born to Med-Se cows. Our results, using OVA as a model for passive transfer, suggest that if calves do not receive adequate colostrum to reach maximum pinocytosis, then supranutritional Se supplementation in beef cattle may improve passive transfer in their calves, if calves receive colostrum within the first 12 h of age., (Published by Elsevier GmbH.)

Food intake changes circulating metabolite concentrations. Thus, a comparison of circulating metabolites between dogs and cats is necessarily confounded by the composition of foods offered. The objective of this study was to determine differences between dogs and cats when given the opportunity to choose their own macronutrient intake. Four experimental foods with similar palatability, but varying in macronutrient content were prepared for dogs, and four for cats. Foods were available to dogs ( n =17) for food intake once a day and to cats ( n =27) at all times. Food 1 was high protein; Food 2 was high fat; Food 3 was high carbohydrates and Food 4 was balanced for macronutrients. By choosing a combination of foods, each animal could individually set its own macronutrient intake. Plasma metabolomics were determined after pets had consumed their food intake of choice for 28 days. Cats had higher concentrations of the essential amino acids histidine, isoleucine, phenylalanine and valine, but lower concentrations of lysine, methionine and threonine compared with dogs. Overall, non-essential amino acids were higher in cats. Regarding lipids, cats had increased concentrations of highly polyunsaturated fatty acids (PUFA) after 28 days, although arachidonic acid (AA) was consistently higher in dogs. Regarding circulating microbial metabolites, there was more stability for dogs compared with cats (none changed over time in dogs versus 42% changed in cats; P <0.01). Concentrations of urea cycle intermediates, antioxidants and methylated compounds were also different between species. In conclusion, metabolite differences between dogs and cats reflected differences in species and food choices., Competing Interests: Competing interestsHill's Pet Nutrition, Inc. provided support in the form of salaries for authors [J.C.V., M.A.V., D.E.J.], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript., (© 2018. Published by The Company of Biologists Ltd.)

Background: The PRAMI and CvLPRIT trials support preventive percutaneous coronary intervention (PCI) for multivessel coronary disease found during ST-segment elevation myocardial infarction (STEMI). We assess our real-world experience of the management of multivessel disease identified during primary PCI (PPCI) in a large UK regional centre., Patients and Methods: All STEMI patients who underwent culprit-only PPCI during the study period (August 2011 to August 2013) were retrospectively assessed for eligibility to each trial. The two resulting groups were designated as the 'observational' cohorts. Primary outcomes were then determined and compared with the culprit-only revascularisation cohorts from the respective published randomized controlled trials (RCTs)., Results: A total of 1143 consecutive cases were presented during the study period. Of these, 343 would have been suitable for inclusion to PRAMI and were included in the 'observational PRAMI' cohort; 196 patients were included in the 'observational CvLPRIT' cohort.The 'observational PRAMI' cohort experienced fewer primary outcome events (13.1 vs. 22.9%), cardiac deaths (0.6 vs. 4.3%) and nonfatal myocardial infarctions (3.5 vs. 8.7%) than the culprit-only PCI PRAMI cohort (n=231); there were significantly more diabetics (P=0.022) and anterior STEMI initial presentations in the culprit-only PCI PRAMI cohort. Primary outcomes were comparable to those of the preventive PCI PRAMI cohort.The 'observational CvLPRIT' cohort showed no significant difference in primary outcomes over 12 months (16.8 vs. 21.2%), but significantly lower all-cause mortality (2 vs. 6.9%) than the culprit-only PCI CvPLRIT cohort (n=146). The 30-day event rates were similar to the preventive PCI arm; the 12-month events were better than the nonpreventive, but not as good as the preventive RCT cohorts., Conclusion: Outcomes from culprit-only primary PCI for multivessel disease in patients selected by the RCT criteria from an all-comers population representing real-life experience are better than those published in the two main RCTs. The RCTs may have selected a high-risk population for study exaggerating the benefits of preventive PCI.

Aims: In addition to providing external quality assessment (EQA) schemes, United Kingdom National External Quality Assessment service (UK NEQAS) for Molecular Genetics also supports the education of laboratories. As an enhancement to the Molecular Pathology EQA scheme, a human cell-line reference sample, manufactured by Thermo Fisher Scientific (AcroMetrix), was provided for analysis. This contained many variants, present at frequencies between 1% and 17.9%., Methods: One hundred and one laboratories submitted results, with a total of 2889 test results on 53 genes being reported. Known polymorphisms, 46/2889 (1.59%) results, were excluded. Variants detected in the seven most commonly reported (and clinically relevant) genes, KRAS, NRAS, BRAF, EGFR, PIK3CA, KIT and PDGFRA , are reported here, as these genes fall within the scope of UK NEQAS EQA schemes., Results: Next generation sequencing (NGS) was the most commonly performed testing platform. There were between 5 and 27 validated variants in the seven genes reported here. Eight laboratories correctly reported all five NRAS variants, and two correctly reported all eight BRAF variants. The validated mean variant frequency was lower than that determined by participating laboratories, with single-gene testing methodologies showing less variation in estimated frequencies than NGS platforms. Laboratories were more likely to correctly identify clinically relevant variants., Conclusions: Over 100 laboratories took the opportunity to test the 'educational reference sample', showing a willingness to further validate their testing platforms. While it was encouraging to see that the most widely reported variants were those which should be included in routine testing panels, reporting of variants was potentially open to interpretation, thus clarity is still required on whether laboratories selectively reported variants, by either clinical relevance or variant frequency., Competing Interests: Competing interests: NN, MB, AL and KLN were employed by Thermo Fisher Scientific. Other authors have no competing interest to declare., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Background: It is unclear whether unintended pregnancies are associated with adverse outcomes. Data are predominantly from high-income countries and have methodological limitations, calling the findings into question. This research was designed to overcome these limitations and assess the relationships between pregnancy intention and miscarriage, stillbirth, low birthweight, neonatal death and postnatal depression in a low-income country., Methods: The pregnancy intention of 4,244 pregnant women in Mchinji District, Malawi, was measured using the validated Chichewa version of the London Measure of Unplanned Pregnancy (LMUP). Women were re-interviewed postnatally to assess pregnancy outcome. Postnatal depression was assessed using the WHO's Self-Reporting Questionnaire. Multivariable regressions were conducted, with the choice of confounders informed by a pre-existing conceptual epidemiological hierarchy., Results: Planned pregnancies are associated with a reduced risk of any (adjusted RR 0.90 [95%CI 0.86, 0.95]) or high symptoms of depression (adjusted RR 0.76 [95%CI 0.63, 0.91]) compared to unplanned pregnancies in rural Malawi. There was no relationship between pregnancy intention and the composite measure of miscarriage, stillbirth, low birthweight and neonatal death. There was some evidence that greater pregnancy intention was associated with reduced adjusted risk of stillbirth (0·93 [95%CI 0·87, 1·00])., Conclusion: Our study is the first to use a psychometrically valid measure of pregnancy intention, and to do so antenatally. As pregnancy intention increases, the risk of postnatal depression and, possibly, stillbirth decreases. This suggests a new, clinical use for the LMUP; identifying women antenatally who are at risk of these adverse pregnancy outcomes., Competing Interests: The authors have declared that no competing interests exist.