Search

Exposure to extreme temperatures can trigger a cascade of adverse cardiovascular and respiratory events. However, in Cyprus, a hotspot of climate change in the Eastern Mediterranean region, little is known about the temperature-related cardiorespiratory morbidity risks. We analyzed daily counts of hospital admissions for cardiovascular and respiratory diseases from four general hospitals in three districts in Cyprus from 2000 through 2019. For each district, we fitted time-series quasi-Poisson regression with distributed lag non-linear models to analyze the associations between daily mean temperature (lag 0–21 d) and hospital admissions for cardiorespiratory, cardiovascular, and respiratory diseases. A random-effects meta-analytical model was then applied to pool the district-specific estimates and obtain the national average associations. We analyzed 20 years of cause-specific hospitalization data with a total of 179 988 cardiovascular and respiratory events. The relationships between cardiorespiratory morbidity and temperature were overall U-shaped. During extreme temperature days, 15.85% (95% empirical CI [eCI]: 8.24, 22.40%) excess cardiovascular hospitalizations and 9.59% (95% eCI: −0.66, 18.69%) excess respiratory hospitalizations were attributable to extreme cold days (below the 2.5th percentile). Extreme hot days (above the 97.5th percentile) accounted for 0.17% (95% eCI: 0.03, 0.29%) excess cardiovascular hospitalizations and 0.23% (95% eCI: 0.07, 0.35%) excess respiratory hospitalizations. We found evidence of increased cardiovascular morbidity risk associated with extreme temperatures in Cyprus. Our study highlights the necessity to implement public health interventions and adaptive measures to mitigate the related temperature effects in an understudied region.

Amplification of the epidermal growth factor receptor gene (EGFR) represents one of the most commonly observed genetic lesions in glioblastoma (GBM); however, therapies targeting this signaling pathway have failed clinically. Here, using human tumors, primary patient-derived xenografts (PDX), and a murine model for GBM, we demonstrate that EGFR inhibition leads to increased invasion of tumor cells. Further, EGFR inhibitor-treated GBM demonstrates altered oxidative stress, with increased lipid peroxidation, and generation of toxic lipid peroxidation products. A tumor cell subpopulation with elevated aldehyde dehydrogenase (ALDH) levels was determined to comprise a significant proportion of the invasive cells observed in EGFR inhibitor-treated GBM. Our analysis of the ALDH1A1 protein in newly diagnosed GBM revealed detectable ALDH1A1 expression in 69% (35/51) of the cases, but in relatively low percentages of tumor cells. Analysis of paired human GBM before and after EGFR inhibitor therapy showed an increase in ALDH1A1 expression in EGFR-amplified tumors (P < 0.05, n = 13 tumor pairs), and in murine GBM ALDH1A1-high clones were more resistant to EGFR inhibition than ALDH1A1-low clones. Our data identify ALDH levels as a biomarker of GBM cells with high invasive potential, altered oxidative stress, and resistance to EGFR inhibition, and reveal a therapeutic target whose inhibition should limit GBM invasion.

Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.

Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

Glioblastoma is a particularly challenging cancer, as there are currently limited options for treatment. New delivery routes are being explored, including direct intratumoral injection via convection-enhanced delivery (CED). While promising, convection-enhanced delivery of traditional chemotherapeutics such as doxorubicin (DOX) has seen limited success. Several studies have demonstrated that attaching a drug to polymeric nanoscale materials can improve drug delivery efficacy via CED. We therefore set out to evaluate a panel of morphologically distinct protein nanoparticles for their potential as CED drug delivery vehicles for glioblastoma treatment. The panel consisted of three different virus-like particles (VLPs), MS2 spheres, tobacco mosaic virus (TMV) disks and nanophage filamentous rods modified with DOX. While all three VLPs displayed adequate drug delivery and cell uptake in vitro, increased survival rates were only observed for glioma-bearing mice that were treated via CED with TMV disks and MS2 spheres conjugated to doxorubicin, with TMV-treated mice showing the best response. Importantly, these improved survival rates were observed after only a single VLP⁻DOX CED injection several orders of magnitude smaller than traditional IV doses. Overall, this study underscores the potential of nanoscale chemotherapeutic CED using virus-like particles and illustrates the need for further studies into how the overall morphology of VLPs influences their drug delivery properties.

BackgroundDiffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG.MethodsWe performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT.ResultsThirty-one patients were included (8-reRT with nivolumab; 4-reRT alone; 19-no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4 months-reRT alone; 8.3 months-no reRT; p

Within current interfaith dialogue scholarship, perspective transformation towards the religious other is one of the most desired outcomes. However, exactly how such transformed perspectives come about and the characteristics of this transformation have not been adequately researched. In this study, we examine transformative learning within interfaith dialogue. Using a theoretical framework that combines Buber's philosophy of dialogue and transformative learning theory, we equate the transformative process with the dynamics of becoming "Thou." Through thematic analysis of qualitative interview data, we found that transformative learning within this context is contingent upon the creation of genuine and deep relatedness, that are constitutive of becoming "Thou." Our findings report how dynamic relatedness serves as a foundation, a catalyst, and culmination of transformative learning processes. We conclude with a discussion of the implications of these findings and suggestions for future research.

ABSTRACT Considering that literature can work as an instigator of constructive emotions (ROSIEK, 2003), and given that the Sociocultural Historical Theory based on Vygotsky recognizes emotions as an important aspect of the individual’s development (VYGOTSKY, 1989), this study aims at analyzing the multimodal narratives (BARKHUIZEN; BENSON; CHIK, 2014) provided by ten public high school students. Data for this study were generated on-line due to the COVID-19 pandemic and regard their memories of the use of literature in 2018 and 2019. We analyzed the presence of emotions as motivators for engagement and, thus, beneficial for language development, collaborating to fulfill the gap in empirical research on literature and emotions in lessons of English as an Additional Language (PARAN, 2008; BLOEMERT et. al., 2019).

Objectives—To conduct a secondary analysis of prediction accuracy of biophysical markers for suspected Preeclampsia (PE), Fetal Growth Restriction (FGR) and the two combined near delivery in a Slovenian cohort. Methods—This was a secondary analysis of a database of a total 125 Slovenian pregnant women attending a high-risk pregnancy clinic due to suspected PE (n = 31), FGR (n = 16) and PE + FGR (n = 42) from 28–39 weeks gestation and their corresponding term (n = 21) and preterm (PTD, n = 15) controls. Data for Mean Arterial blood Pressure (MAP) and Uterine artery pulsatility index (UtA PI) estimated by Doppler sonography were extracted from the database of patients who were tested at admission to the high-risk clinic with the suspected complications. The reactive hyperemia index (RHI), and the Augmentation Index (AIX%) were extracted from the patient database using measured values obtained with the assistance of the Endo PAT, a device set to measure the signal of the peripheral arterial tone (PAT) from the blood vessels endothelium. Linear regression coefficients, Box and Whisker plots, Area under the Curve (AUC) of receiver Operation Characteristic (ROC) curves, and multiple regression were used to assess the marker accuracy using detection rate (DR) and false-positive rate (FPR) and previously reported cut-offs for estimating the positive and negative predictive value (NPV and PPV). The SPSS non-parametric statistics (Kruskal Wallis and Mann–Whitney) and Spearman’s regression coefficient were used to assess marker accuracy; p < 0.05 was considered significant. Results—MAP values reached diagnostic accuracy (AUC = 1.00, DR = 100%) for early PE cases delivered < 34, whereas UtA Doppler PI values yielded such results for early FGR < 34 weeks and the two combined reached such accuracy for PE + FGR. To reach diagnostic accuracy for all cases of the complications, the Endo PAT markers with values for MAP and UtA Doppler PI were required for cases near delivery. Multiple regression analyses showed added value for advanced maternal age and gestational week in risk assessment for all cases of PE, FGR, and PE + FGR. Spearman’s regression coefficient yielded r > 0.6 for UtA Doppler PI over GA for PE and FGR, whereas for RHI over BMI, the regression coefficient was r > 0.5 (p < 0.001 for each). Very high correlations were also found between UtA Doppler PI and sFlt-1/PlGF or PlGF (r = −0.495, p < 0.001), especially in cases of FGR. Conclusion—The classical biophysical markers MAP and UtA Doppler PI provided diagnostic accuracy for PE and FGR < 34 wks gestation. A multiple biophysical marker analysis was required to reach diagnostic accuracy for all cases of these complications. The UtA Doppler PI and maternal serum sFlt-1/PlGF or PlGF were equally accurate for early cases to enable the choice of the markers for the clinical use according to the more accessible method.

Objective: To compare maternal vascular indices and hemodynamic parameters at 35–37 weeks' gestation in pregnancies complicated by gestational diabetes mellitus (GDM), those with pre‐existing diabetes mellitus (DM) and those without GDM or pre‐existing DM. Methods: This was a prospective observational study in women with a singleton pregnancy attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, and measurement of vascular indices and hemodynamic parameters using a non‐invasive operator‐independent device. These included carotid‐to‐femoral pulse‐wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressure, total peripheral resistance and heart rate. The values in the GDM and pre‐existing DM groups were compared to those in the unaffected group. Results: We examined 6746 women, of whom 396 were excluded because they had chronic hypertension or developed pre‐eclampsia or gestational hypertension. The study population of 6350 pregnancies contained 99 (1.6%) with pre‐existing Type‐I or Type‐II DM and 617 (9.7%) that developed GDM, including 261 (42.3%) that were treated with diet alone, 239 (38.7%) treated with metformin alone and 117 (19.0%) treated with insulin with or without metformin. Among women with GDM and those with pre‐existing DM, compared to those without GDM or pre‐existing DM, there was a higher median cardiac output and heart rate, central systolic and diastolic blood pressure and pulse‐wave velocity, but there was no significant difference in stroke volume or total peripheral resistance. There were no significant differences within the GDM group according to treatment type, except for higher heart rate in women treated with metformin alone compared to the group treated with diet alone. Conclusion: Women with GDM and those with pre‐existing DM have evidence of early vascular disease in the third trimester, and this may contribute to their increased long‐term cardiovascular risk. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Introduction: Poor outcomes following IVF treatments are speculated to be due to the transfer of aneuploid embryos that cannot be identified based on morphological evaluation alone. This leads to patients requiring numerous embryo transfers and, consequently, a prolonged time interval before live birth. Embryo selection following preimplantation genetic testing for aneuploidy (PGT-A) with next-generation sequencing (NGS) has been suggested as an intervention to shorten time to pregnancy in women undergoing in vitro fertilisation (IVF). Past studies assessing the clinical efficacy of PGT-A in improving clinical outcomes have been conflicting and the associated clinical pregnancy rates and live birth rates following the transfer of a mosaic embryos have yet to be determined. None of the existing studies solely included women of advanced reproductive age (ARA). The pilot study and proposed RCT will determine if, compared to morphological evaluation alone, the use of PGT-A through NGS is a more clinically effective, safer, and more cost-effective way to provide IVF treatment in women of advanced reproductive age. Method and Analysis: The proposed pilot study will aim to randomise 100 patients within a single-centre study to evaluate recruitment, randomisation, and adherence to study protocol and allocated trail arms by participating patients. The results of the pilot study will enable us to determine the sample size for a larger study to establish the effectiveness of PGT-A in ARA women. Ethics and Dissemination: The study (Integrated Research Application System Number 236067) received approval from the Health Research Authority and Health and Care Research Wales (HCRW) and the East Midlands—Leicester South Research Ethics Committee (20/EM/0290). The results will be made available to patients, the funders, the Reproductive Medicine societies, and other researchers. Trial registration: ClinicalTrials.gov Identifier: NCT05009745, n. [ABSTRACT FROM AUTHOR]

Objective: To investigate the validity of the conclusion from Cochrane reviews and meta‐analyses that treatment with calcium supplementation during pregnancy reduces the risk for pre‐eclampsia by 55%, which has been influential in international guidelines and future research. Design: Sensitivity analysis of data from Cochrane reviews of trials evaluating high‐dose calcium supplementation (of at least 1 g/day) for reduction of pre‐eclampsia risk. Setting: Systematic review and meta‐analysis. Population: The Cochrane reviews and meta‐analyses included 13 trials enrolling a total of 15 730 women. Random‐effects meta‐analysis of these studies resulted in a mean risk ratio (RR, calcium/placebo) of 0.45 (95% confidence interval [CI] 0.31–0.65; p < 0.0001). Methods: We carried out a sensitivity analysis of evidence from the relevant Cochrane review, to examine the impact of study size. Main outcome measures: pre‐eclampsia. Results: In the three largest studies, accounting for 13 815 (88%) of total recruitment, mean RR was 0.92 (95% CI 0.80–1.06) and there was no evidence of heterogeneity between studies (I2 = 0). With inclusion of the smaller studies, mean RR decreased to 0.45 and I2 increased to 70%. Conclusions: In assessment of the effect of calcium supplementation on pre‐eclampsia risk, the naive focus on the mean of the random‐effects meta‐analysis in the presence of substantial heterogeneity is highly misleading. Linked article: This article is commented on by Thornton pp. 1530–1531 in this issue. To view this article visit https://doi.org/10.1111/1471‐0528.17805. [ABSTRACT FROM AUTHOR]

Objective: To compare maternal vascular indices and hemodynamic parameters at 35–37 weeks' gestation in pregnancies complicated by delivery of a small‐for‐gestational‐age (SGA) or growth‐restricted (FGR) neonate. Methods: This was a prospective observational study of women with a singleton pregnancy attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. The visit included recording of maternal demographic characteristics, medical history, vascular indices and hemodynamic parameters, which were obtained using a non‐invasive operator‐independent device and included pulse‐wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressure, total peripheral resistance and heart rate. Women with hypertensive disorders of pregnancy were excluded. SGA was diagnosed if birth weight was < 10th percentile. FGR was diagnosed if, in addition to birth weight < 10th percentile, at the 35–37‐week scan, uterine artery or umbilical artery pulsatility index (PI) was > 95th percentile or fetal middle cerebral artery PI was < 5th percentile. Results: Among the 6413 women included in the study, there were 605 (9.4%) cases of SGA, 133 (2.1%) cases of FGR and 5675 (88.5%) cases that were unaffected by SGA or FGR. Women with SGA or FGR, compared to unaffected pregnancies, had increased peripheral vascular resistance and reduced cardiac output. Central systolic and diastolic blood pressure were increased in the FGR group compared with the unaffected group. Aortic stiffness, as assessed by pulse‐wave velocity, and augmentation index did not differ between affected and unaffected pregnancies. In the FGR group, compared with the SGA group, central systolic and diastolic blood pressure were higher, whereas heart rate was lower. Conclusions: SGA and FGR pregnancies exhibit deranged maternal hemodynamic responses compared with unaffected pregnancies. Pregnancies with FGR have higher central blood pressure compared to those with SGA, but it remains unclear whether these differences are driven by the size of the fetus or pathological fetal growth. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

The aim of the current study was to investigate the tear proteome in children and adolescents with type 1 diabetes (T1D) compared to healthy controls, and to identify differences in the tear proteome of children with T1D depending on different characteristics of the disease. Fifty-six children with T1D at least one year after diagnosis, aged 6–17 years old, and fifty-six healthy age- and sex-matched controls were enrolled in this cross-sectional study. The proteomic analysis was based on liquid chromatography tandem mass spectrometry (LC-MS/MS) enabling the identification and quantification of the protein content via Data-Independent Acquisition by Neural Networks (DIA-NN). Data are available via ProteomeXchange with the identifier PXD052994. In total, 3302 proteins were identified from tear samples. Two hundred thirty-nine tear proteins were differentially expressed in children with T1D compared to healthy controls. Most of them were involved in the immune response, tissue homeostasis and inflammation. The presence of diabetic ketoacidosis at diagnosis and the level of glycemic control of children with T1D influenced the tear proteome. Tear proteomics analysis revealed a different proteome pattern in children with T1D compared to healthy controls offering insights on deregulated biological processes underlying the pathogenesis of T1D. Differences within the T1D group could unravel biomarkers for early detection of long-term complications of T1D. [ABSTRACT FROM AUTHOR]

Background: The risk of cardiovascular disease (CVD) has traditionally been predicted via the assessment of carotid plaques. In the proposed study, AtheroEdge™ 3.0HDL (AtheroPoint™, Roseville, CA, USA) was designed to demonstrate how well the features obtained from carotid plaques determine the risk of CVD. We hypothesize that hybrid deep learning (HDL) will outperform unidirectional deep learning, bidirectional deep learning, and machine learning (ML) paradigms. Methodology: 500 people who had undergone targeted carotid B-mode ultrasonography and coronary angiography were included in the proposed study. ML feature selection was carried out using three different methods, namely principal component analysis (PCA) pooling, the chi-square test (CST), and the random forest regression (RFR) test. The unidirectional and bidirectional deep learning models were trained, and then six types of novel HDL-based models were designed for CVD risk stratification. The AtheroEdge™ 3.0HDL was scientifically validated using seen and unseen datasets while the reliability and statistical tests were conducted using CST along with p-value significance. The performance of AtheroEdge™ 3.0HDL was evaluated by measuring the p-value and area-under-the-curve for both seen and unseen data. Results: The HDL system showed an improvement of 30.20% (0.954 vs. 0.702) over the ML system using the seen datasets. The ML feature extraction analysis showed 70% of common features among all three methods. The generalization of AtheroEdge™ 3.0HDL showed less than 1% (p-value < 0.001) difference between seen and unseen data, complying with regulatory standards. Conclusions: The hypothesis for AtheroEdge™ 3.0HDL was scientifically validated, and the model was tested for reliability and stability and is further adaptable clinically. [ABSTRACT FROM AUTHOR]

Objectives: Women with a hypertensive disorder of pregnancy (HDP) are at increased risk of developing hypertension and cardiovascular disease later in life. However, from previous studies, it is difficult to define whether this association reflects pre‐existing maternal cardiovascular risk or a potentially causal relationship between HDP and later cardiovascular risk. In this study, we performed detailed cardiovascular assessment in women in midgestation, prior to development of HDP, and at 2 years postpartum, aiming to identify cardiovascular changes prior to development of HDP and to assess persistent cardiovascular alterations long after the HDP event. Methods: This was a prospective observational study in which we performed detailed cardiovascular assessment in midgestation and at a median of 2.3 (interquartile range, 2.1–2.4) years postpartum. We examined 112 women who developed HDP and 451 women whose pregnancy was not complicated by hypertension. We used conventional and more advanced (i.e. speckle tracking) echocardiographic techniques to determine accurately left ventricular systolic and diastolic function. We used M‐mode measurements to determine left ventricular remodeling and estimate left ventricular mass. Maternal vascular status was assessed using ophthalmic artery Doppler and by calculating peak systolic velocity (PSV) ratio, as a marker of peripheral vascular resistance. Results: In midgestation, women who subsequently developed HDP had increased ophthalmic artery PSV ratio. These women also had mild cardiac functional and morphological alterations, which were accounted for mostly by maternal cardiovascular risk factors. At 2 years postpartum, women who had experienced HDP, compared to those who did not, had cardiovascular abnormalities with reduction in left ventricular systolic and diastolic function, which remained after multivariable analysis. Longitudinal analysis demonstrated that the evolution of cardiovascular changes in the HDP and non‐HDP groups was similar. Conclusions: Mild cardiac functional and morphological alterations precede the development of HDP and such changes persist for at least 2 years postpartum. The cardiac changes are likely to be the consequence of pre‐existing maternal cardiovascular risk factors rather than an adverse consequence of HDP. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

During his final years, John Stuart Mill reportedly attempted to update the argument of On Liberty (1859). Published posthumously in 1907, ‘On Social Freedom’ represents the initial, unrefined draft of his reworked ideas. This article argues that John Stuart Mill was not the author of ‘On Social Freedom’. First, we revisit the question of the essay’s authorship traditionally: the emphasis is on the essay’s content and the historical context of the mid-twentieth-century debate on Mill as its author. We trace the disagreement to two broad reactions to Mill’s thought. Ultimately, the question of whether the manuscript’s substantial divergence from J. S. Mill’s renowned works is enough to refute his authorship depends on one’s interpretation of Mill as a systematic philosopher. Second, we tackle this task non-traditionally: the focus shifts to the tools of computer-assisted authorship identification and the use of machine learning (ML) techniques. Once we establish some key ideas, methods, and limitations of this field of studies, we present our attempts at a computer-assisted solution to the puzzle. The results of our experiments, using ML techniques, corroborate the conclusions reached via the traditional route.

Background: Cardiovascular disease (CVD) is challenging to diagnose and treat since symptoms appear late during the progression of atherosclerosis. Conventional risk factors alone are not always sufficient to properly categorize at-risk patients, and clinical risk scores are inadequate in predicting cardiac events. Integrating genomic-based biomarkers (GBBM) found in plasma/serum samples with novel non-invasive radiomics-based biomarkers (RBBM) such as plaque area, plaque burden, and maximum plaque height can improve composite CVD risk prediction in the pharmaceutical paradigm. These biomarkers consider several pathways involved in the pathophysiology of atherosclerosis disease leading to CVD. Objective: This review proposes two hypotheses: (i) The composite biomarkers are strongly correlated and can be used to detect the severity of CVD/Stroke precisely, and (ii) an explainable artificial intelligence (XAI)-based composite risk CVD/Stroke model with survival analysis using deep learning (DL) can predict in preventive, precision, and personalized (aiP3) framework benefiting the pharmaceutical paradigm. Method: The PRISMA search technique resulted in 214 studies assessing composite biomarkers using radiogenomics for CVD/Stroke. The study presents a XAI model using AtheroEdgeTM 4.0 to determine the risk of CVD/Stroke in the pharmaceutical framework using the radiogenomics biomarkers. Conclusions: Our observations suggest that the composite CVD risk biomarkers using radiogenomics provide a new dimension to CVD/Stroke risk assessment. The proposed review suggests a unique, unbiased, and XAI model based on AtheroEdgeTM 4.0 that can predict the composite risk of CVD/Stroke using radiogenomics in the pharmaceutical paradigm.

Purpose: The purpose of this study is to examine the impact of psychological safety on transformative learning in the workplace. This study focused on psychological safety as a specific practice that may or may not independently contribute to transformative learning outcomes. Design/methodology/approach: Data was gathered from 132 employees in one US manufacturing company through a survey asking about the perception of psychological safety and the experience of transformative learning. A mediation analysis was conducted to test the effects of transformative learning processes -- social support, attitude toward uncertainty and criticality -- on the relationship between psychological safety and transformative learning outcomes. Findings: The results of this study showed that psychological safety led to transformative learning outcomes mediated by transformative learning processes including social support, attitude toward uncertainty and criticality. Originality/value: Existing literature reveals little about the mechanism of how transformative learning occurs in the workplace. This study contributes to the field of human resource development by explaining the relationship between psychological safety and transformative learning, as well as first attempting to use transformative learning as a viable construct in workplace research.

Background/Aims The residual risk of colectomy after infliximab salvage in steroid-refractory acute severe ulcerative colitis (ASUC) is required to inform the need for subsequent maintenance biologic therapy. The aim of this study was to determine the dynamic response of common serum biomarkers to infliximab salvage and assess their utility in predicting subsequent colectomy. Methods A retrospective single-center cohort study was conducted on all patients who received infliximab salvage for steroid-refractory ASUC between January 1, 2010, and July 31, 2019. Biomarkers were assessed on admission and days 1 and 3 post infliximab, and included C-reactive protein (CRP)-albumin-ratio (CAR), CRP-lymphocyte-ratio (CLR), platelet-lymphocyte-ratio (PLR) and neutrophil-lymphocyte-ratio (NLR). Results Of 94 patients (median age, 35 years; 67% of male), 20% required colectomy at 12 months. Biomarkers on day 3 post-infliximab best differentiated nonresponders, who had higher CRP, lower albumin and lower lymphocyte count (each P < 0.05). Day 3 predictive performance (area under the curve) for 12-month colectomy was best for CAR (0.871) and CLR (0.874), which were similar to Lindgren (0.829; P > 0.05) but superior to Mayo (0.726), partial Mayo (0.719), PLR (0.719), Ho index (0.714), NLR (0.675), Travis score (0.657) and endoscopic Mayo (0.609) (each P < 0.05). A day 3 CAR cutoff of 0.47 mg/g had 79% sensitivity, 80% specificity, 94% negative predictive value (NPV) to predict colectomy; while a day 3 CLR cutoff of 6.0 mg/109 had 84% sensitivity, 84% specificity, 96% NPV. Conclusions CAR and CLR measured on day 3 post infliximab salvage for steroid-refractory ASUC represent simple and routinely performed biomarkers that appear to be strong predictors of colectomy. Prospective studies are required to confirm the utility of these predictive scores.

Completing large-scale projects on time is a daunting challenge, partly due to the intricate network of dependencies between a project’s activities. To support this challenge, existing theory focuses on predicting whether a delay in completing a single activity is likely to spread and impact downstream activities. Using fine-grained information from 68 546 activities and 84 934 pairs, associated with the delivery of a $1.86Bn infrastructure project, we show that the core mechanism that underpins existing theory underestimates delay propagation. To elucidate the mechanisms that drive delay, we generated null models that destroyed the structural and temporal correlations of the original project activity network. By doing so, we argue that this underestimation is the result of neglecting endogenous structural features within the project’s activity network. Formulating a new mechanism that utilizes both temporal and structural features may help improve our capacity to predict how delays spread within projects.

Subsets of tumor-produced cell surface and secreted proteins can bind to IgG1 type antibodies and suppress their immune-effector activities. As they affect antibody and complement-mediated immunity, we call these proteins humoral immuno-oncology (HIO) factors. Antibody-drug conjugates (ADCs) use antibody targeting to bind cell surface antigens, internalize into the cell, then kill target cells upon liberation of the cytotoxic payload. Binding of the ADC antibody component by a HIO factor may potentially hamper ADC efficacy due to reduced internalization. To determine the potential effects of HIO factor ADC suppression, we evaluated the efficacy of a HIO-refractory, mesothelin-directed ADC (NAV-001) and a HIO-bound, mesothelin-directed ADC (SS1). The HIO factor MUC16/CA125 binding to SS1 ADC was shown to have a negative effect on internalization and tumor cell killing. The MUC16/CA125 refractory NAV-001 ADC was shown to have robust killing of MUC16/CA125 expressing and non-expressing tumor cells in vitro and in vivo at single, sub-mg/kg dosing. Moreover, NAV-001-PNU, which contains the PNU-159682 topoisomerase II inhibitor, demonstrated good stability in vitro and in vivo as well as robust bystander activity of resident cells while maintaining a tolerable safety profile in vivo. Single-dose NAV-001-PNU demonstrated robust tumor regression of a number of patient-derived xenografts from different tumor types regardless of MUC16/CA125 expression. These findings suggest that identification of HIO-refractory antibodies to be used in ADC format may improve therapeutic efficacy as observed by NAV-001 and warrants NAV-001-PNU's advancement to human clinical trials as a monotherapy to treat mesothelin-positive cancers.

IntroductionPre-launch advertising communications are critical for the early adoption of experiential products. Often, companies release a variety of advertising messages for the same product, which results in a lack of information consistency. Research on the effect of advertising communications with different message content is scarce. Further, most studies on information consistency rely on experimental methods, leaving the actual effect of consumer response on product adoption unknown.MethodsTreating online comments to movie trailers as consumer response to advertising communication, we propose a natural language processing methodology to measure information consistency. We validate our measurement through an online experiment and test it on 1.3 million YouTube comments.ResultsOur empirical results provide evidence that information consistency driven by trailer-viewing is a key driver of opening box office success.DiscussionInsights deriving from this study are important to marketing communications research, especially in contexts where early product adoption is critical.

The question of land is indeed a vexing one in contemporary South Africa. White control of land and the unequal distribution thereof was one of the pillars of the apartheid system. During colonial rule and under apartheid, numerous communities were simply expelled from their land. The Land Act of 1913 had a diabolical effect in dislocating communities and separated people from their traditional inheritance and from each other. Dispossession of land by its original inhabitants in waves of incessant forced removals proved to be highly distressing and ultimately led to enduring poverty for the masses. It is important in our predominantly Christian society to atone for past ills and to redress some of the ills relating to land which were in fact human rights abuses, by considering inter alia, Leviticus 25 as a starting point. Thus, a Christian stance is considered to be important from both a biblical and ethical perspective as land dispossession due to inhuman laws is addressed. We are stressing the fact that only in a liberating relationship with God can we consider and apply human rights and that in African thought social issues are viewed from a communitarian perspective in which the common good takes precedence.

Michel Foucault (1926-1984) was indisputably one of the most significant theorists of the twentieth century. His work is generally interdisciplinary in nature delving especially into the humanities, and to a greater extent it includes philosophically oriented historical research in philosophy, history and theology. All this was in a quest for truth and to reflect on humanity which is the focus. Foucault recurrently pursued a manner in which to comprehend the ideas that form our present. In the materialist and consumer driven world of the 21st Century, spiritual practices in Christianity are often viewed by growing numbers of subjects as being based on what are considered to be obsolete religious traditions. The article focuses on the notion that Christianity indeed has a huge role to play in life and in understanding contemporary spirituality and religious life. Foucault was seemingly motivated by a strong yearning to discover a substitute for intimacy with the creator God and a desire to see power relations made devoid of the ability to limit a subjects freedom and domination by, for example, churches and their doctrines and dogmas. He argued that self-awareness was not a goal in itself, but rather something that is pursued in order for one to care for oneself in a world in which there are power relations in existence. Foucault maintained that by caring for oneself, one could transform oneself into a more ethical person. Through considering one’s previous and imminent actions and by evaluating if the actions align with ones ethics and goals, one can get to realise how insignificant one is when compared to the limitlessness creation. A standpoint on spirituality and Christianity per se, is advanced based on Michel Foucault’s work on spiritual observances in Christianity.

Glioblastoma is the most common and aggressive adult brain cancer. Tumors show frequent dysregulation of the PI3K-mTOR pathway. Although a number of small molecules target the PI3K-AKT-mTOR axis, their preclinical and clinical efficacy has been limited. Reasons for treatment failure include poor penetration of agents into the brain and observations that blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Clinical trials using allosteric mTOR inhibitors (rapamycin and rapalogs) to treat patients with glioblastoma have also been unsuccessful or uncertain, in part, because rapamycin inefficiently blocks the mTORC1 target 4EBP1 and feeds back to activate PI3K-AKT signaling. Inhibitors of the mTOR kinase (TORKi) such as TAK-228/MLN0128 interact orthosterically with the ATP- and substrate-binding pocket of mTOR kinase, efficiently block 4EBP1 in vitro, and are currently being investigated in the clinical trials. Preclinical studies suggest that TORKi have poor residence times of mTOR kinase, and our data suggest that this poor pharmacology translates into disappointing efficacy in glioblastoma xenografts. RapaLink-1, a TORKi linked to rapamycin, represents a drug with improved pharmacology against 4EBP1. In this review, we clarify the importance of 4EBP1 as a biomarker for the efficacy of PI3K-AKT-mTOR inhibitors in glioblastoma. We also review mechanistic data by which RapaLink-1 blocks p-4EBP1 and discuss future clinical strategies for 4EBP1 inhibition in glioblastoma. Clin Cancer Res; 24(1); 14-21. ©2017 AACR.